Knockdown of long non-coding RNA LINC01006 represses the development of hepatocellular carcinoma by modulating the miR-194-5p/CADM1 axis

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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2022;27 Supl 1:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "miR-221-3p regulates hepatocellular carcinoma cell proliferation, migration and invasion via targeting LIFR" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1276 "Ancho" => 3500 "Tamanyo" => 461245 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "MiR-221-3p fosters HCC cell proliferation, migration and invasion (A) qRT-PCR was conducted to detect the expression of miR-221-3p in HepG2 and Huh7 cell lines upon over-expression or inhibition of miR-221-3p; (B) Proliferative ability of HepG2 and Huh7 cell lines was examined by MTT; (C-D) Migratory and invasive capacities of HepG2 cells were evaluated via (C) wound healing assay and (D) Transwell assay; p < 0.05." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Wei Tan, Zhuokai Li, Weifen Xia, Jinde Zhu, Rengen Fan" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Wei" "apellidos" => "Tan" ] 1 => array:2 [ "nombre" => "Zhuokai" "apellidos" => "Li" ] 2 => array:2 [ "nombre" => "Weifen" "apellidos" => "Xia" ] 3 => array:2 [ "nombre" => "Jinde" "apellidos" => "Zhu" ] 4 => array:2 [ "nombre" => "Rengen" "apellidos" => "Fan" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268121002660?idApp=UINPBA00004N" "url" => "/16652681/00000027000000S1/v3_202303011411/S1665268121002660/v3_202303011411/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Knockdown of long non-coding RNA LINC01006 represses the development of hepatocellular carcinoma by modulating the miR-194-5p/CADM1 axis" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Zhaoxia Sun, Li Zhao, Shuang Wang, Honggang Wang" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Zhaoxia" "apellidos" => "Sun" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 1 => array:3 [ "nombre" => "Li" "apellidos" => "Zhao" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 2 => array:3 [ "nombre" => "Shuang" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 3 => array:4 [ "nombre" => "Honggang" "apellidos" => "Wang" "email" => array:1 [ 0 => "wanghonggang2130@163.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0002" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0001" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Infectious Diseases, Weifang Yidu Central Hospital, No.4138, Linglongshan South Road, Qingzhou City, Weifang, Shandong 262500, China." "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "Clinical Laboratory, Weifang People's Hospital, No.151, Guangwen Street, Kuiwen District, Weifang, Shandong 261041, China." "etiqueta" => "b" "identificador" => "aff0002" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 892 "Ancho" => 2833 "Tamanyo" => 146746 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01006 was highly expressed in hepatocellular carcinoma (HCC) tissues and HCC cells. (A) Relative expression of LINC01006 in tumour tissues and adjacent normal tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). P < 0.001, vs. Adjacent normal tissues. (B) Relative expression of LINC01006 at tumour node metastasis (TNM) stage I/II and TNM stage III/IV was determined by qRT-PCR in tumour. P < 0.01, vs. I/II. (C) Relative expression of LINC01006 in HepG2, SMMC-7721, Hep3B, Sk-Hep1 and LO2 cells was determined by qRT-PCR. ⁎⁎P < 0.01, vs. LO2." ] ] ] "textoCompleto" => "1IntroductionHepatocellular carcinoma (HCC), which is considered to be the third most fatal cancer worldwide, comprises 90% of all liver cancers <a class="elsevierStyleCrossRef" href="#bib0001">[1]</a>. As a rapidly growing and invasive tumour, HCC is chiefly induced by long-term liver injury caused by inherited metabolic disorders, viral hepatitis, excessive alcohol consumption, and toxin exposure <a class="elsevierStyleCrossRef" href="#bib0002">[2]</a>. The high probability of tumour metastasis and recurrence is the primary factor leading to the poor prognosis of patients with HCC <a class="elsevierStyleCrossRef" href="#bib0003">[3]</a>. There are many therapeutic modalities for HCC, including surgical options and ablative electrochemical therapies [<a class="elsevierStyleCrossRef" href="#bib0004">4</a>,<a class="elsevierStyleCrossRef" href="#bib0005">5</a>]. Currently, although HCC therapy has made great strides, the treatment effect on recurrent or metastatic HCC remains unsatisfactory, and the prevalence of HCC continues to rise <a class="elsevierStyleCrossRefs" href="#bib0006">[6–8]</a>. Therefore, it is imperative to discover additional insights into the mechanism of HCC and exploit novel targets for HCC therapy.Long non-coding RNAs (lncRNAs), which comprise over 200 nucleotides in length, are a subgroup of non-coding RNAs that exhibit limited or no protein-coding potential [<a class="elsevierStyleCrossRef" href="#bib0009">9</a>,<a class="elsevierStyleCrossRef" href="#bib0010">10</a>]. Several studies have confirmed the indispensable roles of lncRNAs in HCC <a class="elsevierStyleCrossRefs" href="#bib0011">[11–13]</a>. A document from Zou et al. stated that silencing of lncRNA HLA complex group 18 suppresses the proliferation and migration of HCC cells while stimulating their apoptosis <a class="elsevierStyleCrossRef" href="#bib0011">[11]</a>. Another report from Wang et al. showed that knockdown of long intergenic non-protein coding RNA (LINC) 1134 inhibits the migration and invasion of HCC cells in vitro and restrains HCC liver metastasis in vivo<a class="elsevierStyleCrossRef" href="#bib0012">[12]</a>. A similar study by Wu et al. confirmed that lncRNA metallothionein 1J, pseudogene markedly impairs proliferation while also enhancing apoptosis in HCC cells <a class="elsevierStyleCrossRef" href="#bib0013">[13]</a>.LINC01006, located on human chromosome 7q36.37, has been shown to be implicated in several cancers [<a class="elsevierStyleCrossRef" href="#bib0014">14</a>,<a class="elsevierStyleCrossRef" href="#bib0015">15</a>]. Downregulation of LINC01006 is closely associated with age, tumour size, tumour location, and venous invasion in gastric cancer <a class="elsevierStyleCrossRef" href="#bib0014">[14]</a>. Silencing of LINC01006 attenuates the proliferative, migratory, and invasive abilities of pancreatic cancer cells <a class="elsevierStyleCrossRef" href="#bib0015">[15]</a>. Nonetheless, there are few studies on the function and mechanism of LINC01006 in HCC.MicroRNAs (miRNAs/miRs), which have a length of 19–24 nucleotides, are short single-stranded non-coding RNAs that can modulate gene expression at the post-transcriptional level <a class="elsevierStyleCrossRef" href="#bib0016">[16]</a>. In the past few years, increasing attention has been paid to miRNAs in the progression of HCC [<a class="elsevierStyleCrossRef" href="#bib0017">17</a>,<a class="elsevierStyleCrossRef" href="#bib0018">18</a>]. Wang et al. reported that upregulation of miR-302b represses the proliferation of HCC cells and the G1-S transition in vitro<a class="elsevierStyleCrossRef" href="#bib0017">[17]</a>. Li et al. indicated that inhibition of miR-221 restrains the proliferation, migration, and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0018">[18]</a>. LncRNAs can act as competing endogenous RNAs (ceRNAs) or sponges of miRNAs. Minichromosome maintenance complex component 3 associated protein antisense RNA 1 (MCM3AP-AS1) is known to contribute to the progression of HCC by targeting miR-194-5p <a class="elsevierStyleCrossRef" href="#bib0019">[19]</a>. X-inactive specific transcript (XIST) functions as a molecular sponge of miR-194-5p to accelerate HCC tumorigenesis <a class="elsevierStyleCrossRef" href="#bib0020">[20]</a>. In addition, miR-194-5p is reported to target numerous downstream genes that are involved in HCC progression, such as forkhead box A1 (FOXA1) <a class="elsevierStyleCrossRef" href="#bib0019">[19]</a>, mitogen-activated protein kinase 1 (MAPK1) <a class="elsevierStyleCrossRef" href="#bib0020">[20]</a>, and Wee1-like protein kinase <a class="elsevierStyleCrossRef" href="#bib0021">[21]</a>. More importantly, a recent study conducted by Niu et al. revealed that miR-194 interaction with cell adhesion molecule 1 (CADM1) affects the progression of HCC <a class="elsevierStyleCrossRef" href="#bib0022">[22]</a>. However, the interactions among LINC01006, miR-194-5p, and CADM1 in HCC have not yet been explored.In the current study, we attempted to evaluate the expression and function of LINC01006 in HCC. Moreover, the molecular basis of LINC01006 in HCC progression was further investigated. We aimed to provide novel insights into the biological role of LINC01006 in HCC as well as a potential target for HCC treatment.2Materials and methods2.1HCC samplesFrom March 2018 to February 2019, paired HCC and adjacent normal tissues (n = 61) were acquired from patients who underwent hepatectomy. None of the HCC patients received any chemotherapy or embolotherapy before surgery. The tissue samples were affirmed by two histopathologists. The present study was approved by the ethics committee of Weifang Yidu Central Hospital on the basis of the Declaration of Helsinki. Each participant enrolled in this research provided written informed consent before the surgical operation.2.2Cell cultureThe human immortalised liver cell line (MIHA) and human HCC cell lines (Huh7, SNU-398, Hep3B, and Sk-Hep1) were purchased from the American Type Culture Collection (Manassas, VA, USA). The cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM; Gibco, Grand Island, NY, USA) supplemented with 10% foetal bovine serum (FBS; Gibco) and antibiotics (100 U/mL penicillin and 100 μg/mL streptomycin) at 37 °C with 5% CO2.2.3Quantitative real-time polymerase chain reaction (qRT-PCR)Trizol reagent (Sangon Biotech, Shanghai, China) was used for RNA isolation. Total RNA was reverse transcribed into complementary DNA using an M-MLV Reverse Transcriptase kit (Sangon Biotech). The qRT-PCR assay was implemented using SYBR® Premix Ex Taq™ II (Takara, Dalian, China). The PCR 额ing conditions were as follows: 94 °C for 5 min, followed by 40 cycles of 94 °C for 30 s, 60 °C for 20 s, and 72 °C for 5 min. All primers were purchased from Invitrogen (Carlsbad, CA, USA), and the primer sequences are shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>. The relative expression levels of LINC01006, miR-194-5p, and CADM1 were calculated using the 2−ΔΔct method. Glyceraldehyde 3-phosphate dehydrogenase was used as an internal reference.<elsevierMultimedia ident="tbl0001"></elsevierMultimedia>2.4Cell transfectionShort hairpin RNAs (shRNAs) against LINC01006 (sh-LINC01006-1 and sh-LINC01006-2), shRNA negative control (sh-NC), miR-NC, miR-194-5p mimics, miR-194-5p inhibitor, pcDNA-NC, and pcDNA-CADM1 were purchased from RiboBio Company (Beijing, China). Next, the above factors were transfected into Hep3B and Sk-Hep1 cells using Lipofectamine 3000 (Invitrogen) for 48 h according to the provided protocol.2.5Dual-luciferase reporter (DLR) assayThe 3′-untranslated region (UTR) of LINC01006 or CADM1 harbouring the binding sequence of miR-194-5p was introduced into the pGL3 luciferase reporter vector (Promega, Madison, WI, USA), forming the LINC01006 wild type (WT) or CADM1 WT. Analogously, the 3′-UTR segment of LINC01006 or CADM1, including the mutated binding sequence of miR-194-5p, was introduced into the pGL3 luciferase reporter vector (Promega), generating the LINC01006 mutant (MUT) or CADM1 MUT. The above reporters, along with miR-194-5p mimics or miR-NC, were transfected into cells using Lipofectamine 3000 (Invitrogen). After transfection for 48 h, relative luciferase activity was measured with a DLR assay system (Promega).2.63-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assayCells were seeded into 96-well plates at a density of 6,000 cells/well. At 0, 24, 48, 72, and 96 h after incubation, MTT (10 μL; Sigma-Aldrich, St. Louis, MO, USA) was added, and the cells were incubated at 37 °C for another 4 h. At the end of the culture, 150 μL dimethyl sulfoxide was added. The optical density at 490 nm was measured with an FL600 fluorescence plate reader (Bio-Rad, Hercules, CA, USA).2.7Wound healing assayCells were seeded into 6-well plates at a density of 6 × 104 cells/well and cultured with DMEM containing 10% FBS until the cell monolayer was generated. Unilaminar cells were scratched with a 10 μL sterile pipette tip. Then, PBS was added to remove the scratched cells. The cells were then cultured in serum-free medium at 37°C. After culturing for 24 h, the migration distance of the cell scratch region was examined under an inverted microscope (TE2000; Nikon, Tokyo, Japan). The formula for calculating the wound healing rate was as follows: (1–24 h scratch width/0 h scratch width) × 100.2.8Transwell assayThe cell invasion capacity was determined using a transwell chamber coated with Matrigel (BD Biosciences, Sparks, MD, USA). First, cells in serum-free medium were shifted to the upper chamber (BD Biosciences). The lower chamber was loaded with 600 μL DMEM containing 10% FBS. After incubation for 24 h, the transwell chamber was removed. Cells in the upper compartment were sponged with cotton swabs, and cells in the lower compartment were stained with 0.1% crystal violet for 5 min. After washing with PBS, the invasive ability of the cells was evaluated by counting the number of invading cells under a fluorescence microscope (TE2000; Nikon).2.9Western blotTotal cells were lysed using radioimmunoprecipitation assay buffer (Thermo Fisher Scientific, Waltham, MA, USA). Protein samples were isolated by 10% sodium dodecyl sulphate-polyacrylamide gel electrophoresis, transferred to polyvinylidene difluoride membranes, and blocked with 5% non-fat milk. The membranes were then incubated with the anti-CADM1 (1:1000, ab216585; Abcam, Cambridge, MA, USA) and anti-β-tubulin (1:500, ab6046; Abcam) primary antibodies overnight at 4°C. After washing with tris-buffered saline-Tween 20, the secondary antibody (1:2000, ab6747; Abcam) was supplemented and cultured with the protein samples at 37 °C for 1 h. The blot signals were visualised using electrochemiluminescence reagents (Millipore, Plano, TX, USA). The relative expression of CADM1 over the β-tubulin band was quantified using a Gel-Pro Analyser (Media Cybernetics, Rockville, MD, USA).2.10Nude mouse tumorigenesis assayAll animal experiments were approved by the animal ethics committee of our hospital and abided by the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Four-week-old male BALB/C nude mice were purchased from the National Laboratory Animal Center (Beijing, China) and divided into two groups (n = 5 per group). Hep3B cells (5 × 106) transfected with the lentivirus vector of sh-LINC01006-1 (Lv-sh-LINC01006-1) or the lentivirus vector of sh-NC (Lv-sh-NC) were subcutaneously implanted into the right flank of the nude mice at 100 μL cell suspension per injection as previously described <a class="elsevierStyleCrossRef" href="#bib0023">[23]</a>. Tumour volumes were gauged once every 5 days and calculated using the following formula: (A × B2) / 2 (A, the longest diameter; B, the shortest diameter). On the 30th day after injection, the mice were anaesthetized with pentobarbital sodium (50 mg/kg) and sacrificed. The tumours were then dissected and weighed.2.11Statistical analysisIn vitro experiments were repeated three times. Additionally, the MTT assay, DLR assay, and qRT-PCR were performed in triplicate (3 × 3). In vivo experiments were performed using five mice in each group. Data were analysed using SPSS Statistics 22.0 software (IBM SPSS, Armonk, NY, USA) and are presented as means ± standard deviations. The Student's t-test was used to compare differences between two groups. A one-way analysis of variance was used to analyse differences among multiple groups, and Tukey's multiple comparisons test was used for pairwise comparisons. The correlations between two genes were analysed using the Pearson correlation test. Differences were considered statistically significant at P < 0.05.3Results3.1LINC01006 is highly expressed in HCC tissues and cellsTo determine the role of LINC01006 in HCC, we determined the expression of LINC01006 in tumour tissues from HCC patients and in HCC cell lines. The qRT-PCR results showed that the relative expression level of LINC01006 in tumour tissues was distinctly elevated compared to that in adjacent normal tissues (P < 0.001; <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>A). Next, to determine the clinical significance of LINC01006 in HCC, we analysed the relationships between clinicopathological features and the expression of LINC01006 in HCC cases. We discovered that LINC01006 was closely associated with metastasis and tumour node metastasis (TNM) stage (<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>). The relative expression of LINC01006 in HCC patients at TNM stage III-IV was boosted compared to that in patients at TNM stage I-II (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>B). We also observed that LINC01006 was upregulated in HCC cell lines (Huh7, SNU-398, Hep3B, and Sk-Hep1) compared to MIHA cells (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>C). Among them, Hep3B and Sk-Hep1 were selected for the subsequent trials because of the relatively high expression levels of LINC01006.<elsevierMultimedia ident="fig0001"></elsevierMultimedia><elsevierMultimedia ident="tbl0002"></elsevierMultimedia>3.2Downregulation of LINC01006 suppresses the proliferation, migration, and invasion of HCC cells and represses HCC tumour growth in miceNext, we probed the potential role of LINC01006 in HCC cells. First, we silenced LINC01006 using sh-LINC01006-1 or sh-LINC01006-2 in Hep3B and Sk-Hep1 cells. As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>A, the expression of LINC01006 was markedly reduced by sh-LINC01006-1 or sh-LINC01006-2 in Hep3B and Sk-Hep1 cells (P < 0.01), and sh-LINC01006-1 was selected for subsequent experiments on account of its relatively high knockdown efficiency. The results of the MTT assay indicated that the viability of Hep3B and Sk-Hep1 cells in the sh-LINC01006-1 group was lower than that in the sh-NC group (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>B). The wound healing assay showed that the wound healing rate of Hep3B and Sk-Hep1 cells was decreased by the knockdown of LINC01006 (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>C). The transwell assay demonstrated that the number of invading cells was diminished by the knockdown of LINC01006 in Hep3B and Sk-Hep1 cells (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>D). To elucidate the biological role of LINC01006 in HCC in vivo, we performed a mouse tumorigenesis assay. As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>E, the tumour volume in the Lv-sh-LINC01006-1 group was dramatically reduced on the 20th, 25th, and 30th days after injection relative to the Lv-sh-NC group (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>E). Moreover, the tumour weight in the Lv-sh-LINC01006-1 group was also evidently reduced compared to the Lv-sh-NC group on the 30th day after injection (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>E).<elsevierMultimedia ident="fig0002"></elsevierMultimedia>3.3LINC01006 acts as a sponge of miR-194-5pTo gain mechanistic insight into LINC01006, we predicted its target using the LncBase Predicted v2 database. The results illustrated that miR-194-5p shared complementary binding to LINC01006 (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>A). Meanwhile, miR-194-5p was upregulated by the transfection of sh-LINC01006-1 into Hep3B and Sk-Hep1 cells (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>B), suggesting a negative modulation loop between miR-194-5p and LINC01006 in human HCC cells. To test the association between miR-194-5p and LINC01006, a DLR assay was conducted, which showed that upregulation of miR-194-5p reduced the relative luciferase activity of Hep3B and Sk-Hep1 cells transfected with the LINC01006 WT reporter but had no significant impact on the relative luciferase activity of Hep3B and Sk-Hep1 cells transfected with LINC01006 MUT (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>C). In addition, miR-194-5p was notably diminished in tumour tissues compared to adjacent normal tissues (P < 0.001; <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>D). The outcome of Pearson correlation analysis indicated that there was an inverse correlation between miR-194-5p and LINC01006 in human HCC tissues (P = 0.0009, r = -0.4155; <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>E). In addition, the expression of miR-194-5p was determined in HCC cell lines. As illustrated in <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>F, we observed decreased expression of miR-194-5p in HCC cell lines compared to MIHA cells (P < 0.01).<elsevierMultimedia ident="fig0003"></elsevierMultimedia>3.4Overexpression of miR-194-5p represses cell viability, migration, and invasion in HCC cellsSubsequently, we examined the function of miR-194-5p in HCC cells. As illustrated in <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>A, we observed that the expression of miR-194-5p in Hep3B and Sk-Hep1 cells was increased by transfection with miR-194a-5p mimics and decreased by the miR-194a-5p inhibitor (P < 0.01). The cell viability of Hep3B and Sk-Hep1 cells was decreased by miR-194-5p overexpression (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>B). In addition, the migratory and invasive abilities of Hep3B and Sk-Hep1 cells were repressed by overexpression of miR-194-5p (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>C and D).<elsevierMultimedia ident="fig0004"></elsevierMultimedia>3.5CADM1 is the target of miR-194-5pIn order to identify the downstream target of miR-194-5p, we performed a prediction using StarBase. The results showed that there were binding sites between CADM1 and miR-194-5p (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>A). To confirm this prediction, a DLR assay was performed. The results revealed that the relative luciferase activity of Hep3B and Sk-Hep1 cells was visibly decreased by co-transfection with the CADM1 WT reporter and miR-194-5p mimics, whereas the relative luciferase activity of Hep3B and Sk-Hep1 cells was not significantly different after co-transfection with miR-194-5p mimics and the CADM1 MUT reporter (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>B). Western blot analysis showed that CADM1 expression was distinctly reduced by miR-194-5p overexpression in Hep3B and Sk-Hep1 cells (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>C). Data from The Cancer Genome Atlas database indicated that expression of CADM1 was augmented in HCC tissues compared to adjacent normal tissues (P < 0.05; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>D). The results from qRT-PCR showed that CADM1 was also elevated in tumour tissues relative to that in adjacent normal tissues (P < 0.001; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>E). Pearson correlation analysis demonstrated that LINC01006 was positively correlated with CADM1 in human HCC tissues (P = 0.0008, r = 0.4190; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>F), and miR-194-5p was inversely correlated with CADM1 in human HCC tissues (P = 0.0004, r = -0.4389; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>G). Moreover, the results of the western blot assay demonstrated that the protein level of CADM1 was significantly elevated in HCC cell lines compared to that in MIHA cells (P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>H).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>3.6Downregulation of LINC01006 represses cell invasion, migration, and proliferation by sponging miR-194-5p to modulate the expression of CADM1To further validate the relationships among LINC01006, miR-194-5p, and CADM1, sh-LINC01006-1 or sh-LINC01006-1 + miR-194a-5p inhibitor was transfected into Hep3B cells to determine the protein level of CADM1. As presented in <a class="elsevierStyleCrossRef" href="#fig0006">Fig. 6</a>A, the CADM1 protein level was downregulated by sh-LINC01006-1 (P < 0.01), whereas transfection with miR-194a-5p reversed the inhibitory effect of sh-LINC01006-1 on the CADM1 protein level (P < 0.05). Next, the transfection efficiency of pcDNA-CADM1 was determined. We found that CADM1 expression was significantly elevated in Hep3B cells transfected with pcDNA-CADM1 (P < 0.01, <a class="elsevierStyleCrossRef" href="#fig0006">Fig. 6</a>B), which suggested that pcDNA-CADM1 was transfected successfully. Next, we carried out rescue experiments. We discovered that the addition of sh-LINC01006-1 significantly decreased cell viability in Hep3B cells (P < 0.01), and the inhibitory effect of sh-LINC01006-1 on cell viability was reversed by the addition of pcDNA-CADM1 or miR-194-5p inhibitor in Hep3B cells (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0006">Fig. 6</a>C). Furthermore, the cell migration and invasion abilities were restrained by sh-LINC01006-1 in Hep3B cells (all P < 0.01), and the suppressive effects of sh-LINC01006-1 on the migratory and invasive abilities of Hep3B cells were reversed by pcDNA-CADM1 or the miR-194-5p inhibitor (all P < 0.01; <a class="elsevierStyleCrossRef" href="#fig0006">Fig. 6</a>D and E).<elsevierMultimedia ident="fig0006"></elsevierMultimedia>4DiscussionHCC is regarded as a common hepatic malignancy worldwide that continues to increase in prevalence [<a class="elsevierStyleCrossRef" href="#bib0024">24</a>, <a class="elsevierStyleCrossRef" href="#bib0025">25</a>]. Previous studies have revealed upregulation of several lncRNAs in HCC, including myocardial infarction-associated transcript <a class="elsevierStyleCrossRef" href="#bib0026">[26]</a>, lncRNA activated by transforming growth factor-β <a class="elsevierStyleCrossRef" href="#bib0027">[27]</a> and HOX antisense intergenic RNA <a class="elsevierStyleCrossRef" href="#bib0028">[28]</a>. Consistent with the above studies, we observed that LINC01006 was augmented in HCC tissues and cells compared to their controls, implying that LINC01006 is involved in HCC. Moreover, a prior study stated that LINC01006 is relevant to tumour location, tumour size, venous invasion, and age in gastric cancer <a class="elsevierStyleCrossRef" href="#bib0014">[14]</a>. Similarly, we found that LINC01006 was associated with metastasis and TNM stage. Its association with metastasis also indicates that LINC01006 may be applied as a tool for predicting prognosis, given that metastasis is relevant to the poor prognosis of patients with HCC <a class="elsevierStyleCrossRef" href="#bib0003">[3]</a>.Recent studies have shown that LINC01006 plays a critical role in pancreatic cancer [<a class="elsevierStyleCrossRef" href="#bib0015">15</a>, <a class="elsevierStyleCrossRef" href="#bib0029">29</a>]. Ma et al. revealed that overexpression of LINC01006 significantly contributes to enhancing the proliferation, migration, and invasion of prostate cancer cells <a class="elsevierStyleCrossRef" href="#bib0029">[29]</a>. Zhang et al. stated that LINC01006 knockdown represses the cell invasion, migration, and proliferation abilities in pancreatic cancer <a class="elsevierStyleCrossRef" href="#bib0015">[15]</a>. Similarly, we discovered that the knockdown of LINC01006 also represses cell proliferation, invasion, and migration in HCC. Additionally, in nude mouse xenograft models, downregulation of LINC01006 remarkably repressed HCC tumour growth. These findings indicate that LINC01006 may act as a novel target for HCC therapy.Previous studies have shown that lncRNAs can serve as ceRNAs to sponge miRNAs in diverse cancers, including HCC <a class="elsevierStyleCrossRef" href="#bib0030">[30]</a>. EPB41L4A-AS2-miR-301a-5p <a class="elsevierStyleCrossRef" href="#bib0031">[31]</a>, PCAT-1-miR-215 <a class="elsevierStyleCrossRef" href="#bib0032">[32]</a> and MALAT1-miR-200a <a class="elsevierStyleCrossRef" href="#bib0033">[33]</a> have been verified in HCC. Here, we validated that lncRNA LINC01006 functions as a ceRNA to sponge miR-194-5p and that it is inversely correlated with miR-194-5p. In addition, downregulation of miR-194-5p has previously been demonstrated to participate in the progression of HCC cells [<a class="elsevierStyleCrossRef" href="#bib0019">19</a>,<a class="elsevierStyleCrossRef" href="#bib0020">20</a>]. Downregulation of miR-194-5p was affirmed in HCC tissues compared to paracancerous tissues, and MCM3AP-AS1 was revealed to exert an oncogenic role by targeting miR-194-5p in HCC <a class="elsevierStyleCrossRef" href="#bib0019">[19]</a>. MiR-194-5p was shown to be diminished in HCC tissues compared to non-tumour tissues, and overexpression of miR-194-5p appeared to suppress the proliferation and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0020">[20]</a>. Similarly, we discovered that upregulation of miR-194-5p attenuates the cell proliferation, invasion, and migration abilities in HCC cells. We also found that the miR-194-5p inhibitor reversed the suppressive effects of sh-LINC01006 on the viability, invasion, and migration of HCC cells. Taken together, we inferred that sh-LINC01006 fulfils a tumour suppressor role by targeting miR-194-5p in HCC.CADM1, also known as tumour suppressor in lung cancer 1, encodes a 442 amino acid protein that contains a cytoplasmic domain, an extracellular domain, and a transmembrane domain [<a class="elsevierStyleCrossRef" href="#bib0034">34</a>,<a class="elsevierStyleCrossRef" href="#bib0035">35</a>]. Aberrant expression of CADM1 has been demonstrated to play a notable role in the progression of HCC [<a class="elsevierStyleCrossRef" href="#bib0036">36</a>,<a class="elsevierStyleCrossRef" href="#bib0037">37</a>]. Sun et al. affirmed that suppression of CADM1 can stimulate the migration and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0038">[38]</a>. Zhang et al. declared that upregulation of CADM1 represses the tumorigenicity of HCC both in vitro and in vivo<a class="elsevierStyleCrossRef" href="#bib0037">[37]</a>. In the current study, CADM1 was found to have increased expression in HCC cells and tissues compared to their controls, suggesting that CADM1 may be implicated in the development of HCC. Moreover, CADM1 has also been reported to act as the downstream target of other miRNAs in HCC, such as miR-1246 <a class="elsevierStyleCrossRef" href="#bib0038">[38]</a> and miR-10b <a class="elsevierStyleCrossRef" href="#bib0039">[39]</a>. Here, CADM1 was the target of miR-194-5p, and Pearson correlation analysis revealed that there was an inverse association between CADM1 and miR-194-5p in HCC tissues. In view of the above findings, we speculated that miR-194-5p acted as a tumour suppressor by targeting CADM1 in HCC. We also found that CADM1 was inversely correlated with LINC01006, and the suppressive effects of sh-LINC01006 on the viability, migration, and invasion of HCC cells were reversed by pcDNA-CADM1. We found that sh-LINC01006 may repress the development of HCC by modulating the miR-194-5p/CADM1 axis. In addition, LINC01006 interaction with other regulatory axes in pancreatic cancer and prostate cancer has previously been reported [<a class="elsevierStyleCrossRef" href="#bib0015">15</a>,<a class="elsevierStyleCrossRef" href="#bib0029">29</a>]. Zhang et al. demonstrated that the LINC01006/miR-2682-5p/HOXB8 axis accelerates the tumorigenesis of pancreatic cancer and thus may be a treatment target <a class="elsevierStyleCrossRef" href="#bib0015">[15]</a>. Ma et al. showed that LINC01006 is involved in the enhancement of cell proliferation, migration, and invasion in prostate cancer via interaction with the miR-34a-5p/DAAM1 axis <a class="elsevierStyleCrossRef" href="#bib0029">[29]</a>. Meanwhile, the functions of the miR-194-5p/FOXA1 <a class="elsevierStyleCrossRef" href="#bib0019">[19]</a> and miR-194-5p/MAPK1 axes <a class="elsevierStyleCrossRef" href="#bib0020">[20]</a> as well as the CADM1-Rb-E2F <a class="elsevierStyleCrossRef" href="#bib0037">[37]</a> and CADM1-STAT3 pathways <a class="elsevierStyleCrossRef" href="#bib0040">[40]</a> have been confirmed in HCC. We speculated that these downstream targets and pathways may also be involved in the regulatory mechanism of LINC01006 in HCC.To conclude, our results uncovered that LINC01006 is upregulated in HCC tissues and cells. LINC01006 directly interacts with miR-194-5p, and CADM1 is targeted by miR-194-5p. Mechanistically, sh-LINC01006 serves as a tumour suppressor lncRNA by sponging miR-194-5p and subsequently modulating the expression of CADM1. Thus, our results illustrate that LINC01006 may be a promising target for HCC therapy.Availability of data and materialsThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable requestEthics approval and consent to participateThe present study was authorized by the ethics committee of Weifang Yidu Central Hospital on the basis of the Declaration of Helsinki. Each participant enrolled in this research had written informed consent before surgical operation.Consent for publicationNot applicableFundingFunding information is not applicable.CRediT authorship contribution statementZhaoxia Sun: Visualization, Data curation, Formal analysis. Li Zhao: Investigation, Writing – original draft, Writing – review & editing. Shuang Wang: Visualization, Data curation, Formal analysis, Writing – review & editing. Honggang Wang: Investigation, Writing – original draft, Writing – review & editing." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1856178" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1614019" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0002" "titulo" => "Materials and methods" "secciones" => array:11 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "HCC samples" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Cell culture" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Quantitative real-time polymerase chain reaction (qRT-PCR)" ] 3 => array:2 [ "identificador" => "sec0006" "titulo" => "Cell transfection" ] 4 => array:2 [ "identificador" => "sec0007" "titulo" => "Dual-luciferase reporter (DLR) assay" ] 5 => array:2 [ "identificador" => "sec0008" "titulo" => "3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay" ] 6 => array:2 [ "identificador" => "sec0009" "titulo" => "Wound healing assay" ] 7 => array:2 [ "identificador" => "sec0010" "titulo" => "Transwell assay" ] 8 => array:2 [ "identificador" => "sec0011" "titulo" => "Western blot" ] 9 => array:2 [ "identificador" => "sec0012" "titulo" => "Nude mouse tumorigenesis assay" ] 10 => array:2 [ "identificador" => "sec0013" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0014" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "LINC01006 is highly expressed in HCC tissues and cells" ] 1 => array:2 [ "identificador" => "sec0016" "titulo" => "Downregulation of LINC01006 suppresses the proliferation, migration, and invasion of HCC cells and represses HCC tumour growth in mice" ] 2 => array:2 [ "identificador" => "sec0017" "titulo" => "LINC01006 acts as a sponge of miR-194-5p" ] 3 => array:2 [ "identificador" => "sec0018" "titulo" => "Overexpression of miR-194-5p represses cell viability, migration, and invasion in HCC cells" ] 4 => array:2 [ "identificador" => "sec0019" "titulo" => "CADM1 is the target of miR-194-5p" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Downregulation of LINC01006 represses cell invasion, migration, and proliferation by sponging miR-194-5p to modulate the expression of CADM1" ] ] ] 5 => array:2 [ "identificador" => "sec0021" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0022" "titulo" => "Availability of data and materials" ] 7 => array:2 [ "identificador" => "sec0023" "titulo" => "Ethics approval and consent to participate" ] 8 => array:2 [ "identificador" => "sec0024" "titulo" => "Consent for publication" ] 9 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0025a" "titulo" => "CRediT authorship contribution statement" ] 11 => array:2 [ "identificador" => "xack654237" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-03-08" "fechaAceptado" => "2021-05-21" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1614019" "palabras" => array:4 [ 0 => "Hepatocellular carcinoma" 1 => "LINC01006" 2 => "miR-194-5p" 3 => "CADM1" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesLong non-coding RNAs (lncRNAs) have great potential as therapeutic targets in hepatocellular carcinoma (HCC). In this study, we aimed to uncover the function and molecular mechanism of long intergenic non-protein coding RNA 1006 (LINC01006) in HCC. Materials and methodsMice were injected with HCC cells in order to establish the HCC model. Quantitative reverse transcription polymerase chain reaction was used to determine the expression levels of LINC01006, cell adhesion molecule 1 (CADM1), and microRNA (miR)-194-5p in HCC tissues and cells. The cell proliferation, invasion, and migration abilities were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, transwell, and wound healing assays. The interrelation between LINC01006, miR-194-5p, and CADM1 was confirmed by a dual-luciferase reporter assay. Western blotting was employed to assess the relative protein expression level of CADM1. ResultsLINC01006 and CADM1 displayed upregulation, but miR-194-5p exhibited downregulation in HCC cells and tissues. Short hairpin (sh)-LINC01006 and miR-194-5p mimics repressed the proliferative, migratory, and invasive capacities of HCC cells, and injection of sh-LINC01006 restrained the growth of HCC tumours in mice. LINC01006 served as a competing endogenous RNA of miR-194-5p and was inversely correlated with miR-194-5p. CADM1 was targeted by miR-194-5p, inversely correlated with miR-194-5p, and positively associated with LINC01006. Furthermore, transfection of pcDNA-CADM1 or the miR-194-5p inhibitor reversed the suppressive effects of sh-LINC01006 on the proliferation, invasion, and migration abilities of HCC cells. ConclusionsDownregulation of LINC01006 repressed the development of HCC by sponging miR-194-5p to modulate the expression of CADM1, implying its potential as a therapeutic target for HCC." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 892 "Ancho" => 2833 "Tamanyo" => 146746 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01006 was highly expressed in hepatocellular carcinoma (HCC) tissues and HCC cells. (A) Relative expression of LINC01006 in tumour tissues and adjacent normal tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). P < 0.001, vs. Adjacent normal tissues. (B) Relative expression of LINC01006 at tumour node metastasis (TNM) stage I/II and TNM stage III/IV was determined by qRT-PCR in tumour. P < 0.01, vs. I/II. (C) Relative expression of LINC01006 in HepG2, SMMC-7721, Hep3B, Sk-Hep1 and LO2 cells was determined by qRT-PCR. ⁎⁎P < 0.01, vs. LO2." ] ] 1 => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3012 "Ancho" => 2833 "Tamanyo" => 685742 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Knockdown of LINC01006 suppressed cell viability, migration and invasion in hepatocellular carcinoma (HCC) cells, and repressed tumour growth in mice. (A) Relative expression of LINC01006 in Hep3B and Sk-Hep1 cells after transfection with shRNA-LINC01006-1 (sh-LINC01006-1), sh-LINC01006-2 and shRNA negative control (sh-NC) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). ⁎⁎P < 0.01, vs. sh-NC. (B) Cell viability in Hep3B and Sk-Hep1 cells was detected by 3-(4, 5-Dimethyl-2-Thiazolyl)-2, 5-Diphenyl-2-H-Tetrazolium Bromide (MTT) assay. *P < 0.05, ⁎⁎P < 0.01, vs. sh-NC. (C) Wound healing rate of Hep3B and Sk-Hep1 cells was detected by wound healing assay. ⁎⁎P < 0.01, vs. sh-NC. (D) Number of invasion cells in Hep3B and Sk-Hep1 cells was detected by transwell assay. ⁎⁎P < 0.01, vs. sh-NC. (E) Three representative images of solid tumours, and the growth of tumours in mice injected with Hep3B cells transfected with Lentivirus vector carrying sh-LINC01006-1 (Lv-sh-LINC01006-1) or Lv-sh-NC. ⁎⁎P < 0.01, vs. Lv-sh-NC." ] ] 2 => array:8 [ "identificador" => "fig0003" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2168 "Ancho" => 3000 "Tamanyo" => 378582 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01006 acted as a sponge of miR-194-5p. (A) The binding sequence between LINC01006 and miR-194-5p was predicted by LncBase Predicted v.2. (B) Relative expression of miR-194-5p in Hep3B and Sk-Hep1 cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). ⁎⁎P < 0.01, vs. sh-NC. (C) The interaction between LINC01006 and miR-194-5p in Hep3B and Sk-Hep1 cells was confirmed by dual-luciferase reporter (DLR) assay. ⁎⁎P < 0.01, vs. miR-negative control (NC). (D) Relative expression of miR-194-5p was detected by qRT-PCR in tumour tissues and adjacent normal tissues. P < 0.001, vs. Adjacent normal tissues. (E) Correlation analysis of LINC01006 and miR-194-5p in hepatocellular carcinoma (HCC) tissues. P = 0.0009. (F) Relative expression of miR-194-5p in HepG2, Hep3B, SMMC-7721, Sk-Hep1 and LO2 cells was determined by qRT-PCR. ⁎⁎P < 0.01, vs. LO2." ] ] 3 => array:8 [ "identificador" => "fig0004" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2167 "Ancho" => 3000 "Tamanyo" => 694755 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0004" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Overexpression of miR-194-5p repressed cell viability, migration and invasion in hepatocellular carcinoma (HCC) cells. (A) Relative expression of miR-194-5p in Hep3B and Sk-Hep1 cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). ⁎⁎P < 0.01, vs. miR-NC. ##P < 0.01, vs. inhibitor NC. (B) Cell viability in Hep3B and Sk-Hep1 cells was determined by 3-(4, 5-Dimethyl-2-Thiazolyl)-2, 5-Diphenyl-2-H-Tetrazolium Bromide (MTT) assay. ⁎⁎P < 0.01, vs. miR-negative control (NC). (C) Wound healing rate of Hep3B and Sk-Hep1 cells was determined by wound healing assay. ⁎⁎P < 0.01, vs. miR-NC. (D) Number of invasion cells in Hep3B and Sk-Hep1 cells was detected by transwell assay. ⁎⁎P < 0.01, vs. miR-NC." ] ] 4 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2594 "Ancho" => 3000 "Tamanyo" => 448745 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "CADM1 was target gene of miR-194-5p. (A) The binding sites between CADM1 and miR-194-5p were predicted by LncBase Predicted v.2. (B) Dual-luciferase reporter (DLR) assay was used for confirming the relationship between miR-194-5p and CADM1 in Hep3B and Sk-Hep1 cells. ⁎⁎P < 0.01, vs. miR-negative control (NC). (C) Relative protein expression of CADM1 in Hep3B and Sk-Hep1 cells was detected by western blot. ⁎⁎P < 0.01, vs. miR-NC. (D) Relative expression of CADM1 in hepatocellular carcinoma (HCC) tissues and non-cancerous tissues from the cancer genome atlas (TCGA) database. *P < 0.05, vs. Non-cancerous tissues. LIHC: liver hepatocellular carcinoma. (E) Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect relative expression of CADM1 in tumour tissues and adjacent normal tissues. P < 0.001, vs. Adjacent normal tissues. (F) The relationship between LINC01006 and CADM1 in HCC tissues was analyzed by Pearson's correlation analysis. (G) The relationship between CADM1 and miR-194-5p in HCC tissues was analyzed by Pearson's correlation analysis. (H) Relative expression of CADM1 in HepG2, Hep3B, SMMC-7721, Sk-Hep1 and LO2 cells was determined by western blot. ⁎⁎P < 0.01, vs. LO2." ] ] 5 => array:8 [ "identificador" => "fig0006" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 2360 "Ancho" => 3000 "Tamanyo" => 772668 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0006" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Knockdown of LINC01006 inhibited cell invasion, migration and proliferation by sponging miR-194-5p to modulate the expression of CADM1. (A) Relative expression of CADM1 in Hep3B cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). ⁎⁎P < 0.01, vs. pcDNA-NC. (B) Cell viability in Hep3B cells was determined by 3-(4, 5-Dimethyl-2-Thiazolyl)-2, 5-Diphenyl-2-H-Tetrazolium Bromide (MTT) assay. ⁎⁎P < 0.01, vs. sh-negative control (NC). ##P < 0.01, vs. sh-LINC01006-1. (C) Wound healing rate of Hep3B cells was determined by wound healing assay. ⁎⁎P < 0.01, vs. sh-NC. ##P < 0.01, vs. sh-LINC01006-1. (D) Number of invasion cells in Hep3B cells was detected by transwell assay. ⁎⁎P < 0.01, vs. sh-NC. ##P < 0.01, vs. sh-LINC01006-1." ] ] 6 => array:8 [ "identificador" => "tbl0001" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0007" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Forward \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reverse \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0004"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">LINC01006 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0005"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-TTTGTGGTGGTGAAGACGTG-3’ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-TCCTCAAGAATAAGGAACATAGGC-3’ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">MiR-194-5p \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-GCCGCTGTAACAGCAACTCCAT-3’ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-GTGCAGGGTCCGAGGT-3’ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">CADM1 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-TGCTGTGCTTGCTCATCATTCT-3’ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’- TCTGCGTCTGCTGCGTCAT-3’ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">GAPDH \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-CAGGAGGCATTGCTGATGAT -3’ \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5’-GAAGGCTGGGGCTCATTT-3’ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Primers for qRT-PCR in this study." ] ] 7 => array:8 [ "identificador" => "tbl0002" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0008" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Note: *P < 0.05, WHO: world health organization, TNM : tumour node metastasis." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0016"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable</th><a name="en0017"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total</th><a name="en0018"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top" scope="col">LINC01006 expression</th><a name="en0019"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P-value</th></tr><tr title="table-row"><a name="en0022"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Low(30) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0023"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">High(31) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0025"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Gender \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.662 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0030"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0035"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0037"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Age \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.684 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0045"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">< 60years \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">≥ 60 years \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Diameter \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.332 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0060"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">< 6 cm \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0061"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0065"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">≥ 6 cm \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0070"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Metastasis \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0073"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.015* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0075"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NO \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0080"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">YES \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">TNM stage \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.028* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0090"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">I/II \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0095"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">III/IV \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0097"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">23 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n 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Zhaoxia Suna, Li Zhaoa, Shuang Wanga, Honggang Wangb,

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wanghonggang2130@163.com

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a Department of Infectious Diseases, Weifang Yidu Central Hospital, No.4138, Linglongshan South Road, Qingzhou City, Weifang, Shandong 262500, China.

b Clinical Laboratory, Weifang People's Hospital, No.151, Guangwen Street, Kuiwen District, Weifang, Shandong 261041, China.

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    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Knockdown of long non-coding RNA LINC01006 represses the development of hepatocellular carcinoma by modulating the miR-194-5p&#47;CADM1 axis"
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            "entidad" => "Department of Infectious Diseases&#44; Weifang Yidu Central Hospital&#44; No&#46;4138&#44; Linglongshan South Road&#44; Qingzhou City&#44; Weifang&#44; Shandong 262500&#44; China&#46;"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">LINC01006 was highly expressed in hepatocellular carcinoma &#40;HCC&#41; tissues and HCC cells&#46; &#40;A&#41; Relative expression of LINC01006 in tumour tissues and adjacent normal tissues was determined by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#44; vs&#46; Adjacent normal tissues&#46; &#40;B&#41; Relative expression of LINC01006 at tumour node metastasis &#40;TNM&#41; stage I&#47;II and TNM stage III&#47;IV was determined by qRT-PCR in tumour&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; I&#47;II&#46; &#40;C&#41; Relative expression of LINC01006 in HepG2&#44; SMMC-7721&#44; Hep3B&#44; Sk-Hep1 and LO2 cells was determined by qRT-PCR&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; LO2&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="cesectitle0007">Introduction</span><p id="para0005" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma &#40;HCC&#41;&#44; which is considered to be the third most fatal cancer worldwide&#44; comprises 90&#37; of all liver cancers <a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a>&#46; As a rapidly growing and invasive tumour&#44; HCC is chiefly induced by long-term liver injury caused by inherited metabolic disorders&#44; viral hepatitis&#44; excessive alcohol consumption&#44; and toxin exposure <a class="elsevierStyleCrossRef" href="#bib0002">&#91;2&#93;</a>&#46; The high probability of tumour metastasis and recurrence is the primary factor leading to the poor prognosis of patients with HCC <a class="elsevierStyleCrossRef" href="#bib0003">&#91;3&#93;</a>&#46; There are many therapeutic modalities for HCC&#44; including surgical options and ablative electrochemical therapies &#91;<a class="elsevierStyleCrossRef" href="#bib0004">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0005">5</a>&#93;&#46; Currently&#44; although HCC therapy has made great strides&#44; the treatment effect on recurrent or metastatic HCC remains unsatisfactory&#44; and the prevalence of HCC continues to rise <a class="elsevierStyleCrossRefs" href="#bib0006">&#91;6&#8211;8&#93;</a>&#46; Therefore&#44; it is imperative to discover additional insights into the mechanism of HCC and exploit novel targets for HCC therapy&#46;</p><p id="para0006" class="elsevierStylePara elsevierViewall">Long non-coding RNAs &#40;lncRNAs&#41;&#44; which comprise over 200 nucleotides in length&#44; are a subgroup of non-coding RNAs that exhibit limited or no protein-coding potential &#91;<a class="elsevierStyleCrossRef" href="#bib0009">9</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0010">10</a>&#93;&#46; Several studies have confirmed the indispensable roles of lncRNAs in HCC <a class="elsevierStyleCrossRefs" href="#bib0011">&#91;11&#8211;13&#93;</a>&#46; A document from Zou et&#160;al&#46; stated that silencing of lncRNA HLA complex group 18 suppresses the proliferation and migration of HCC cells while stimulating their apoptosis <a class="elsevierStyleCrossRef" href="#bib0011">&#91;11&#93;</a>&#46; Another report from Wang et&#160;al&#46; showed that knockdown of long intergenic non-protein coding RNA &#40;LINC&#41; 1134 inhibits the migration and invasion of HCC cells <span class="elsevierStyleItalic">in vitro</span> and restrains HCC liver metastasis <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0012">&#91;12&#93;</a>&#46; A similar study by Wu et&#160;al&#46; confirmed that lncRNA metallothionein 1J&#44; pseudogene markedly impairs proliferation while also enhancing apoptosis in HCC cells <a class="elsevierStyleCrossRef" href="#bib0013">&#91;13&#93;</a>&#46;</p><p id="para0007" class="elsevierStylePara elsevierViewall">LINC01006&#44; located on human chromosome 7q36&#46;37&#44; has been shown to be implicated in several cancers &#91;<a class="elsevierStyleCrossRef" href="#bib0014">14</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0015">15</a>&#93;&#46; Downregulation of LINC01006 is closely associated with age&#44; tumour size&#44; tumour location&#44; and venous invasion in gastric cancer <a class="elsevierStyleCrossRef" href="#bib0014">&#91;14&#93;</a>&#46; Silencing of LINC01006 attenuates the proliferative&#44; migratory&#44; and invasive abilities of pancreatic cancer cells <a class="elsevierStyleCrossRef" href="#bib0015">&#91;15&#93;</a>&#46; Nonetheless&#44; there are few studies on the function and mechanism of LINC01006 in HCC&#46;</p><p id="para0008" class="elsevierStylePara elsevierViewall">MicroRNAs &#40;miRNAs&#47;miRs&#41;&#44; which have a length of 19&#8211;24 nucleotides&#44; are short single-stranded non-coding RNAs that can modulate gene expression at the post-transcriptional level <a class="elsevierStyleCrossRef" href="#bib0016">&#91;16&#93;</a>&#46; In the past few years&#44; increasing attention has been paid to miRNAs in the progression of HCC &#91;<a class="elsevierStyleCrossRef" href="#bib0017">17</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0018">18</a>&#93;&#46; Wang et&#160;al&#46; reported that upregulation of miR-302b represses the proliferation of HCC cells and the G1-S transition <span class="elsevierStyleItalic">in vitro</span><a class="elsevierStyleCrossRef" href="#bib0017">&#91;17&#93;</a>&#46; Li et&#160;al&#46; indicated that inhibition of miR-221 restrains the proliferation&#44; migration&#44; and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0018">&#91;18&#93;</a>&#46; LncRNAs can act as competing endogenous RNAs &#40;ceRNAs&#41; or sponges of miRNAs&#46; Minichromosome maintenance complex component 3 associated protein antisense RNA 1 &#40;MCM3AP-AS1&#41; is known to contribute to the progression of HCC by targeting miR-194-5p <a class="elsevierStyleCrossRef" href="#bib0019">&#91;19&#93;</a>&#46; X-inactive specific transcript &#40;XIST&#41; functions as a molecular sponge of miR-194-5p to accelerate HCC tumorigenesis <a class="elsevierStyleCrossRef" href="#bib0020">&#91;20&#93;</a>&#46; In addition&#44; miR-194-5p is reported to target numerous downstream genes that are involved in HCC progression&#44; such as forkhead box A1 &#40;FOXA1&#41; <a class="elsevierStyleCrossRef" href="#bib0019">&#91;19&#93;</a>&#44; mitogen-activated protein kinase 1 &#40;MAPK1&#41; <a class="elsevierStyleCrossRef" href="#bib0020">&#91;20&#93;</a>&#44; and Wee1-like protein kinase <a class="elsevierStyleCrossRef" href="#bib0021">&#91;21&#93;</a>&#46; More importantly&#44; a recent study conducted by Niu et&#160;al&#46; revealed that miR-194 interaction with cell adhesion molecule 1 &#40;CADM1&#41; affects the progression of HCC <a class="elsevierStyleCrossRef" href="#bib0022">&#91;22&#93;</a>&#46; However&#44; the interactions among LINC01006&#44; miR-194-5p&#44; and CADM1 in HCC have not yet been explored&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">In the current study&#44; we attempted to evaluate the expression and function of LINC01006 in HCC&#46; Moreover&#44; the molecular basis of LINC01006 in HCC progression was further investigated&#46; We aimed to provide novel insights into the biological role of LINC01006 in HCC as well as a potential target for HCC treatment&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="cesectitle0008">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0009">HCC samples</span><p id="para0010" class="elsevierStylePara elsevierViewall">From March 2018 to February 2019&#44; paired HCC and adjacent normal tissues &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;61&#41; were acquired from patients who underwent hepatectomy&#46; None of the HCC patients received any chemotherapy or embolotherapy before surgery&#46; The tissue samples were affirmed by two histopathologists&#46; The present study was approved by the ethics committee of Weifang Yidu Central Hospital on the basis of the Declaration of Helsinki&#46; Each participant enrolled in this research provided written informed consent before the surgical operation&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0010">Cell culture</span><p id="para0011" class="elsevierStylePara elsevierViewall">The human immortalised liver cell line &#40;MIHA&#41; and human HCC cell lines &#40;Huh7&#44; SNU-398&#44; Hep3B&#44; and Sk-Hep1&#41; were purchased from the American Type Culture Collection &#40;Manassas&#44; VA&#44; USA&#41;&#46; The cells were cultured in Dulbecco&#39;s Modified Eagle&#39;s Medium &#40;DMEM&#59; Gibco&#44; Grand Island&#44; NY&#44; USA&#41; supplemented with 10&#37; foetal bovine serum &#40;FBS&#59; Gibco&#41; and antibiotics &#40;100 U&#47;mL penicillin and 100 &#956;g&#47;mL streptomycin&#41; at 37&#160;&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span>&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0011">Quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;</span><p id="para0012" class="elsevierStylePara elsevierViewall">Trizol reagent &#40;Sangon Biotech&#44; Shanghai&#44; China&#41; was used for RNA isolation&#46; Total RNA was reverse transcribed into complementary DNA using an M-MLV Reverse Transcriptase kit &#40;Sangon Biotech&#41;&#46; The qRT-PCR assay was implemented using SYBR&#174; Premix Ex Taq&#8482; II &#40;Takara&#44; Dalian&#44; China&#41;&#46; The PCR &#39069;ing conditions were as follows&#58; 94&#160;&#176;C for 5&#160;min&#44; followed by 40 cycles of 94&#160;&#176;C for 30&#160;s&#44; 60&#160;&#176;C for 20&#160;s&#44; and 72&#160;&#176;C for 5&#160;min&#46; All primers were purchased from Invitrogen &#40;Carlsbad&#44; CA&#44; USA&#41;&#44; and the primer sequences are shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table&#160;1</a>&#46; The relative expression levels of LINC01006&#44; miR-194-5p&#44; and CADM1 were calculated using the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;ct</span> method&#46; Glyceraldehyde 3-phosphate dehydrogenase was used as an internal reference&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0012">Cell transfection</span><p id="para0013" class="elsevierStylePara elsevierViewall">Short hairpin RNAs &#40;shRNAs&#41; against LINC01006 &#40;sh-LINC01006-1 and sh-LINC01006-2&#41;&#44; shRNA negative control &#40;sh-NC&#41;&#44; miR-NC&#44; miR-194-5p mimics&#44; miR-194-5p inhibitor&#44; pcDNA-NC&#44; and pcDNA-CADM1 were purchased from RiboBio Company &#40;Beijing&#44; China&#41;&#46; Next&#44; the above factors were transfected into Hep3B and Sk-Hep1 cells using Lipofectamine 3000 &#40;Invitrogen&#41; for 48 h according to the provided protocol&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="cesectitle0013">Dual-luciferase reporter &#40;DLR&#41; assay</span><p id="para0014" class="elsevierStylePara elsevierViewall">The 3&#8242;-untranslated region &#40;UTR&#41; of LINC01006 or CADM1 harbouring the binding sequence of miR-194-5p was introduced into the pGL3 luciferase reporter vector &#40;Promega&#44; Madison&#44; WI&#44; USA&#41;&#44; forming the LINC01006 wild type &#40;WT&#41; or CADM1 WT&#46; Analogously&#44; the 3&#8242;-UTR segment of LINC01006 or CADM1&#44; including the mutated binding sequence of miR-194-5p&#44; was introduced into the pGL3 luciferase reporter vector &#40;Promega&#41;&#44; generating the LINC01006 mutant &#40;MUT&#41; or CADM1 MUT&#46; The above reporters&#44; along with miR-194-5p mimics or miR-NC&#44; were transfected into cells using Lipofectamine 3000 &#40;Invitrogen&#41;&#46; After transfection for 48 h&#44; relative luciferase activity was measured with a DLR assay system &#40;Promega&#41;&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="cesectitle0014">3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyl-2H-tetrazolium bromide &#40;MTT&#41; assay</span><p id="para0015" class="elsevierStylePara elsevierViewall">Cells were seeded into 96-well plates at a density of 6&#44;000 cells&#47;well&#46; At 0&#44; 24&#44; 48&#44; 72&#44; and 96&#160;h after incubation&#44; MTT &#40;10 &#956;L&#59; Sigma-Aldrich&#44; St&#46; Louis&#44; MO&#44; USA&#41; was added&#44; and the cells were incubated at 37&#160;&#176;C for another 4&#160;h&#46; At the end of the culture&#44; 150 &#956;L dimethyl sulfoxide was added&#46; The optical density at 490 nm was measured with an FL600 fluorescence plate reader &#40;Bio-Rad&#44; Hercules&#44; CA&#44; USA&#41;&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="cesectitle0015">Wound healing assay</span><p id="para0016" class="elsevierStylePara elsevierViewall">Cells were seeded into 6-well plates at a density of 6&#160;&#215;&#160;10<span class="elsevierStyleSup">4</span>&#8201;cells&#47;well and cultured with DMEM containing 10&#37; FBS until the cell monolayer was generated&#46; Unilaminar cells were scratched with a 10 &#956;L sterile pipette tip&#46; Then&#44; PBS was added to remove the scratched cells&#46; The cells were then cultured in serum-free medium at 37&#176;C&#46; After culturing for 24&#160;h&#44; the migration distance of the cell scratch region was examined under an inverted microscope &#40;TE2000&#59; Nikon&#44; Tokyo&#44; Japan&#41;&#46; The formula for calculating the wound healing rate was as follows&#58; &#40;1&#8211;24&#160;h scratch width&#47;0 h scratch width&#41;&#160;&#215;&#160;100&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="cesectitle0016">Transwell assay</span><p id="para0017" class="elsevierStylePara elsevierViewall">The cell invasion capacity was determined using a transwell chamber coated with Matrigel &#40;BD Biosciences&#44; Sparks&#44; MD&#44; USA&#41;&#46; First&#44; cells in serum-free medium were shifted to the upper chamber &#40;BD Biosciences&#41;&#46; The lower chamber was loaded with 600&#160;&#956;L DMEM containing 10&#37; FBS&#46; After incubation for 24&#160;h&#44; the transwell chamber was removed&#46; Cells in the upper compartment were sponged with cotton swabs&#44; and cells in the lower compartment were stained with 0&#46;1&#37; crystal violet for 5 min&#46; After washing with PBS&#44; the invasive ability of the cells was evaluated by counting the number of invading cells under a fluorescence microscope &#40;TE2000&#59; Nikon&#41;&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;9</span><span class="elsevierStyleSectionTitle" id="cesectitle0017">Western blot</span><p id="para0018" class="elsevierStylePara elsevierViewall">Total cells were lysed using radioimmunoprecipitation assay buffer &#40;Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41;&#46; Protein samples were isolated by 10&#37; sodium dodecyl sulphate-polyacrylamide gel electrophoresis&#44; transferred to polyvinylidene difluoride membranes&#44; and blocked with 5&#37; non-fat milk&#46; The membranes were then incubated with the anti-CADM1 &#40;1&#58;1000&#44; ab216585&#59; Abcam&#44; Cambridge&#44; MA&#44; USA&#41; and anti-&#946;-tubulin &#40;1&#58;500&#44; ab6046&#59; Abcam&#41; primary antibodies overnight at 4&#176;C&#46; After washing with tris-buffered saline-Tween 20&#44; the secondary antibody &#40;1&#58;2000&#44; ab6747&#59; Abcam&#41; was supplemented and cultured with the protein samples at 37&#160;&#176;C for 1&#160;h&#46; The blot signals were visualised using electrochemiluminescence reagents &#40;Millipore&#44; Plano&#44; TX&#44; USA&#41;&#46; The relative expression of CADM1 over the &#946;-tubulin band was quantified using a Gel-Pro Analyser &#40;Media Cybernetics&#44; Rockville&#44; MD&#44; USA&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;10</span><span class="elsevierStyleSectionTitle" id="cesectitle0018">Nude mouse tumorigenesis assay</span><p id="para0019" class="elsevierStylePara elsevierViewall">All animal experiments were approved by the animal ethics committee of our hospital and abided by the National Institutes of Health Guide for the Care and Use of Laboratory Animals&#46; Four-week-old male BALB&#47;C nude mice were purchased from the National Laboratory Animal Center &#40;Beijing&#44; China&#41; and divided into two groups &#40;<span class="elsevierStyleItalic">n</span>&#160;&#61;&#160;5 per group&#41;&#46; Hep3B cells &#40;5&#160;&#215;&#160;10<span class="elsevierStyleSup">6</span>&#41; transfected with the lentivirus vector of sh-LINC01006-1 &#40;Lv-sh-LINC01006-1&#41; or the lentivirus vector of sh-NC &#40;Lv-sh-NC&#41; were subcutaneously implanted into the right flank of the nude mice at 100&#160;&#956;L cell suspension per injection as previously described <a class="elsevierStyleCrossRef" href="#bib0023">&#91;23&#93;</a>&#46; Tumour volumes were gauged once every 5 days and calculated using the following formula&#58; &#40;A&#160;&#215;&#160;B<span class="elsevierStyleSup">2</span>&#41; &#47; 2 &#40;A&#44; the longest diameter&#59; <span class="elsevierStyleItalic">B</span>&#44; the shortest diameter&#41;&#46; On the 30th day after injection&#44; the mice were anaesthetized with pentobarbital sodium &#40;50&#160;mg&#47;kg&#41; and sacrificed&#46; The tumours were then dissected and weighed&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;11</span><span class="elsevierStyleSectionTitle" id="cesectitle0019">Statistical analysis</span><p id="para0020" class="elsevierStylePara elsevierViewall">In vitro experiments were repeated three times&#46; Additionally&#44; the MTT assay&#44; DLR assay&#44; and qRT-PCR were performed in triplicate &#40;3&#160;&#215;&#160;3&#41;&#46; In vivo experiments were performed using five mice in each group&#46; Data were analysed using SPSS Statistics 22&#46;0 software &#40;IBM SPSS&#44; Armonk&#44; NY&#44; USA&#41; and are presented as means&#8201;&#177;&#8201;standard deviations&#46; The Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used to compare differences between two groups&#46; A one-way analysis of variance was used to analyse differences among multiple groups&#44; and Tukey&#39;s multiple comparisons test was used for pairwise comparisons&#46; The correlations between two genes were analysed using the Pearson correlation test&#46; Differences were considered statistically significant at <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#46;</p></span></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="cesectitle0020">Results</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0021">LINC01006 is highly expressed in HCC tissues and cells</span><p id="para0021" class="elsevierStylePara elsevierViewall">To determine the role of LINC01006 in HCC&#44; we determined the expression of LINC01006 in tumour tissues from HCC patients and in HCC cell lines&#46; The qRT-PCR results showed that the relative expression level of LINC01006 in tumour tissues was distinctly elevated compared to that in adjacent normal tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46;&#160;1</a>A&#41;&#46; Next&#44; to determine the clinical significance of LINC01006 in HCC&#44; we analysed the relationships between clinicopathological features and the expression of LINC01006 in HCC cases&#46; We discovered that LINC01006 was closely associated with metastasis and tumour node metastasis &#40;TNM&#41; stage &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table&#160;2</a>&#41;&#46; The relative expression of LINC01006 in HCC patients at TNM stage III-IV was boosted compared to that in patients at TNM stage I-II &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46;&#160;1</a>B&#41;&#46; We also observed that LINC01006 was upregulated in HCC cell lines &#40;Huh7&#44; SNU-398&#44; Hep3B&#44; and Sk-Hep1&#41; compared to MIHA cells &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46;&#160;1</a>C&#41;&#46; Among them&#44; Hep3B and Sk-Hep1 were selected for the subsequent trials because of the relatively high expression levels of LINC01006&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><elsevierMultimedia ident="tbl0002"></elsevierMultimedia></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0022">Downregulation of LINC01006 suppresses the proliferation&#44; migration&#44; and invasion of HCC cells and represses HCC tumour growth in mice</span><p id="para0022" class="elsevierStylePara elsevierViewall">Next&#44; we probed the potential role of LINC01006 in HCC cells&#46; First&#44; we silenced LINC01006 using sh-LINC01006-1 or sh-LINC01006-2 in Hep3B and Sk-Hep1 cells&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>A&#44; the expression of LINC01006 was markedly reduced by sh-LINC01006-1 or sh-LINC01006-2 in Hep3B and Sk-Hep1 cells &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#44; and sh-LINC01006-1 was selected for subsequent experiments on account of its relatively high knockdown efficiency&#46; The results of the MTT assay indicated that the viability of Hep3B and Sk-Hep1 cells in the sh-LINC01006-1 group was lower than that in the sh-NC group &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>B&#41;&#46; The wound healing assay showed that the wound healing rate of Hep3B and Sk-Hep1 cells was decreased by the knockdown of LINC01006 &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>C&#41;&#46; The transwell assay demonstrated that the number of invading cells was diminished by the knockdown of LINC01006 in Hep3B and Sk-Hep1 cells &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>D&#41;&#46; To elucidate the biological role of LINC01006 in HCC <span class="elsevierStyleItalic">in vivo</span>&#44; we performed a mouse tumorigenesis assay&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>E&#44; the tumour volume in the Lv-sh-LINC01006-1 group was dramatically reduced on the 20th&#44; 25th&#44; and 30th days after injection relative to the Lv-sh-NC group &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>E&#41;&#46; Moreover&#44; the tumour weight in the Lv-sh-LINC01006-1 group was also evidently reduced compared to the Lv-sh-NC group on the 30th day after injection &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46;&#160;2</a>E&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0023">LINC01006 acts as a sponge of miR-194-5p</span><p id="para0023" class="elsevierStylePara elsevierViewall">To gain mechanistic insight into LINC01006&#44; we predicted its target using the LncBase Predicted v2 database&#46; The results illustrated that miR-194-5p shared complementary binding to LINC01006 &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>A&#41;&#46; Meanwhile&#44; miR-194-5p was upregulated by the transfection of sh-LINC01006-1 into Hep3B and Sk-Hep1 cells &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>B&#41;&#44; suggesting a negative modulation loop between miR-194-5p and LINC01006 in human HCC cells&#46; To test the association between miR-194-5p and LINC01006&#44; a DLR assay was conducted&#44; which showed that upregulation of miR-194-5p reduced the relative luciferase activity of Hep3B and Sk-Hep1 cells transfected with the LINC01006 WT reporter but had no significant impact on the relative luciferase activity of Hep3B and Sk-Hep1 cells transfected with LINC01006 MUT &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>C&#41;&#46; In addition&#44; miR-194-5p was notably diminished in tumour tissues compared to adjacent normal tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>D&#41;&#46; The outcome of Pearson correlation analysis indicated that there was an inverse correlation between miR-194-5p and LINC01006 in human HCC tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;0009&#44; <span class="elsevierStyleItalic">r</span>&#160;&#61;&#160;-0&#46;4155&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>E&#41;&#46; In addition&#44; the expression of miR-194-5p was determined in HCC cell lines&#46; As illustrated in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46;&#160;3</a>F&#44; we observed decreased expression of miR-194-5p in HCC cell lines compared to MIHA cells &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0024">Overexpression of miR-194-5p represses cell viability&#44; migration&#44; and invasion in HCC cells</span><p id="para0024" class="elsevierStylePara elsevierViewall">Subsequently&#44; we examined the function of miR-194-5p in HCC cells&#46; As illustrated in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>A&#44; we observed that the expression of miR-194-5p in Hep3B and Sk-Hep1 cells was increased by transfection with miR-194a-5p mimics and decreased by the miR-194a-5p inhibitor &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#46; The cell viability of Hep3B and Sk-Hep1 cells was decreased by miR-194-5p overexpression &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>B&#41;&#46; In addition&#44; the migratory and invasive abilities of Hep3B and Sk-Hep1 cells were repressed by overexpression of miR-194-5p &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46;&#160;4</a>C and D&#41;&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="cesectitle0025">CADM1 is the target of miR-194-5p</span><p id="para0025" class="elsevierStylePara elsevierViewall">In order to identify the downstream target of miR-194-5p&#44; we performed a prediction using StarBase&#46; The results showed that there were binding sites between CADM1 and miR-194-5p &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>A&#41;&#46; To confirm this prediction&#44; a DLR assay was performed&#46; The results revealed that the relative luciferase activity of Hep3B and Sk-Hep1 cells was visibly decreased by co-transfection with the CADM1 WT reporter and miR-194-5p mimics&#44; whereas the relative luciferase activity of Hep3B and Sk-Hep1 cells was not significantly different after co-transfection with miR-194-5p mimics and the CADM1 MUT reporter &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>B&#41;&#46; Western blot analysis showed that CADM1 expression was distinctly reduced by miR-194-5p overexpression in Hep3B and Sk-Hep1 cells &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>C&#41;&#46; Data from The Cancer Genome Atlas database indicated that expression of CADM1 was augmented in HCC tissues compared to adjacent normal tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>D&#41;&#46; The results from qRT-PCR showed that CADM1 was also elevated in tumour tissues relative to that in adjacent normal tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>E&#41;&#46; Pearson correlation analysis demonstrated that LINC01006 was positively correlated with CADM1 in human HCC tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;0008&#44; <span class="elsevierStyleItalic">r</span>&#160;&#61;&#160;0&#46;4190&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>F&#41;&#44; and miR-194-5p was inversely correlated with CADM1 in human HCC tissues &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;0004&#44; <span class="elsevierStyleItalic">r</span>&#160;&#61;&#160;-0&#46;4389&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>G&#41;&#46; Moreover&#44; the results of the western blot assay demonstrated that the protein level of CADM1 was significantly elevated in HCC cell lines compared to that in MIHA cells &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46;&#160;5</a>H&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;6</span><span class="elsevierStyleSectionTitle" id="cesectitle0026">Downregulation of LINC01006 represses cell invasion&#44; migration&#44; and proliferation by sponging miR-194-5p to modulate the expression of CADM1</span><p id="para0026" class="elsevierStylePara elsevierViewall">To further validate the relationships among LINC01006&#44; miR-194-5p&#44; and CADM1&#44; sh-LINC01006-1 or sh-LINC01006-1&#160;&#43;&#160;miR-194a-5p inhibitor was transfected into Hep3B cells to determine the protein level of CADM1&#46; As presented in <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46;&#160;6</a>A&#44; the CADM1 protein level was downregulated by sh-LINC01006-1 &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#44; whereas transfection with miR-194a-5p reversed the inhibitory effect of sh-LINC01006-1 on the CADM1 protein level &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#41;&#46; Next&#44; the transfection efficiency of pcDNA-CADM1 was determined&#46; We found that CADM1 expression was significantly elevated in Hep3B cells transfected with pcDNA-CADM1 &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46;&#160;6</a>B&#41;&#44; which suggested that pcDNA-CADM1 was transfected successfully&#46; Next&#44; we carried out rescue experiments&#46; We discovered that the addition of sh-LINC01006-1 significantly decreased cell viability in Hep3B cells &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#44; and the inhibitory effect of sh-LINC01006-1 on cell viability was reversed by the addition of pcDNA-CADM1 or miR-194-5p inhibitor in Hep3B cells &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46;&#160;6</a>C&#41;&#46; Furthermore&#44; the cell migration and invasion abilities were restrained by sh-LINC01006-1 in Hep3B cells &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#41;&#44; and the suppressive effects of sh-LINC01006-1 on the migratory and invasive abilities of Hep3B cells were reversed by pcDNA-CADM1 or the miR-194-5p inhibitor &#40;all <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46;&#160;6</a>D and E&#41;&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="cesectitle0027">Discussion</span><p id="para0027" class="elsevierStylePara elsevierViewall">HCC is regarded as a common hepatic malignancy worldwide that continues to increase in prevalence &#91;<a class="elsevierStyleCrossRef" href="#bib0024">24</a>&#44; <a class="elsevierStyleCrossRef" href="#bib0025">25</a>&#93;&#46; Previous studies have revealed upregulation of several lncRNAs in HCC&#44; including myocardial infarction-associated transcript <a class="elsevierStyleCrossRef" href="#bib0026">&#91;26&#93;</a>&#44; lncRNA activated by transforming growth factor-&#946; <a class="elsevierStyleCrossRef" href="#bib0027">&#91;27&#93;</a> and HOX antisense intergenic RNA <a class="elsevierStyleCrossRef" href="#bib0028">&#91;28&#93;</a>&#46; Consistent with the above studies&#44; we observed that LINC01006 was augmented in HCC tissues and cells compared to their controls&#44; implying that LINC01006 is involved in HCC&#46; Moreover&#44; a prior study stated that LINC01006 is relevant to tumour location&#44; tumour size&#44; venous invasion&#44; and age in gastric cancer <a class="elsevierStyleCrossRef" href="#bib0014">&#91;14&#93;</a>&#46; Similarly&#44; we found that LINC01006 was associated with metastasis and TNM stage&#46; Its association with metastasis also indicates that LINC01006 may be applied as a tool for predicting prognosis&#44; given that metastasis is relevant to the poor prognosis of patients with HCC <a class="elsevierStyleCrossRef" href="#bib0003">&#91;3&#93;</a>&#46;</p><p id="para0028" class="elsevierStylePara elsevierViewall">Recent studies have shown that LINC01006 plays a critical role in pancreatic cancer &#91;<a class="elsevierStyleCrossRef" href="#bib0015">15</a>&#44; <a class="elsevierStyleCrossRef" href="#bib0029">29</a>&#93;&#46; Ma et&#160;al&#46; revealed that overexpression of LINC01006 significantly contributes to enhancing the proliferation&#44; migration&#44; and invasion of prostate cancer cells <a class="elsevierStyleCrossRef" href="#bib0029">&#91;29&#93;</a>&#46; Zhang et&#160;al&#46; stated that LINC01006 knockdown represses the cell invasion&#44; migration&#44; and proliferation abilities in pancreatic cancer <a class="elsevierStyleCrossRef" href="#bib0015">&#91;15&#93;</a>&#46; Similarly&#44; we discovered that the knockdown of LINC01006 also represses cell proliferation&#44; invasion&#44; and migration in HCC&#46; Additionally&#44; in nude mouse xenograft models&#44; downregulation of LINC01006 remarkably repressed HCC tumour growth&#46; These findings indicate that LINC01006 may act as a novel target for HCC therapy&#46;</p><p id="para0029" class="elsevierStylePara elsevierViewall">Previous studies have shown that lncRNAs can serve as ceRNAs to sponge miRNAs in diverse cancers&#44; including HCC <a class="elsevierStyleCrossRef" href="#bib0030">&#91;30&#93;</a>&#46; EPB41L4A-AS2-miR-301a-5p <a class="elsevierStyleCrossRef" href="#bib0031">&#91;31&#93;</a>&#44; PCAT-1-miR-215 <a class="elsevierStyleCrossRef" href="#bib0032">&#91;32&#93;</a> and MALAT1-miR-200a <a class="elsevierStyleCrossRef" href="#bib0033">&#91;33&#93;</a> have been verified in HCC&#46; Here&#44; we validated that lncRNA LINC01006 functions as a ceRNA to sponge miR-194-5p and that it is inversely correlated with miR-194-5p&#46; In addition&#44; downregulation of miR-194-5p has previously been demonstrated to participate in the progression of HCC cells &#91;<a class="elsevierStyleCrossRef" href="#bib0019">19</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0020">20</a>&#93;&#46; Downregulation of miR-194-5p was affirmed in HCC tissues compared to paracancerous tissues&#44; and MCM3AP-AS1 was revealed to exert an oncogenic role by targeting miR-194-5p in HCC <a class="elsevierStyleCrossRef" href="#bib0019">&#91;19&#93;</a>&#46; MiR-194-5p was shown to be diminished in HCC tissues compared to non-tumour tissues&#44; and overexpression of miR-194-5p appeared to suppress the proliferation and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0020">&#91;20&#93;</a>&#46; Similarly&#44; we discovered that upregulation of miR-194-5p attenuates the cell proliferation&#44; invasion&#44; and migration abilities in HCC cells&#46; We also found that the miR-194-5p inhibitor reversed the suppressive effects of sh-LINC01006 on the viability&#44; invasion&#44; and migration of HCC cells&#46; Taken together<span class="elsevierStyleItalic">&#44;</span> we inferred that sh-LINC01006 fulfils a tumour suppressor role by targeting miR-194-5p in HCC&#46;</p><p id="para0030" class="elsevierStylePara elsevierViewall">CADM1&#44; also known as tumour suppressor in lung cancer 1&#44; encodes a 442 amino acid protein that contains a cytoplasmic domain&#44; an extracellular domain&#44; and a transmembrane domain &#91;<a class="elsevierStyleCrossRef" href="#bib0034">34</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0035">35</a>&#93;&#46; Aberrant expression of CADM1 has been demonstrated to play a notable role in the progression of HCC &#91;<a class="elsevierStyleCrossRef" href="#bib0036">36</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0037">37</a>&#93;&#46; Sun et&#160;al&#46; affirmed that suppression of CADM1 can stimulate the migration and invasion of HCC cells <a class="elsevierStyleCrossRef" href="#bib0038">&#91;38&#93;</a>&#46; Zhang et&#160;al&#46; declared that upregulation of CADM1 represses the tumorigenicity of HCC both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0037">&#91;37&#93;</a>&#46; In the current study&#44; CADM1 was found to have increased expression in HCC cells and tissues compared to their controls&#44; suggesting that CADM1 may be implicated in the development of HCC&#46; Moreover&#44; CADM1 has also been reported to act as the downstream target of other miRNAs in HCC&#44; such as miR-1246 <a class="elsevierStyleCrossRef" href="#bib0038">&#91;38&#93;</a> and miR-10b <a class="elsevierStyleCrossRef" href="#bib0039">&#91;39&#93;</a>&#46; Here&#44; CADM1 was the target of miR-194-5p&#44; and Pearson correlation analysis revealed that there was an inverse association between CADM1 and miR-194-5p in HCC tissues&#46; In view of the above findings&#44; we speculated that miR-194-5p acted as a tumour suppressor by targeting CADM1 in HCC&#46; We also found that CADM1 was inversely correlated with LINC01006&#44; and the suppressive effects of sh-LINC01006 on the viability&#44; migration&#44; and invasion of HCC cells were reversed by pcDNA-CADM1&#46; We found that sh-LINC01006 may repress the development of HCC by modulating the miR-194-5p&#47;CADM1 axis&#46; In addition&#44; LINC01006 interaction with other regulatory axes in pancreatic cancer and prostate cancer has previously been reported &#91;<a class="elsevierStyleCrossRef" href="#bib0015">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0029">29</a>&#93;&#46; Zhang et&#160;al&#46; demonstrated that the LINC01006&#47;miR-2682-5p&#47;HOXB8 axis accelerates the tumorigenesis of pancreatic cancer and thus may be a treatment target <a class="elsevierStyleCrossRef" href="#bib0015">&#91;15&#93;</a>&#46; Ma et&#160;al&#46; showed that LINC01006 is involved in the enhancement of cell proliferation&#44; migration&#44; and invasion in prostate cancer via interaction with the miR-34a-5p&#47;DAAM1 axis <a class="elsevierStyleCrossRef" href="#bib0029">&#91;29&#93;</a>&#46; Meanwhile&#44; the functions of the miR-194-5p&#47;FOXA1 <a class="elsevierStyleCrossRef" href="#bib0019">&#91;19&#93;</a> and miR-194-5p&#47;MAPK1 axes <a class="elsevierStyleCrossRef" href="#bib0020">&#91;20&#93;</a> as well as the CADM1-Rb-E2F <a class="elsevierStyleCrossRef" href="#bib0037">&#91;37&#93;</a> and CADM1-STAT3 pathways <a class="elsevierStyleCrossRef" href="#bib0040">&#91;40&#93;</a> have been confirmed in HCC&#46; We speculated that these downstream targets and pathways may also be involved in the regulatory mechanism of LINC01006 in HCC&#46;</p><p id="para0031" class="elsevierStylePara elsevierViewall">To conclude&#44; our results uncovered that LINC01006 is upregulated in HCC tissues and cells&#46; LINC01006 directly interacts with miR-194-5p&#44; and CADM1 is targeted by miR-194-5p&#46; Mechanistically&#44; sh-LINC01006 serves as a tumour suppressor lncRNA by sponging miR-194-5p and subsequently modulating the expression of CADM1&#46; Thus&#44; our results illustrate that LINC01006 may be a promising target for HCC therapy&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Availability of data and materials</span><p id="para0032" class="elsevierStylePara elsevierViewall">The datasets used and&#47;or analyzed during the current study are available from the corresponding author on reasonable request</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Ethics approval and consent to participate</span><p id="para0033" class="elsevierStylePara elsevierViewall">The present study was authorized by the ethics committee of Weifang Yidu Central Hospital on the basis of the Declaration of Helsinki&#46; Each participant enrolled in this research had written informed consent before surgical operation&#46;</p></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Consent for publication</span><p id="para0034" class="elsevierStylePara elsevierViewall">Not applicable</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">Funding</span><p id="para0035" class="elsevierStylePara elsevierViewall">Funding information is not applicable&#46;</p></span><span id="sec0025a" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031a">CRediT authorship contribution statement</span><p id="para0035a" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Zhaoxia Sun&#58;</span> Visualization&#44; Data curation&#44; Formal analysis&#46; <span class="elsevierStyleBold">Li Zhao&#58;</span> Investigation&#44; Writing &#8211; original draft&#44; Writing &#8211; review &#38; editing&#46; <span class="elsevierStyleBold">Shuang Wang&#58;</span> Visualization&#44; Data curation&#44; Formal analysis&#44; Writing &#8211; review &#38; editing&#46; <span class="elsevierStyleBold">Honggang Wang&#58;</span> Investigation&#44; Writing &#8211; original draft&#44; Writing &#8211; review &#38; editing&#46;</p></span></span>"
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        0 => array:3 [
          "identificador" => "xres1856178"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abss0001"
              "titulo" => "Introduction and objectives"
            ]
            1 => array:2 [
              "identificador" => "abss0002"
              "titulo" => "Materials and methods"
            ]
            2 => array:2 [
              "identificador" => "abss0003"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abss0004"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1614019"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "sec0001"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "sec0002"
          "titulo" => "Materials and methods"
          "secciones" => array:11 [
            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "HCC samples"
            ]
            1 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Cell culture"
            ]
            2 => array:2 [
              "identificador" => "sec0005"
              "titulo" => "Quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;"
            ]
            3 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Cell transfection"
            ]
            4 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Dual-luciferase reporter &#40;DLR&#41; assay"
            ]
            5 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyl-2H-tetrazolium bromide &#40;MTT&#41; assay"
            ]
            6 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Wound healing assay"
            ]
            7 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Transwell assay"
            ]
            8 => array:2 [
              "identificador" => "sec0011"
              "titulo" => "Western blot"
            ]
            9 => array:2 [
              "identificador" => "sec0012"
              "titulo" => "Nude mouse tumorigenesis assay"
            ]
            10 => array:2 [
              "identificador" => "sec0013"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        4 => array:3 [
          "identificador" => "sec0014"
          "titulo" => "Results"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "LINC01006 is highly expressed in HCC tissues and cells"
            ]
            1 => array:2 [
              "identificador" => "sec0016"
              "titulo" => "Downregulation of LINC01006 suppresses the proliferation&#44; migration&#44; and invasion of HCC cells and represses HCC tumour growth in mice"
            ]
            2 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "LINC01006 acts as a sponge of miR-194-5p"
            ]
            3 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "Overexpression of miR-194-5p represses cell viability&#44; migration&#44; and invasion in HCC cells"
            ]
            4 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "CADM1 is the target of miR-194-5p"
            ]
            5 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Downregulation of LINC01006 represses cell invasion&#44; migration&#44; and proliferation by sponging miR-194-5p to modulate the expression of CADM1"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0021"
          "titulo" => "Discussion"
        ]
        6 => array:2 [
          "identificador" => "sec0022"
          "titulo" => "Availability of data and materials"
        ]
        7 => array:2 [
          "identificador" => "sec0023"
          "titulo" => "Ethics approval and consent to participate"
        ]
        8 => array:2 [
          "identificador" => "sec0024"
          "titulo" => "Consent for publication"
        ]
        9 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Funding"
        ]
        10 => array:2 [
          "identificador" => "sec0025a"
          "titulo" => "CRediT authorship contribution statement"
        ]
        11 => array:2 [
          "identificador" => "xack654237"
          "titulo" => "Acknowledgments"
        ]
        12 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-03-08"
    "fechaAceptado" => "2021-05-21"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1614019"
          "palabras" => array:4 [
            0 => "Hepatocellular carcinoma"
            1 => "LINC01006"
            2 => "miR-194-5p"
            3 => "CADM1"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Introduction and objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Long non-coding RNAs &#40;lncRNAs&#41; have great potential as therapeutic targets in hepatocellular carcinoma &#40;HCC&#41;&#46; In this study&#44; we aimed to uncover the function and molecular mechanism of long intergenic non-protein coding RNA 1006 &#40;LINC01006&#41; in HCC&#46;</p></span> <span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Materials and methods</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">Mice were injected with HCC cells in order to establish the HCC model&#46; Quantitative reverse transcription polymerase chain reaction was used to determine the expression levels of LINC01006&#44; cell adhesion molecule 1 &#40;CADM1&#41;&#44; and microRNA &#40;miR&#41;-194-5p in HCC tissues and cells&#46; The cell proliferation&#44; invasion&#44; and migration abilities were assessed by 3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyl-2H-tetrazolium bromide&#44; transwell&#44; and wound healing assays&#46; The interrelation between LINC01006&#44; miR-194-5p&#44; and CADM1 was confirmed by a dual-luciferase reporter assay&#46; Western blotting was employed to assess the relative protein expression level of CADM1&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">LINC01006 and CADM1 displayed upregulation&#44; but miR-194-5p exhibited downregulation in HCC cells and tissues&#46; Short hairpin &#40;sh&#41;-LINC01006 and miR-194-5p mimics repressed the proliferative&#44; migratory&#44; and invasive capacities of HCC cells&#44; and injection of sh-LINC01006 restrained the growth of HCC tumours in mice&#46; LINC01006 served as a competing endogenous RNA of miR-194-5p and was inversely correlated with miR-194-5p&#46; CADM1 was targeted by miR-194-5p&#44; inversely correlated with miR-194-5p&#44; and positively associated with LINC01006&#46; Furthermore&#44; transfection of pcDNA-CADM1 or the miR-194-5p inhibitor reversed the suppressive effects of sh-LINC01006 on the proliferation&#44; invasion&#44; and migration abilities of HCC cells&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Conclusions</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">Downregulation of LINC01006 repressed the development of HCC by sponging miR-194-5p to modulate the expression of CADM1&#44; implying its potential as a therapeutic target for HCC&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abss0001"
            "titulo" => "Introduction and objectives"
          ]
          1 => array:2 [
            "identificador" => "abss0002"
            "titulo" => "Materials and methods"
          ]
          2 => array:2 [
            "identificador" => "abss0003"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abss0004"
            "titulo" => "Conclusions"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">LINC01006 was highly expressed in hepatocellular carcinoma &#40;HCC&#41; tissues and HCC cells&#46; &#40;A&#41; Relative expression of LINC01006 in tumour tissues and adjacent normal tissues was determined by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#44; vs&#46; Adjacent normal tissues&#46; &#40;B&#41; Relative expression of LINC01006 at tumour node metastasis &#40;TNM&#41; stage I&#47;II and TNM stage III&#47;IV was determined by qRT-PCR in tumour&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; I&#47;II&#46; &#40;C&#41; Relative expression of LINC01006 in HepG2&#44; SMMC-7721&#44; Hep3B&#44; Sk-Hep1 and LO2 cells was determined by qRT-PCR&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; LO2&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Knockdown of LINC01006 suppressed cell viability&#44; migration and invasion in hepatocellular carcinoma &#40;HCC&#41; cells&#44; and repressed tumour growth in mice&#46; &#40;A&#41; Relative expression of LINC01006 in Hep3B and Sk-Hep1 cells after transfection with shRNA-LINC01006-1 &#40;sh-LINC01006-1&#41;&#44; sh-LINC01006-2 and shRNA negative control &#40;sh-NC&#41; was detected by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; &#40;B&#41; Cell viability in Hep3B and Sk-Hep1 cells was detected by 3-&#40;4&#44; 5-Dimethyl-2-Thiazolyl&#41;-2&#44; 5-Diphenyl-2-H-Tetrazolium Bromide &#40;MTT&#41; assay&#46; &#42;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#44; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; &#40;C&#41; Wound healing rate of Hep3B and Sk-Hep1 cells was detected by wound healing assay&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; &#40;D&#41; Number of invasion cells in Hep3B and Sk-Hep1 cells was detected by transwell assay&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; &#40;E&#41; Three representative images of solid tumours&#44; and the growth of tumours in mice injected with Hep3B cells transfected with Lentivirus vector carrying sh-LINC01006-1 &#40;Lv-sh-LINC01006-1&#41; or Lv-sh-NC&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; Lv-sh-NC&#46;</p>"
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">LINC01006 acted as a sponge of miR-194-5p&#46; &#40;A&#41; The binding sequence between LINC01006 and miR-194-5p was predicted by LncBase Predicted v&#46;2&#46; &#40;B&#41; Relative expression of miR-194-5p in Hep3B and Sk-Hep1 cells was detected by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; &#40;C&#41; The interaction between LINC01006 and miR-194-5p in Hep3B and Sk-Hep1 cells was confirmed by dual-luciferase reporter &#40;DLR&#41; assay&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-negative control &#40;NC&#41;&#46; &#40;D&#41; Relative expression of miR-194-5p was detected by qRT-PCR in tumour tissues and adjacent normal tissues&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#44; vs&#46; Adjacent normal tissues&#46; &#40;E&#41; Correlation analysis of LINC01006 and miR-194-5p in hepatocellular carcinoma &#40;HCC&#41; tissues&#46; <span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;0009&#46; &#40;F&#41; Relative expression of miR-194-5p in HepG2&#44; Hep3B&#44; SMMC-7721&#44; Sk-Hep1 and LO2 cells was determined by qRT-PCR&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; LO2&#46;</p>"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Overexpression of miR-194-5p repressed cell viability&#44; migration and invasion in hepatocellular carcinoma &#40;HCC&#41; cells&#46; &#40;A&#41; Relative expression of miR-194-5p in Hep3B and Sk-Hep1 cells was detected by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-NC&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#35;&#35;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; inhibitor NC&#46; &#40;B&#41; Cell viability in Hep3B and Sk-Hep1 cells was determined by 3-&#40;4&#44; 5-Dimethyl-2-Thiazolyl&#41;-2&#44; 5-Diphenyl-2-H-Tetrazolium Bromide &#40;MTT&#41; assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-negative control &#40;NC&#41;&#46; &#40;C&#41; Wound healing rate of Hep3B and Sk-Hep1 cells was determined by wound healing assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-NC&#46; &#40;D&#41; Number of invasion cells in Hep3B and Sk-Hep1 cells was detected by transwell assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-NC&#46;</p>"
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        "mostrarFloat" => true
        "mostrarDisplay" => false
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            "imagen" => "gr5.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">CADM1 was target gene of miR-194-5p&#46; &#40;A&#41; The binding sites between CADM1 and miR-194-5p were predicted by LncBase Predicted v&#46;2&#46; &#40;B&#41; Dual-luciferase reporter &#40;DLR&#41; assay was used for confirming the relationship between miR-194-5p and CADM1 in Hep3B and Sk-Hep1 cells&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-negative control &#40;NC&#41;&#46; &#40;C&#41; Relative protein expression of CADM1 in Hep3B and Sk-Hep1 cells was detected by western blot&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; miR-NC&#46; &#40;D&#41; Relative expression of CADM1 in hepatocellular carcinoma &#40;HCC&#41; tissues and non-cancerous tissues from the cancer genome atlas &#40;TCGA&#41; database&#46; &#42;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#44; vs&#46; Non-cancerous tissues&#46; LIHC&#58; liver hepatocellular carcinoma&#46; &#40;E&#41; Quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41; was used to detect relative expression of CADM1 in tumour tissues and adjacent normal tissues&#46; <span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;001&#44; vs&#46; Adjacent normal tissues&#46; &#40;F&#41; The relationship between LINC01006 and CADM1 in HCC tissues was analyzed by Pearson&#39;s correlation analysis&#46; &#40;G&#41; The relationship between CADM1 and miR-194-5p in HCC tissues was analyzed by Pearson&#39;s correlation analysis&#46; &#40;H&#41; Relative expression of CADM1 in HepG2&#44; Hep3B&#44; SMMC-7721&#44; Sk-Hep1 and LO2 cells was determined by western blot&#46; <span class="elsevierStyleSup">&#8270;&#8270;</span><span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; LO2&#46;</p>"
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          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Knockdown of LINC01006 inhibited cell invasion&#44; migration and proliferation by sponging miR-194-5p to modulate the expression of CADM1&#46; &#40;A&#41; Relative expression of CADM1 in Hep3B cells was detected by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; pcDNA-NC&#46; &#40;B&#41; Cell viability in Hep3B cells was determined by 3-&#40;4&#44; 5-Dimethyl-2-Thiazolyl&#41;-2&#44; 5-Diphenyl-2-H-Tetrazolium Bromide &#40;MTT&#41; assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-negative control &#40;NC&#41;&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#35;&#35;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-LINC01006-1&#46; &#40;C&#41; Wound healing rate of Hep3B cells was determined by wound healing assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#35;&#35;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-LINC01006-1&#46; &#40;D&#41; Number of invasion cells in Hep3B cells was detected by transwell assay&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#8270;&#8270;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-NC&#46; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">&#35;&#35;</span>P</span>&#160;&#60;&#160;0&#46;01&#44; vs&#46; sh-LINC01006-1&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Forward&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reverse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0004"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">LINC01006&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-TTTGTGGTGGTGAAGACGTG-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-TCCTCAAGAATAAGGAACATAGGC-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">MiR-194-5p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-GCCGCTGTAACAGCAACTCCAT-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-GTGCAGGGTCCGAGGT-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">CADM1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-TGCTGTGCTTGCTCATCATTCT-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;- TCTGCGTCTGCTGCGTCAT-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">GAPDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-CAGGAGGCATTGCTGATGAT -3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#8217;-GAAGGCTGGGGCTCATTT-3&#8217;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Primers for qRT-PCR in this study&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0008"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara009" class="elsevierStyleSimplePara elsevierViewall">Note&#58; &#42;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#44; WHO&#58; world health organization&#44; TNM &#58; tumour node metastasis&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0016"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable</th><a name="en0017"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total</th><a name="en0018"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top" scope="col">LINC01006 expression</th><a name="en0019"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>-value</th></tr><tr title="table-row"><a name="en0022"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Low&#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0023"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">High&#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;662&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;684&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60; 60years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8805; 60 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Diameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;332&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60; 6 cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0061"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8805; 6 cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0070"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0073"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;015&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">YES&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">TNM stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;028&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0090"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">III&#47;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Clinical parameters of the patients with HCC who were included in this study&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2021.100571

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	10	0	10
2024 October	33	2	35
2024 September	30	5	35
2024 August	27	4	31
2024 July	32	4	36
2024 June	31	3	34
2024 May	29	4	33
2024 April	44	5	49
2024 March	75	7	82
2024 February	61	5	66
2024 January	30	17	47
2023 December	31	9	40
2023 November	47	6	53
2023 October	35	13	48
2023 September	30	1	31
2023 August	24	4	28
2023 July	22	3	25
2023 June	24	2	26
2023 May	48	4	52
2023 April	46	3	49
2023 March	44	1	45
2023 February	49	3	52
2023 January	42	5	47
2022 December	32	3	35
2022 November	19	8	27
2022 October	22	5	27
2022 September	19	10	29
2022 August	16	11	27
2022 July	17	12	29
2022 June	19	11	30
2022 May	19	7	26
2022 April	34	15	49
2022 March	27	19	46
2022 February	25	4	29
2022 January	57	8	65
2021 December	24	13	37
2021 November	8	9	17
2021 October	1	4	5

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