Long noncoding RNA LINC01189 is associated with HCV-hepatocellular carcinoma and regulates cancer cell proliferation and chemoresistance through hsa-miR-155-5p

array:24 ["pii" => "S1665268120301848" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.09.013" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "269" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2021;22C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S166526812030185X" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.09.014" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "270" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2021;22C:" "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" => "Renal and brain failure predict mortality of patients with acute-on-chronic liver failure admitted to the intensive care unit" "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" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1785 "Ancho" => 3175 "Tamanyo" => 303687 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Kaplan–Meier survival curve in patients based on the type of organ failure. Patients with the following organ failures (A) brain failure (B) circulatory failure (C) liver failure (D) renal failure and (E) coagulation failure, have lower survival (log rank, p:0.001) - (log rank, p:0.02) compared to those without any of these organs. (F) No differences were found between patients with lung failure and those without (log rank, p:0.415)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Osvely Méndez-Guerrero, Daniel A. Calle-Rodas, Eduardo Cervantes-Alvarez, Elisa Alatorre-Arenas, Juanita Pérez-Escobar, Nalu Navarro-Alvarez, Aldo Torre" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Osvely" "apellidos" => "Méndez-Guerrero" ] 1 => array:2 [ "nombre" => "Daniel A." "apellidos" => "Calle-Rodas" ] 2 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Cervantes-Alvarez" ] 3 => array:2 [ "nombre" => "Elisa" "apellidos" => "Alatorre-Arenas" ] 4 => array:2 [ "nombre" => "Juanita" "apellidos" => "Pérez-Escobar" ] 5 => array:2 [ "nombre" => "Nalu" "apellidos" => "Navarro-Alvarez" ] 6 => array:2 [ "nombre" => "Aldo" "apellidos" => "Torre" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S166526812030185X?idApp=UINPBA00004N" "url" => "/16652681/000000220000000C/v3_202107300613/S166526812030185X/v3_202107300613/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268120302027" "issn" => "16652681" "doi" => "10.1016/j.aohep.2020.10.005" "estado" => "S300" "fechaPublicacion" => "2021-05-01" "aid" => "277" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2021;22C:" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Health-related quality of life in Cuban patients with chronic liver disease: A real-world experience" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "en" ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 899 "Ancho" => 2925 "Tamanyo" => 144440 ] ] "descripcion" => array:1 [ "en" => "Independent association of Chronic Liver Disease etiology with PRO scores measured by FACIT-F (A) and WPAI: SHP (B) (adjusted for clinic-demographic factors from <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Marlen I. Castellanos-Fernández, Susana A. Borges-González, Maria Stepanova, Mirtha E. Infante-Velázquez, Caridad Ruenes-Domech, Sila M. González-Suero, Zaily Dorta-Guridi, Enrique R. Arus-Soler, Andrei Racila, Zobair M. Younossi" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Marlen I." "apellidos" => "Castellanos-Fernández" ] 1 => array:2 [ "nombre" => "Susana A." "apellidos" => "Borges-González" ] 2 => array:2 [ "nombre" => "Maria" "apellidos" => "Stepanova" ] 3 => array:2 [ "nombre" => "Mirtha E." "apellidos" => "Infante-Velázquez" ] 4 => array:2 [ "nombre" => "Caridad" "apellidos" => "Ruenes-Domech" ] 5 => array:2 [ "nombre" => "Sila M." "apellidos" => "González-Suero" ] 6 => array:2 [ "nombre" => "Zaily" "apellidos" => "Dorta-Guridi" ] 7 => array:2 [ "nombre" => "Enrique R." "apellidos" => "Arus-Soler" ] 8 => array:2 [ "nombre" => "Andrei" "apellidos" => "Racila" ] 9 => array:2 [ "nombre" => "Zobair M." "apellidos" => "Younossi" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Patient reported outcomes (PROs) are important to understanding the impact a disease from the patients’ point of view.</li><li class="elsevierStyleListItem" id="lsti0010">•Chronic liver disease (CLD) can carry a high clinical and PRO burden.</li><li class="elsevierStyleListItem" id="lsti0015">•PRO data are few among patients with CLD who reside in the Latin America and the Caribbean areas.</li><li class="elsevierStyleListItem" id="lsti0020">•Using valid and reliable PRO instruments, we quantified PROs for patients with CLD living in Cuba.</li><li class="elsevierStyleListItem" id="lsti0025">•We determined that patients from Cuba with hepatitis C virus and autoimmune liver disease had the worst PRO scores most likely related to more severe underlying liver disease (fibrosis) and/or to extrahepatic manifestations (fatigue, abdominal pain, anxiety, and depression).</li></ul>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268120302027?idApp=UINPBA00004N" "url" => "/16652681/000000220000000C/v3_202107300613/S1665268120302027/v3_202107300613/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Long noncoding RNA LINC01189 is associated with HCV-hepatocellular carcinoma and regulates cancer cell proliferation and chemoresistance through hsa-miR-155-5p" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ying Yao, Fang Shu, Fang Wang, Xiaoqiang Wang, Zhengshe Guo, Haili Wang, Lu Li, Haigang Lv" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Ying" "apellidos" => "Yao" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Fang" "apellidos" => "Shu" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] 2 => array:3 [ "nombre" => "Fang" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Xiaoqiang" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Zhengshe" "apellidos" => "Guo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Haili" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Lu" "apellidos" => "Li" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 7 => array:4 [ "nombre" => "Haigang" "apellidos" => "Lv" "email" => array:1 [ 0 => "doctorlhg@aol.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Anaesthesiology department, Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054, Shaanxi, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Clinical laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054 Shaanxi, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA, 91010, USA" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Clinical laboratory, Third Hospital of Xi’an, 710000, Shaanxi, China" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3260 "Ancho" => 2326 "Tamanyo" => 320838 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01189 attaches to hsa-miR-155-5p. (A) Two DNA sequences on wild-type LINC01189 3’-UTR were predicted to attach to hsa-miR-155-5p. The binding sites were then point-mutated. (B) The wild type and mutant LINC01189 3’-UTRs were used to generate two luciferase reporter vectors, WT_1189 and MU_1189. Then, hsa-miR-155-5p mimics (mimics_miR155) or a non-specific miRNA mimics (mimics_NS) were co-transfected with WT_1189 or MU_1189 in human HEK293T cells. And a dual-luciferase activity assay was conducted 48h later. (C) In pc_1189- or pc_NS- transfected Huh7 and Hep3B cells, qRT-PCR was performed to compare hsa-miR-155-5p expressions levels (* P<0.05)." ] ] ] "textoCompleto" => "1IntroductionHepatocellular carcinoma (HCC) is one of the most commonly diagnosed and most malignant types of liver cancers worldwide. In USA, there are approximately 42,000 newly diagnosed cases of liver cancers and more than 30,000 associated deaths every year [<a class="elsevierStyleCrossRef" href="#bib0005">1</a>]. In China, liver cancer is the fourth-most diagnosed cancer (>390,000 cases / year) and third-most cause of cancer-related mortality (>360,000 cases / year) in both male and female patients [<a class="elsevierStyleCrossRef" href="#bib0010">2</a>,<a class="elsevierStyleCrossRef" href="#bib0015">3</a>]. While various risk factors may be associated with HCC or other liver cancer subtypes, the most common conditions for patients to eventually develop into HCC are hepatitis B virus (HBV) or hepatitis C virus (HCV) infections [<a class="elsevierStyleCrossRef" href="#bib0020">4</a>,<a class="elsevierStyleCrossRef" href="#bib0025">5</a>].Long noncoding RNAs (lncRNAs) are families of long (>200 nucleotides) and non-protein-coding transcripts that had been recently shown to exert broad ranges of regulatory roles in various types of human disease [<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0035">7</a>]. Specifically, lncRNAs have been demonstrated to be aberrantly expressed, and exert promoting or suppressing functions in many types of human cancers [<a class="elsevierStyleCrossRef" href="#bib0040">8</a>,<a class="elsevierStyleCrossRef" href="#bib0045">9</a>]. Recently, a genomic study conducted by Yang and colleagues showed that there might be more than 1,000 lncRNAs that are recurrently deregulated in HCC [<a class="elsevierStyleCrossRef" href="#bib0050">10</a>]. In addition, prognostic and functional roles of lncRNAs had been revealed in HCC [<a class="elsevierStyleCrossRef" href="#bib0055">11</a>,<a class="elsevierStyleCrossRef" href="#bib0060">12</a>]. Particularly, it has been noticed that lncRNAs may be closely associated with HCV progression and the pathological development of HCC among patients with chronic liver diseases [<a class="elsevierStyleCrossRef" href="#bib0065">13</a>,<a class="elsevierStyleCrossRef" href="#bib0070">14</a>].Similar to lncRNAs, microRNAs (miRNAs) are other families of non-protein-coding, but short (∼20 nucleotides) transcripts that are also shown to be aberrantly expressed and playing critical roles in human cancer development [<a class="elsevierStyleCrossRef" href="#bib0075">15</a>,<a class="elsevierStyleCrossRef" href="#bib0080">16</a>]. Moreover, new lines of evidence have demonstrated that lncRNAs could act as competing endogenous RNAs (ceRNAs) of miRNAs, so that the transcriptional regulations of lncRNAs-miRNAs axes could have even more significant impacts on regulating cancer cell oncogenesis, progression, apoptosis and metastasis [<a class="elsevierStyleCrossRef" href="#bib0085">17</a>,<a class="elsevierStyleCrossRef" href="#bib0090">18</a>].In the current work, we examined the expression of a newly identified lncRNA, LINC01189 in HCC and its correlation with HCV-infected HCC. We also ectopically overexpressed LINC01189 in HCC cancer cells to study its functions on HCV-associated HCC proliferation and 5-FU chemoresistance. In addition, we studied the possible ceRNA candidate of LINC01189, hsa-miR-145-5p in HCC. The goal of this work is to further our understanding on the epigenetic regulation of lncRNA in HCC.2Materials and methods2.1HCC human samplesA total of 67-paired hepatocellular carcinoma (HCC) tissues and surrounding non-tumorous tissues were obtained from the participating hospital. Among the HCC tissues, 21 were diagnosed with hepatitis C virus (HCV) infection. Human samples were immediately snap-frozen with liquid nitrogen and then stored at −75°C, until further processing.2.2HCC cell lines and HCV-infectionHCC cell lines of HeG2, HuH7 and Hep3B were purchased from the American Type Culture Collection (ATCC, USA), and incubated in GlutaMAX-RPMI 1640 Medium (Thermo Fisher Scientific, USA) supplemented with 10% fetal bovine serum (FBS, Beyotime, China) and 1X Penicillin-Streptomycin (10,000 U/ml, Thermo Fisher Scientific, USA) in a humidified environment at 37°C with 5% CO2.The method of infecting HCC cell line with HCV was described in a previous publication with slight modifications [<a class="elsevierStyleCrossRef" href="#bib0095">19</a>]. Briefly, HepG2 cells were cultured in FBS-free medium and inoculated with human serum collected from HCV-infected patients. After 2hours, HepG2 cells were replenished with FBS-containing medium, supplemented with 4% polyethylene glycol (Beyotime, China) and cultured for another 24hours. QRT-PCR was then performed to examine the infection efficacy of HCV viral RNA.2.3RNA extraction and quantitative real time-PCRTotal RNA was extracted and purified using a PureLink™ Pro 96 total RNA Purification Kit (Thermo Fisher Scientific, USA) according to the manufacturer’s recommendation. The quality of RNA were verified using a Vairoskan Lux uDrop kit (Thermo Fisher Scientific, USA), and reverse transcription was performed using a SuperScript™ VILO™ cDNA Synthesis Kit (Invitrogen, USA) according to the manufacturer’s recommendations. An ABI PRISM® 7000 Sequence Detection System (Applied Biosystems, USA) was used for quantitative real time-PCR (qRT-PCR). To quantitatively compare HCV viral RNA, the method was described in the previous publication [<a class="elsevierStyleCrossRef" href="#bib0095">19</a>]. To compare lncRNA LINC01189 expression level, a customized TaqMan™ noncoding RNA Assay (Invitrogen, USA) was used. To measure hsa-miR-155-5p expression level, a customized TaqMan™ microRNA Assay (Invitrogen, USA) was used. Finally, the relative expression levels were calculated by the 2(−ΔΔCt) method.2.4LINC01189 upregulation and downregulation assayThe whole sequence of human LINC01189 was amplified and sub-cloned into the pcDNA/3.4 plasmid (Addgene, USA) to generated a LINC01189 overexpressing vector, pc_1189. An empty pcDNA/3.4 plasmid (Addgene, USA) was used as the non-specific overexpression vector, pc_NS in this study. Alternatively, a siRNA specifically targeting human LINC01189, si_1189 and a non-specific lncRNA siRNA, si_NS, were designed and manufactured by GenePharma (Shanghai GenePharma, Shanghai, China). In Hu7, Hep3B, and HCV-infected HepG2 (HepG2-HCV) cells, they were transfected with pc_1189, pc_NS, si_1189 and si_NS for 48hours using the Lipofectamine 3000 transfection reagent (Thermo Fisher Scientific, USA). After that, qRT-PCR was performed to examine the transfection efficacies.2.5Proliferation assayHCC cell proliferation was measured using a CCK-8 Assay (Dojindo, Japan) according to the manufacturer’s recommendation. With the application of a highly water-soluble tetrazolium salt, WST-8, this assay produces a water-soluble formazan dye upon reduction in the presence of an electron mediator, thus providing quantitative method to assess proliferating cells in the culture. To do so, HCC cells were cultured in a 96-well plate, with a starting density of 1500 cells /well, for 5 days. Every 24h, CCK-8 reagent (10μL) was mixed into tested wells for 2hours at 37 C. Then, proliferating rates were directly estimated by measuring the optical absorbance at 570nm using a Varioskan Lux microplate reader (Thermo Fisher Scientific, USA) according to the manufacturer’s recommendation.2.65-FU chemoresistance assayThe method of examining HCC fluorouracil (5-FU) chemoresistance was described in a previous publication with slight modification [<a class="elsevierStyleCrossRef" href="#bib0100">20</a>]. Briefly, HCC cells were cultured in a 96-well plate, with a starting density of 5,000 cells /well. 5-FU was added into cell culture at concentration (μM) of 0, 2, 5, 10, 20 for 48h. The relative cell viability was then measured using the CCK-8 assay.2.7Dual-luciferase reporter assayUsing online bioinformatics database of StarBase 2.0 [<a class="elsevierStyleCrossRef" href="#bib0105">21</a>], we identified two DNA sequences on LINC01189 3’-UTR that might be putative binding sites for human microRNA-155-5p (hsa-miR-155-5p). We thus constructed two pmiR-RB-REPORT vectors (Shanghai GenePharma, Shanghai, China), one containing the wild-type (WT) LINC01189 3’-UTR (WT_1189), and the other containing a mutant LINC01189 3’-UTR (MU_1189) to deactivate hsa-miR-155-5p binding. In addition, a synthetic hsa-miR-155-5p mimics (mimics_miR155) and a non-specific human miRNA mimics (mimics-NS) were commercially bought from GenePharma (Shanghai GenePharma, Shanghai, China). Then, a dual-luciferase reporter assay was conducted using the method described in our previous publication [<a class="elsevierStyleCrossRef" href="#bib0110">22</a>].2.8Hsa-miR-155-5p overexpression assayIn Huh7 and Hep3B cells which were pre-transfected with pc_1189, they were secondary transfected with mimics_miR155 or mimics-NS using the Lipofectamine 3000 reagent for 48h. QRT-PCR was then performed to examine the overexpression efficacy.2.9Statistical analysisAll experiments were performed in at least three independent repeats. The averaged data were presented as mean±standard error of mean (mean±S.E.M.). One-way analysis of variance (ANOVA) followed by Tukey’s multiple-comparison tests in a SPSS software (SPSS, version 16.0, USA) was used for all analysis. Significance was set at 0.05 for all statistical tests.3Results3.1LINC01189 is lowly expressed in HCV-infected HCC tumors and cell linesWe used qRT-PCR to detect the expression pattern of LINC01189 in HCC tumors and cell lines. It was demonstrated that LINC01189 expression is markedly lower in HCC tumors than in adjacent tissues (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A, * P<0.05). In addition, LINC01189 expression was even lower in HCC tumors with HCV-infected (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A, ** P<0.05).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Next, HCC cell line of HepG2 was infected with HCV virus. QRT-PCR confirmed that HCV RNA expression was significantly upregulated in HCV-infected HepG2 cells (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B, * P< 0.05; Note: expression level of 100% was based on arbitrary value). On the other hand, LINC01189 expressed at a much lower level in HCV-infected HepG2 cells (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C, * P<0.05).Thus, these data indicated that LINC01189 downregulation may be closely associated with HCV infection in HCC.3.2LINC01189 overexpression inhibited proliferation in HCV-infected HCC cell linesWe either overexpressed or downregulated LINC01189 in HCV-infected HepG2 cells. The result of qRT-PCR showed that, in cells transfected with pc_1189, endogenous LINC01189 expression was much higher than in cells transfected with pc_NS, confirming the overexpression strategy (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A, * P<0.05). However, LINC01189 expression levels were not different between cells transfected Si_1189 and Si_NS, indicating that LINC01189 was unable to be downregulated in HCV-infected HepG2 cells (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B, Δ P>0.05). Then, a CKK-8 assay was conducted for 5 consecutive days to compare proliferation between pc_1189- and pc_NS- transfected HCV-HepG2 cells. It showed that LINC01189 overexpression significantly inhibited proliferation in HCV-infected HCC cells. (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C, * P<0.05).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>3.3LINC01189 overexpression reduced HCC proliferation and chemoresistanceTo further investigate the effects of LINC01189 on HCC development, we either overexpressed or downregulated LINC01189 in two HCC cell lines, Huh7 and Hep3B. In one set of experiments, HCC cells were transfected with either pc_1189 or p_NS. QRT-PCR showed that, in HCC cells transfected with pc_1189, endogenous LINC01189 expression was much higher than in those transfected with pc_NS (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A, * P< 0.05). In the other set of experiments, Huh7 and Hep3B were transfect with either si_1189 or si_NS. This time, qRT-PCR did not show significantly difference in endogenous LINC01189 expressions (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B, Δ P>0.05), suggesting that genetic modification was unable to knock down LINC01189 in Huh7 or Hep3B cells.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Then, pc_1189- or pc_NS- transfected Huh7 and Hep3B were examined by the CKK-8 assay for 5 days. It showed that LINC01189 overexpression markedly reduced proliferation in HCC cells (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>C, * P<0.05).In addition, pc_1189- or pc_NS- transfected Huh7 and Hep3B were treated by low-to-high concentrations of 5-FU to compare their chemoresistance. The results showed that LINC01189 overexpression also significantly reduced 5-FU chemoresistance in HCC cells (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>D, * P<0.05).3.4Hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 in HCCWe then explored the downstream ceRNA candidates of LINC01189. Through bioinformatics research (StarBase 2.0) [<a class="elsevierStyleCrossRef" href="#bib0105">21</a>], it was noticed that human microRNA-155-5p (hsa-miR-155-5p) may be attached to two complementary DNA sequences in the 3′-UTR of LINC01189 (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A). Based on this information, two luciferase reporters were constructed. One included the wild type LINC01189 3’-UTR, WT_1189. The other included a mutant LINC01189 3’-UTR, MU_1189, with hsa-miR-155-5p binding sequences point-mutated. Then, in a dual-luciferase activity assay, it was confirmed that hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B, * P<0.05; Δ P>0.05). Moreover, in Huh7 and Hep3B cells transfected with pc_1189, qRT-PCR demonstrated that their endogenous hsa-miR-155-5p expression levels were significantly lower than in HCC cells transfected with pc_NS (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C, * P<0.05).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>3.5Upregulating hsa-miR-155-5p reversed the inhibitory effects of LINC01189 in HCCFinally, we investigated the functional relationship between hsa-miR-155-5p and LINC01189 in HCC. In Huh7 and Hep3B cells transfected with pc_1189, we double-transfected them with mimics_miR155 to upregulate hsa-miR-155-5p expression. QRT-PCR demonstrated that, as compared to mimics_NS transfection, mimics_miR155 transfection significantly drove up hsa-miR-155-5p expressions in pc_1189-overexpressed HCC cells (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>A, * P< 0.05).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Then, double-transfected Huh7 and Hep3B were examined by the CKK-8 assay for 5 days. It showed that upregulating hsa-miR-155-5p markedly promoted proliferation in LINC01189-overexpessed HCC cells (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>C, * P<0.05).In addition, double-transfected Huh7 and Hep3B were examined by the 5-FU chemoresistance assay. The results showed that upregulating hsa-miR-155-5p significantly increased 5-FU chemoresistance in LINC01189-overexpessed HCC cells (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>D, * P< 0.05).4DiscussionsEmerging evidence has demonstrated that, lncRNAs may play critical roles in various aspects of human liver diseases, including chronic HCV infection, fibrosis and HCC [<a class="elsevierStyleCrossRefs" href="#bib0060">12–14</a>,<a class="elsevierStyleCrossRef" href="#bib0115">23</a>]. In the current study, the main focus was to investigate the expression and functions of a novel lncRNA, LINC01189 in HCC. In a very recent clinical study, it was demonstrated that LINC01189 was aberrantly regulated in peripheral blood mononuclear cells of patients with rheumatoid arthritis, suggesting that LINC01189 may be a potential biomarker for rheumatoid arthritis [<a class="elsevierStyleCrossRef" href="#bib0120">24</a>]. Other than that, the expressing pattern or regulatory effects of LINC01189 in other human diseases have never been elucidated, thus very much highlighting the clinical significance and importance of our study.Firstly in the current study, we applied quantitative qRT-PCR to measure LINC01189 expression pattern in HCC tumors, as well as HCV-infected HCC tumors and cell lines. We discovered that LINC01189 was predominantly downregulated in HCC, especially in HCV-infected HCC tumors and cell lines. Particularly, we discovered that ectopically overexpressing LINC01189 could functionally regulation proliferation in HCV-infected HCC cancer cells. In an early study, Diaz and colleagues indicated that epigenetic transcripts, miRNAs were closely correlated with HCV-related HCC [<a class="elsevierStyleCrossRef" href="#bib0065">13</a>]. In another study, it was demonstrated that lncRNA of LINC01419 was drastically upregulated in Hepatitis B Virus- and HCV-associated HCCs [<a class="elsevierStyleCrossRef" href="#bib0065">13</a>]. Along with the discovery in our study, it’s becoming more obvious that epigenetic factors, including miRNAs and lncRNAs, may have profound roles in the development of HCV-related HCC.An interesting observation in the current study is that, we were not able to knock down LINC01189 expression in HCC cell lines, either with or without HCV infection. One may suspect that the reason we did not observe LINC01189 downregulation after siRNA transfection was due to technique difficulty. Several lines of evidence argue against it. First, while we manufactured the LINC01189-specific siRNA, we did not use single siRNA. Instead, we mixed four different siRNAs aiming at different targets on LINC01189, which was confirmed by the manufacturer to be able to efficiently knock down >∼85% gene expression of LINC01189 in various types of hosting cells (data not shown). Second, besides siRNA, we also tried other downregulating strategies, such as lentiviral transfection of short hair-pin RNAs (shRNAs). However, we discovered a large portion of transfected HCC cells was apoptotic or dead that we could not efficiently maintain them in the culture. Thus, while we could not rule out the possibility that other technique manipulations may achieve the goal of LINC01189 downregulation in HCC cell lines, the possible explanation for the obtained results might be that LINC01189 was already maximally suppressed (or at the minimal level of expression), that any downregulation approach may not be sustainable to maintain cell health. On the other hand, it is worth-noting that, our strategy of overexpressing LINC01189 was a success, which allowed us to reveal functional roles of LINC01189 in regulating cancer cell development in both HCV-related and HCV-unrelated manners, a novel discovery of biological implication of LINC01189 in human diseases.Another important finding of our study is that we demonstrated that LINC01189 acted as a ceRNA to regulate downstream target of hsa-miR-155-5p in HCC. Dual-luciferase assay and qRT-PCR assay demonstrated that LINC01189 did attach to hsa-miR-155-5p, and inhibited hsa-miR-155-5p in HCC cells. Moreover, we showed that LINC01189 -mediated inhibition on cancer cell proliferation and 5-FU chemoresistance were reversed by hsa-miR-155-5p upregulation, thus indicating the functional role of epigenetic axis of LINC01189 / hsa-miR-155-5p in regulating HCC development. In previous studies, the prognostic implication and functional roles of hsa-miR-155 in HCC were well-documented [<a class="elsevierStyleCrossRefs" href="#bib0125">25–27</a>]. However, the current work is the first study to reveal a possible upstream regulatory mechanism of hsa-miR-155-5p. Future works, possibly focusing on the downstream upregulated or downregulated signaling pathways of LINC01189 / hsa-miR-155-5p axis may further broaden our understanding on underlying mechanisms of modulations in HCC.Ethics statementIn this study, the ethics approval was obtained from the Medical Research and Ethics Committees at the Xi’an Jiaotong University Medical College Red Cross hospital in Xi’an, Shaanxi, China. Consent forms were signed by all participating patients. Clinical and experimental procedures were performed according to the guideline of the WMA Declaration of Helsinki — ethical principles for medical research involving human subjects (<a href="https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/">https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/</a>).Conflict of InterestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1555527" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients or Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1403993" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1403994" "titulo" => "Abbreviations" ] 3 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "HCC human samples" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "HCC cell lines and HCV-infection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "RNA extraction and quantitative real time-PCR" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "LINC01189 upregulation and downregulation assay" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Proliferation assay" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "5-FU chemoresistance assay" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Dual-luciferase reporter assay" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Hsa-miR-155-5p overexpression assay" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Statistical analysis" ] ] ] 5 => array:3 [ "identificador" => "sec0060" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "LINC01189 is lowly expressed in HCV-infected HCC tumors and cell lines" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "LINC01189 overexpression inhibited proliferation in HCV-infected HCC cell lines" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "LINC01189 overexpression reduced HCC proliferation and chemoresistance" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 in HCC" ] 4 => array:2 [ "identificador" => "sec0085" "titulo" => "Upregulating hsa-miR-155-5p reversed the inhibitory effects of LINC01189 in HCC" ] ] ] 6 => array:2 [ "identificador" => "sec0090" "titulo" => "Discussions" ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Ethics statement" ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Conflict of Interest" ] 9 => array:2 [ "identificador" => "xack548174" "titulo" => "Acknowledgement" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-08-25" "fechaAceptado" => "2020-09-22" "PalabrasClave" => array:1 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1403993" "palabras" => array:5 [ 0 => "HCV" 1 => "HCC" 2 => "lncRNA" 3 => "LINC01189" 4 => "hsa-miR-155-5p" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1403994" "palabras" => array:4 [ 0 => "lncRNA" 1 => "HCV" 2 => "HCC" 3 => "ceRNA" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and ObjectivesEmerging evidence has demonstrated that long noncoding RNAs (lncRNAs) may be closely associated with Hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC). In this study, we investigated the expression and functions of a lncRNA, LINC01189, in HCV-associated HCC. Patients or Materials and MethodsLINC01189 expression was measured in HCC tumors, HCV-infected HCC tumors and HCV-infected HCC cells. LINC01189 was overexpressed in HCV-infected HepG2 cells to measure its function on HCV-correlated cancer proliferation. In HCC cell lines of Huh7 and Hep3B, LINC01189 was upregulated to investigate its effects on cancer cell proliferation and 5-FU chemoresistance. The competing endogenous RNA (ceRNA) target of LINC01189, human microRNA-155-5p (hsa-miR-155-5p) was probed by dual-luciferase assay and qRT-PCR. Hsa-miR-155-5p was upregulated in LINC01189-overexpessed Huh7 and Hep3B cells to investigate their epigenetic correlation on HCC development regulation. ResultsLINC01189 is downregulated in HCV-infected HCC tumors and cell lines. LINC01189 overexpression inhibited HCC cancer cell proliferation and 5-FU chemoresistance. Hsa-miR-155-5p was confirmed to be a ceRNA target of LINC01189 in HCC. Upregulating hsa-miR-155-5p reversed the LINC01189-mediated inhibition on HCC proliferation and 5-FU chemoresistance. ConclusionsLINC01189 downregulation is associated with HCV infection in HCC, and it has tumor-suppressing effects on HCC development through hsa-miR-155-5p." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients or Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "These authors contributed equally." "identificador" => "fn0005" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1821 "Ancho" => 2091 "Tamanyo" => 129401 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01189 may be closely associated with HCV infection in HCC. (A) Expression of LINC01189 was probed, by qRT-PCR in paired HCC tumor tissues and adjacent non-tumor tissues (n=67) (* P<0.05). In addition, LINC01189 was also probed in a sub-set of HCV-infected HCC tumors (n=21) (** P<0.05). (B) A HCC cell line, HepG2 was infected with HCV virus. After that, HCV RNA expression levels were compared, by qRT-PCR, between infected (HepG2-HCV) and un-infected cells (* P<0.05). (C) Relative expression of LINC01189 in infected (HepG2-HCV) and un-infected HepG2 cells was probed by qRT-PCR (** P<0.05)." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1374 "Ancho" => 1507 "Tamanyo" => 87066 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Upregulating LINC01189 reduced proliferation in HCV-infected HepG2 cells. (A) HCV-infected HepG2 cells were transfected with a LINC01189 overexpressing vector, pc_1189 or a non-specific overexpression vector, pc_NS. Relative LINC01189 expressions were detected by qRT-PCR (* P<0.05). (B) HCV-infected HepG2 cells were transfected with a siRNA specifically targeting human LINC01189, si_1189 or a non-specific lncRNA siRNA, si_NS. After that, relative LINC01189 expressions were detected by qRT-PCR (Δ P>0.05). (C) CCK-8 assay was conducted to compare proliferation in HCV-infected HepG2 cells transfected with pc_1189 and those transfected with pc_NS (* P<0.05)." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3029 "Ancho" => 2323 "Tamanyo" => 306592 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Upregulating LINC01189 suppressed HCC proliferation and chemoresistance. (A) HCC cell lines, Huh7 and Hep3B cells, were transfected with a LINC01189 overexpressing vector, pc_1189 or a non-specific overexpression vector, pc_NS. After that, relative LINC01189 expressions were detected by qRT-PCR (* P<0.05). (B) Huh7 and Hep3B cells were transfected with a siRNA specifically targeting human LINC01189, si_1189 or a non-specific lncRNA siRNA, si_NS. After that, relative LINC01189 expressions were detected by qRT-PCR (Δ P>0.05). (C) CCK-8 assay was conducted to compare proliferation in HCC cells transfected with pc_1189 and those transfected with pc_NS (* P< 0.05). (D) For Huh7 and Hep3B cells transfected with either pc_1189 or pc_NS, they were incubated with 5-FU at 0, 2, 5, 10 and 20μM for 24h. After that, chemoresistance was compared using a viability assay (* P<0.05)." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3260 "Ancho" => 2326 "Tamanyo" => 320838 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01189 attaches to hsa-miR-155-5p. (A) Two DNA sequences on wild-type LINC01189 3’-UTR were predicted to attach to hsa-miR-155-5p. The binding sites were then point-mutated. (B) The wild type and mutant LINC01189 3’-UTRs were used to generate two luciferase reporter vectors, WT_1189 and MU_1189. Then, hsa-miR-155-5p mimics (mimics_miR155) or a non-specific miRNA mimics (mimics_NS) were co-transfected with WT_1189 or MU_1189 in human HEK293T cells. And a dual-luciferase activity assay was conducted 48h later. (C) In pc_1189- or pc_NS- transfected Huh7 and Hep3B cells, qRT-PCR was performed to compare hsa-miR-155-5p expressions levels (* P<0.05)." ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 3004 "Ancho" => 2158 "Tamanyo" => 292989 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "LINC01189 -mediated HCC proliferation and chemoresistance was regulated by hsa-miR-155-5p. (A) Pc_1189-transfected Huh7 and Hep3B cells were double-transfected with a hsa-miR-155-5p mimics (mimics_miR155) or a non-specific miRNA mimics (mimics_NS). QRT-PCR was used to compare endogenous hsa-miR-155-5p expression levels (* P<0.05). (B) CCK-8 assay was conducted to compare proliferation in HCC cells transfected with pc_1189 / mimics_miR155 and those transfected with pc_1189 / mimics_NS (* P<0.05). (C) For double-transfected Huh7 and Hep3B cells, they were incubated with 5-FU at 0, 2, 5, 10 and 20μM for 24h. After that, chemoresistance was compared using a viability assay (* P< 0.05)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:27 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer statistics, 2019" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.L. Siegel" 1 => "K.D. Miller" 2 => "A. 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Ying Yaob,1, Fang Shud,1, Fang Wanga, Xiaoqiang Wangc, Zhengshe Guoa, Haili Wanga, Lu Lia, Haigang Lva,

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doctorlhg@aol.com

Corresponding author.

a Anaesthesiology department, Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054, Shaanxi, China

b Clinical laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054 Shaanxi, China

c Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA, 91010, USA

d Clinical laboratory, Third Hospital of Xi’an, 710000, Shaanxi, China

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    "pii" => "S1665268120302027"
    "issn" => "16652681"
    "doi" => "10.1016/j.aohep.2020.10.005"
    "estado" => "S300"
    "fechaPublicacion" => "2021-05-01"
    "aid" => "277"
    "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
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      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "Health-related quality of life in Cuban patients with chronic liver disease&#58; A real-world experience"
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            "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Independent association of Chronic Liver Disease etiology with PRO scores measured by FACIT-F &#40;A&#41; and WPAI&#58; SHP &#40;B&#41; &#40;adjusted for clinic-demographic factors from <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p>"
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          "autoresLista" => "Marlen I&#46; Castellanos-Fern&#225;ndez, Susana A&#46; Borges-Gonz&#225;lez, Maria Stepanova, Mirtha E&#46; Infante-Vel&#225;zquez, Caridad Ruenes-Domech, Sila M&#46; Gonz&#225;lez-Suero, Zaily Dorta-Guridi, Enrique R&#46; Arus-Soler, Andrei Racila, Zobair M&#46; Younossi"
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              "nombre" => "Susana A&#46;"
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          "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Patient reported outcomes &#40;PROs&#41; are important to understanding the impact a disease from the patients&#8217; point of view&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">Chronic liver disease &#40;CLD&#41; can carry a high clinical and PRO burden&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">PRO data are few among patients with CLD who reside in the Latin America and the Caribbean areas&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">Using valid and reliable PRO instruments&#44; we quantified PROs for patients with CLD living in Cuba&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">We determined that patients from Cuba with hepatitis C virus and autoimmune liver disease had the worst PRO scores most likely related to more severe underlying liver disease &#40;fibrosis&#41; and&#47;or to extrahepatic manifestations &#40;fatigue&#44; abdominal pain&#44; anxiety&#44; and depression&#41;&#46;</p></li></ul></p></span>"
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    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Long noncoding RNA LINC01189 is associated with HCV-hepatocellular carcinoma and regulates cancer cell proliferation and chemoresistance through hsa-miR-155-5p"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">LINC01189 attaches to hsa-miR-155-5p&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> Two DNA sequences on wild-type LINC01189 3&#8217;-UTR were predicted to attach to hsa-miR-155-5p&#46; The binding sites were then point-mutated&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> The wild type and mutant LINC01189 3&#8217;-UTRs were used to generate two luciferase reporter vectors&#44; WT&#95;1189 and MU&#95;1189&#46; Then&#44; hsa-miR-155-5p mimics &#40;mimics&#95;miR155&#41; or a non-specific miRNA mimics &#40;mimics&#95;NS&#41; were co-transfected with WT&#95;1189 or MU&#95;1189 in human HEK293T cells&#46; And a dual-luciferase activity assay was conducted 48<span class="elsevierStyleHsp" style=""></span>h later&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> In pc&#95;1189- or pc&#95;NS- transfected Huh7 and Hep3B cells&#44; qRT-PCR was performed to compare hsa-miR-155-5p expressions levels &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0040">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma &#40;HCC&#41; is one of the most commonly diagnosed and most malignant types of liver cancers worldwide&#46; In USA&#44; there are approximately 42&#44;000 newly diagnosed cases of liver cancers and more than 30&#44;000 associated deaths every year &#91;<a class="elsevierStyleCrossRef" href="#bib0005">1</a>&#93;&#46; In China&#44; liver cancer is the fourth-most diagnosed cancer &#40;&#62;390&#44;000 cases &#47; year&#41; and third-most cause of cancer-related mortality &#40;&#62;360&#44;000 cases &#47; year&#41; in both male and female patients &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0015">3</a>&#93;&#46; While various risk factors may be associated with HCC or other liver cancer subtypes&#44; the most common conditions for patients to eventually develop into HCC are hepatitis B virus &#40;HBV&#41; or hepatitis C virus &#40;HCV&#41; infections &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#93;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Long noncoding RNAs &#40;lncRNAs&#41; are families of long &#40;&#62;200 nucleotides&#41; and non-protein-coding transcripts that had been recently shown to exert broad ranges of regulatory roles in various types of human disease &#91;<a class="elsevierStyleCrossRef" href="#bib0030">6</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0035">7</a>&#93;&#46; Specifically&#44; lncRNAs have been demonstrated to be aberrantly expressed&#44; and exert promoting or suppressing functions in many types of human cancers &#91;<a class="elsevierStyleCrossRef" href="#bib0040">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0045">9</a>&#93;&#46; Recently&#44; a genomic study conducted by Yang and colleagues showed that there might be more than 1&#44;000 lncRNAs that are recurrently deregulated in HCC &#91;<a class="elsevierStyleCrossRef" href="#bib0050">10</a>&#93;&#46; In addition&#44; prognostic and functional roles of lncRNAs had been revealed in HCC &#91;<a class="elsevierStyleCrossRef" href="#bib0055">11</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0060">12</a>&#93;&#46; Particularly&#44; it has been noticed that lncRNAs may be closely associated with HCV progression and the pathological development of HCC among patients with chronic liver diseases &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0070">14</a>&#93;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Similar to lncRNAs&#44; microRNAs &#40;miRNAs&#41; are other families of non-protein-coding&#44; but short &#40;&#8764;20 nucleotides&#41; transcripts that are also shown to be aberrantly expressed and playing critical roles in human cancer development &#91;<a class="elsevierStyleCrossRef" href="#bib0075">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0080">16</a>&#93;&#46; Moreover&#44; new lines of evidence have demonstrated that lncRNAs could act as competing endogenous RNAs &#40;ceRNAs&#41; of miRNAs&#44; so that the transcriptional regulations of lncRNAs-miRNAs axes could have even more significant impacts on regulating cancer cell oncogenesis&#44; progression&#44; apoptosis and metastasis &#91;<a class="elsevierStyleCrossRef" href="#bib0085">17</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0090">18</a>&#93;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the current work&#44; we examined the expression of a newly identified lncRNA&#44; LINC01189 in HCC and its correlation with HCV-infected HCC&#46; We also ectopically overexpressed LINC01189 in HCC cancer cells to study its functions on HCV-associated HCC proliferation and 5-FU chemoresistance&#46; In addition&#44; we studied the possible ceRNA candidate of LINC01189&#44; hsa-miR-145-5p in HCC&#46; The goal of this work is to further our understanding on the epigenetic regulation of lncRNA in HCC&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0045">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0050">HCC human samples</span><p id="par0025" class="elsevierStylePara elsevierViewall">A total of 67-paired hepatocellular carcinoma &#40;HCC&#41; tissues and surrounding non-tumorous tissues were obtained from the participating hospital&#46; Among the HCC tissues&#44; 21 were diagnosed with hepatitis C virus &#40;HCV&#41; infection&#46; Human samples were immediately snap-frozen with liquid nitrogen and then stored at &#8722;75<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; until further processing&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0055">HCC cell lines and HCV-infection</span><p id="par0030" class="elsevierStylePara elsevierViewall">HCC cell lines of HeG2&#44; HuH7 and Hep3B were purchased from the American Type Culture Collection &#40;ATCC&#44; USA&#41;&#44; and incubated in GlutaMAX-RPMI 1640 Medium &#40;Thermo Fisher Scientific&#44; USA&#41; supplemented with 10&#37; fetal bovine serum &#40;FBS&#44; Beyotime&#44; China&#41; and 1X Penicillin-Streptomycin &#40;10&#44;000 U&#47;ml&#44; Thermo Fisher Scientific&#44; USA&#41; in a humidified environment at 37<span class="elsevierStyleHsp" style=""></span>&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The method of infecting HCC cell line with HCV was described in a previous publication with slight modifications &#91;<a class="elsevierStyleCrossRef" href="#bib0095">19</a>&#93;&#46; Briefly&#44; HepG2 cells were cultured in FBS-free medium and inoculated with human serum collected from HCV-infected patients&#46; After 2<span class="elsevierStyleHsp" style=""></span>hours&#44; HepG2 cells were replenished with FBS-containing medium&#44; supplemented with 4&#37; polyethylene glycol &#40;Beyotime&#44; China&#41; and cultured for another 24<span class="elsevierStyleHsp" style=""></span>hours&#46; QRT-PCR was then performed to examine the infection efficacy of HCV viral RNA&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0060">RNA extraction and quantitative real time-PCR</span><p id="par0040" class="elsevierStylePara elsevierViewall">Total RNA was extracted and purified using a PureLink&#8482; Pro 96 total RNA Purification Kit &#40;Thermo Fisher Scientific&#44; USA&#41; according to the manufacturer&#8217;s recommendation&#46; The quality of RNA were verified using a Vairoskan Lux uDrop kit &#40;Thermo Fisher Scientific&#44; USA&#41;&#44; and reverse transcription was performed using a SuperScript&#8482; VILO&#8482; cDNA Synthesis Kit &#40;Invitrogen&#44; USA&#41; according to the manufacturer&#8217;s recommendations&#46; An ABI PRISM&#174; 7000 Sequence Detection System &#40;Applied Biosystems&#44; USA&#41; was used for quantitative real time-PCR &#40;qRT-PCR&#41;&#46; To quantitatively compare HCV viral RNA&#44; the method was described in the previous publication &#91;<a class="elsevierStyleCrossRef" href="#bib0095">19</a>&#93;&#46; To compare lncRNA LINC01189 expression level&#44; a customized TaqMan&#8482; noncoding RNA Assay &#40;Invitrogen&#44; USA&#41; was used&#46; To measure hsa-miR-155-5p expression level&#44; a customized TaqMan&#8482; microRNA Assay &#40;Invitrogen&#44; USA&#41; was used&#46; Finally&#44; the relative expression levels were calculated by the 2<span class="elsevierStyleSup">&#40;&#8722;&#916;&#916;Ct&#41;</span> method&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0065">LINC01189 upregulation and downregulation assay</span><p id="par0045" class="elsevierStylePara elsevierViewall">The whole sequence of human LINC01189 was amplified and sub-cloned into the pcDNA&#47;3&#46;4 plasmid &#40;Addgene&#44; USA&#41; to generated a LINC01189 overexpressing vector&#44; pc&#95;1189&#46; An empty pcDNA&#47;3&#46;4 plasmid &#40;Addgene&#44; USA&#41; was used as the non-specific overexpression vector&#44; pc&#95;NS in this study&#46; Alternatively&#44; a siRNA specifically targeting human LINC01189&#44; si&#95;1189 and a non-specific lncRNA siRNA&#44; si&#95;NS&#44; were designed and manufactured by GenePharma &#40;Shanghai GenePharma&#44; Shanghai&#44; China&#41;&#46; In Hu7&#44; Hep3B&#44; and HCV-infected HepG2 &#40;HepG2-HCV&#41; cells&#44; they were transfected with pc&#95;1189&#44; pc&#95;NS&#44; si&#95;1189 and si&#95;NS for 48<span class="elsevierStyleHsp" style=""></span>hours using the Lipofectamine 3000 transfection reagent &#40;Thermo Fisher Scientific&#44; USA&#41;&#46; After that&#44; qRT-PCR was performed to examine the transfection efficacies&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0070">Proliferation assay</span><p id="par0050" class="elsevierStylePara elsevierViewall">HCC cell proliferation was measured using a CCK-8 Assay &#40;Dojindo&#44; Japan&#41; according to the manufacturer&#8217;s recommendation&#46; With the application of a highly water-soluble tetrazolium salt&#44; WST-8&#44; this assay produces a water-soluble formazan dye upon reduction in the presence of an electron mediator&#44; thus providing quantitative method to assess proliferating cells in the culture&#46; To do so&#44; HCC cells were cultured in a 96-well plate&#44; with a starting density of 1500 cells &#47;well&#44; for 5 days&#46; Every 24<span class="elsevierStyleHsp" style=""></span>h&#44; CCK-8 reagent &#40;10<span class="elsevierStyleHsp" style=""></span>&#956;L&#41; was mixed into tested wells for 2<span class="elsevierStyleHsp" style=""></span>hours at 37 C&#46; Then&#44; proliferating rates were directly estimated by measuring the optical absorbance at 570<span class="elsevierStyleHsp" style=""></span>nm using a Varioskan Lux microplate reader &#40;Thermo Fisher Scientific&#44; USA&#41; according to the manufacturer&#8217;s recommendation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0075">5-FU chemoresistance assay</span><p id="par0055" class="elsevierStylePara elsevierViewall">The method of examining HCC fluorouracil &#40;5-FU&#41; chemoresistance was described in a previous publication with slight modification &#91;<a class="elsevierStyleCrossRef" href="#bib0100">20</a>&#93;&#46; Briefly&#44; HCC cells were cultured in a 96-well plate&#44; with a starting density of 5&#44;000 cells &#47;well&#46; 5-FU was added into cell culture at concentration &#40;&#956;M&#41; of 0&#44; 2&#44; 5&#44; 10&#44; 20 for 48<span class="elsevierStyleHsp" style=""></span>h&#46; The relative cell viability was then measured using the CCK-8 assay&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0080">Dual-luciferase reporter assay</span><p id="par0060" class="elsevierStylePara elsevierViewall">Using online bioinformatics database of StarBase 2&#46;0 &#91;<a class="elsevierStyleCrossRef" href="#bib0105">21</a>&#93;&#44; we identified two DNA sequences on LINC01189 3&#8217;-UTR that might be putative binding sites for human microRNA-155-5p &#40;hsa-miR-155-5p&#41;&#46; We thus constructed two pmiR-RB-REPORT vectors &#40;Shanghai GenePharma&#44; Shanghai&#44; China&#41;&#44; one containing the wild-type &#40;WT&#41; LINC01189 3&#8217;-UTR &#40;WT&#95;1189&#41;&#44; and the other containing a mutant LINC01189 3&#8217;-UTR &#40;MU&#95;1189&#41; to deactivate hsa-miR-155-5p binding&#46; In addition&#44; a synthetic hsa-miR-155-5p mimics &#40;mimics&#95;miR155&#41; and a non-specific human miRNA mimics &#40;mimics-NS&#41; were commercially bought from GenePharma &#40;Shanghai GenePharma&#44; Shanghai&#44; China&#41;&#46; Then&#44; a dual-luciferase reporter assay was conducted using the method described in our previous publication &#91;<a class="elsevierStyleCrossRef" href="#bib0110">22</a>&#93;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="sect0085">Hsa-miR-155-5p overexpression assay</span><p id="par0065" class="elsevierStylePara elsevierViewall">In Huh7 and Hep3B cells which were pre-transfected with pc&#95;1189&#44; they were secondary transfected with mimics&#95;miR155 or mimics-NS using the Lipofectamine 3000 reagent for 48<span class="elsevierStyleHsp" style=""></span>h&#46; QRT-PCR was then performed to examine the overexpression efficacy&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;9</span><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">All experiments were performed in at least three independent repeats&#46; The averaged data were presented as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard error of mean &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>S&#46;E&#46;M&#46;&#41;&#46; One-way analysis of variance &#40;ANOVA&#41; followed by Tukey&#8217;s multiple-comparison tests in a SPSS software &#40;SPSS&#44; version 16&#46;0&#44; USA&#41; was used for all analysis&#46; Significance was set at 0&#46;05 for all statistical tests&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0100">LINC01189 is lowly expressed in HCV-infected HCC tumors and cell lines</span><p id="par0075" class="elsevierStylePara elsevierViewall">We used qRT-PCR to detect the expression pattern of LINC01189 in HCC tumors and cell lines&#46; It was demonstrated that LINC01189 expression is markedly lower in HCC tumors than in adjacent tissues &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In addition&#44; LINC01189 expression was even lower in HCC tumors with HCV-infected &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#44; &#42;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Next&#44; HCC cell line of HepG2 was infected with HCV virus&#46; QRT-PCR confirmed that HCV RNA expression was significantly upregulated in HCV-infected HepG2 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#59; Note&#58; expression level of 100&#37; was based on arbitrary value&#41;&#46; On the other hand&#44; LINC01189 expressed at a much lower level in HCV-infected HepG2 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Thus&#44; these data indicated that LINC01189 downregulation may be closely associated with HCV infection in HCC&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0105">LINC01189 overexpression inhibited proliferation in HCV-infected HCC cell lines</span><p id="par0090" class="elsevierStylePara elsevierViewall">We either overexpressed or downregulated LINC01189 in HCV-infected HepG2 cells&#46; The result of qRT-PCR showed that&#44; in cells transfected with pc&#95;1189&#44; endogenous LINC01189 expression was much higher than in cells transfected with pc&#95;NS&#44; confirming the overexpression strategy &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; LINC01189 expression levels were not different between cells transfected Si&#95;1189 and Si&#95;NS&#44; indicating that LINC01189 was unable to be downregulated in HCV-infected HepG2 cells &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#44; &#916; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Then&#44; a CKK-8 assay was conducted for 5 consecutive days to compare proliferation between pc&#95;1189- and pc&#95;NS- transfected HCV-HepG2 cells&#46; It showed that LINC01189 overexpression significantly inhibited proliferation in HCV-infected HCC cells&#46; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0110">LINC01189 overexpression reduced HCC proliferation and chemoresistance</span><p id="par0095" class="elsevierStylePara elsevierViewall">To further investigate the effects of LINC01189 on HCC development&#44; we either overexpressed or downregulated LINC01189 in two HCC cell lines&#44; Huh7 and Hep3B&#46; In one set of experiments&#44; HCC cells were transfected with either pc&#95;1189 or p&#95;NS&#46; QRT-PCR showed that&#44; in HCC cells transfected with pc&#95;1189&#44; endogenous LINC01189 expression was much higher than in those transfected with pc&#95;NS &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#41;&#46; In the other set of experiments&#44; Huh7 and Hep3B were transfect with either si&#95;1189 or si&#95;NS&#46; This time&#44; qRT-PCR did not show significantly difference in endogenous LINC01189 expressions &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#44; &#916; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; suggesting that genetic modification was unable to knock down LINC01189 in Huh7 or Hep3B cells&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Then&#44; pc&#95;1189- or pc&#95;NS- transfected Huh7 and Hep3B were examined by the CKK-8 assay for 5 days&#46; It showed that LINC01189 overexpression markedly reduced proliferation in HCC cells &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In addition&#44; pc&#95;1189- or pc&#95;NS- transfected Huh7 and Hep3B were treated by low-to-high concentrations of 5-FU to compare their chemoresistance&#46; The results showed that LINC01189 overexpression also significantly reduced 5-FU chemoresistance in HCC cells &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>D&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0115">Hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 in HCC</span><p id="par0110" class="elsevierStylePara elsevierViewall">We then explored the downstream ceRNA candidates of LINC01189&#46; Through bioinformatics research &#40;StarBase 2&#46;0&#41; &#91;<a class="elsevierStyleCrossRef" href="#bib0105">21</a>&#93;&#44; it was noticed that human microRNA-155-5p &#40;hsa-miR-155-5p&#41; may be attached to two complementary DNA sequences in the 3&#8242;-UTR of LINC01189 &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#46; Based on this information&#44; two luciferase reporters were constructed&#46; One included the wild type LINC01189 3&#8217;-UTR&#44; WT&#95;1189&#46; The other included a mutant LINC01189 3&#8217;-UTR&#44; MU&#95;1189&#44; with hsa-miR-155-5p binding sequences point-mutated&#46; Then&#44; in a dual-luciferase activity assay&#44; it was confirmed that hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; &#916; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Moreover&#44; in Huh7 and Hep3B cells transfected with pc&#95;1189&#44; qRT-PCR demonstrated that their endogenous hsa-miR-155-5p expression levels were significantly lower than in HCC cells transfected with pc&#95;NS &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0120">Upregulating hsa-miR-155-5p reversed the inhibitory effects of LINC01189 in HCC</span><p id="par0115" class="elsevierStylePara elsevierViewall">Finally&#44; we investigated the functional relationship between hsa-miR-155-5p and LINC01189 in HCC&#46; In Huh7 and Hep3B cells transfected with pc&#95;1189&#44; we double-transfected them with mimics&#95;miR155 to upregulate hsa-miR-155-5p expression&#46; QRT-PCR demonstrated that&#44; as compared to mimics&#95;NS transfection&#44; mimics&#95;miR155 transfection significantly drove up hsa-miR-155-5p expressions in pc&#95;1189-overexpressed HCC cells &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Then&#44; double-transfected Huh7 and Hep3B were examined by the CKK-8 assay for 5 days&#46; It showed that upregulating hsa-miR-155-5p markedly promoted proliferation in LINC01189-overexpessed HCC cells &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>C&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In addition&#44; double-transfected Huh7 and Hep3B were examined by the 5-FU chemoresistance assay&#46; The results showed that upregulating hsa-miR-155-5p significantly increased 5-FU chemoresistance in LINC01189-overexpessed HCC cells &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>D&#44; &#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#41;&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0125">Discussions</span><p id="par0130" class="elsevierStylePara elsevierViewall">Emerging evidence has demonstrated that&#44; lncRNAs may play critical roles in various aspects of human liver diseases&#44; including chronic HCV infection&#44; fibrosis and HCC &#91;<a class="elsevierStyleCrossRefs" href="#bib0060">12&#8211;14</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115">23</a>&#93;&#46; In the current study&#44; the main focus was to investigate the expression and functions of a novel lncRNA&#44; LINC01189 in HCC&#46; In a very recent clinical study&#44; it was demonstrated that LINC01189 was aberrantly regulated in peripheral blood mononuclear cells of patients with rheumatoid arthritis&#44; suggesting that LINC01189 may be a potential biomarker for rheumatoid arthritis &#91;<a class="elsevierStyleCrossRef" href="#bib0120">24</a>&#93;&#46; Other than that&#44; the expressing pattern or regulatory effects of LINC01189 in other human diseases have never been elucidated&#44; thus very much highlighting the clinical significance and importance of our study&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Firstly in the current study&#44; we applied quantitative qRT-PCR to measure LINC01189 expression pattern in HCC tumors&#44; as well as HCV-infected HCC tumors and cell lines&#46; We discovered that LINC01189 was predominantly downregulated in HCC&#44; especially in HCV-infected HCC tumors and cell lines&#46; Particularly&#44; we discovered that ectopically overexpressing LINC01189 could functionally regulation proliferation in HCV-infected HCC cancer cells&#46; In an early study&#44; Diaz and colleagues indicated that epigenetic transcripts&#44; miRNAs were closely correlated with HCV-related HCC &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93;&#46; In another study&#44; it was demonstrated that lncRNA of LINC01419 was drastically upregulated in Hepatitis B Virus- and HCV-associated HCCs &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93;&#46; Along with the discovery in our study&#44; it&#8217;s becoming more obvious that epigenetic factors&#44; including miRNAs and lncRNAs&#44; may have profound roles in the development of HCV-related HCC&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">An interesting observation in the current study is that&#44; we were not able to knock down LINC01189 expression in HCC cell lines&#44; either with or without HCV infection&#46; One may suspect that the reason we did not observe LINC01189 downregulation after siRNA transfection was due to technique difficulty&#46; Several lines of evidence argue against it&#46; First&#44; while we manufactured the LINC01189-specific siRNA&#44; we did not use single siRNA&#46; Instead&#44; we mixed four different siRNAs aiming at different targets on LINC01189&#44; which was confirmed by the manufacturer to be able to efficiently knock down &#62;&#8764;85&#37; gene expression of LINC01189 in various types of hosting cells &#40;data not shown&#41;&#46; Second&#44; besides siRNA&#44; we also tried other downregulating strategies&#44; such as lentiviral transfection of short hair-pin RNAs &#40;shRNAs&#41;&#46; However&#44; we discovered a large portion of transfected HCC cells was apoptotic or dead that we could not efficiently maintain them in the culture&#46; Thus&#44; while we could not rule out the possibility that other technique manipulations may achieve the goal of LINC01189 downregulation in HCC cell lines&#44; the possible explanation for the obtained results might be that LINC01189 was already maximally suppressed &#40;or at the minimal level of expression&#41;&#44; that any downregulation approach may not be sustainable to maintain cell health&#46; On the other hand&#44; it is worth-noting that&#44; our strategy of overexpressing LINC01189 was a success&#44; which allowed us to reveal functional roles of LINC01189 in regulating cancer cell development in both HCV-related and HCV-unrelated manners&#44; a novel discovery of biological implication of LINC01189 in human diseases&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Another important finding of our study is that we demonstrated that LINC01189 acted as a ceRNA to regulate downstream target of hsa-miR-155-5p in HCC&#46; Dual-luciferase assay and qRT-PCR assay demonstrated that LINC01189 did attach to hsa-miR-155-5p&#44; and inhibited hsa-miR-155-5p in HCC cells&#46; Moreover&#44; we showed that LINC01189 -mediated inhibition on cancer cell proliferation and 5-FU chemoresistance were reversed by hsa-miR-155-5p upregulation&#44; thus indicating the functional role of epigenetic axis of LINC01189 &#47; hsa-miR-155-5p in regulating HCC development&#46; In previous studies&#44; the prognostic implication and functional roles of hsa-miR-155 in HCC were well-documented &#91;<a class="elsevierStyleCrossRefs" href="#bib0125">25&#8211;27</a>&#93;&#46; However&#44; the current work is the first study to reveal a possible upstream regulatory mechanism of hsa-miR-155-5p&#46; Future works&#44; possibly focusing on the downstream upregulated or downregulated signaling pathways of LINC01189 &#47; hsa-miR-155-5p axis may further broaden our understanding on underlying mechanisms of modulations in HCC&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Ethics statement</span><p id="par0150" class="elsevierStylePara elsevierViewall">In this study&#44; the ethics approval was obtained from the Medical Research and Ethics Committees at the Xi&#8217;an Jiaotong University Medical College Red Cross hospital in Xi&#8217;an&#44; Shaanxi&#44; China&#46; Consent forms were signed by all participating patients&#46; Clinical and experimental procedures were performed according to the guideline of the WMA Declaration of Helsinki &#8212; ethical principles for medical research involving human subjects &#40;<a href="https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/">https&#58;&#47;&#47;www&#46;wma&#46;net&#47;policies-post&#47;wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects&#47;</a>&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of Interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Abstract"
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            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Introduction and Objectives"
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            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Patients or Materials and Methods"
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            2 => array:2 [
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              "titulo" => "Results"
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              "titulo" => "Conclusions"
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          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1403994"
          "titulo" => "Abbreviations"
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        3 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        4 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:9 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "HCC human samples"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "HCC cell lines and HCV-infection"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "RNA extraction and quantitative real time-PCR"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "LINC01189 upregulation and downregulation assay"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Proliferation assay"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "5-FU chemoresistance assay"
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            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Dual-luciferase reporter assay"
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            7 => array:2 [
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              "titulo" => "Hsa-miR-155-5p overexpression assay"
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          "titulo" => "Results"
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              "identificador" => "sec0065"
              "titulo" => "LINC01189 is lowly expressed in HCV-infected HCC tumors and cell lines"
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            1 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "LINC01189 overexpression inhibited proliferation in HCV-infected HCC cell lines"
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              "identificador" => "sec0075"
              "titulo" => "LINC01189 overexpression reduced HCC proliferation and chemoresistance"
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              "identificador" => "sec0080"
              "titulo" => "Hsa-miR-155-5p is a downstream ceRNA candidate of LINC01189 in HCC"
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              "identificador" => "sec0085"
              "titulo" => "Upregulating hsa-miR-155-5p reversed the inhibitory effects of LINC01189 in HCC"
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          "titulo" => "Discussions"
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          "titulo" => "Ethics statement"
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          "titulo" => "Conflict of Interest"
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          "titulo" => "Acknowledgement"
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          "titulo" => "References"
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    "fechaRecibido" => "2020-08-25"
    "fechaAceptado" => "2020-09-22"
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          "titulo" => "Keywords"
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          "palabras" => array:5 [
            0 => "HCV"
            1 => "HCC"
            2 => "lncRNA"
            3 => "LINC01189"
            4 => "hsa-miR-155-5p"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1403994"
          "palabras" => array:4 [
            0 => "lncRNA"
            1 => "HCV"
            2 => "HCC"
            3 => "ceRNA"
          ]
        ]
      ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Emerging evidence has demonstrated that long noncoding RNAs &#40;lncRNAs&#41; may be closely associated with Hepatitis C virus &#40;HCV&#41; infection and the development of hepatocellular carcinoma &#40;HCC&#41;&#46; In this study&#44; we investigated the expression and functions of a lncRNA&#44; LINC01189&#44; in HCV-associated HCC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients or Materials and Methods</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">LINC01189 expression was measured in HCC tumors&#44; HCV-infected HCC tumors and HCV-infected HCC cells&#46; LINC01189 was overexpressed in HCV-infected HepG2 cells to measure its function on HCV-correlated cancer proliferation&#46; In HCC cell lines of Huh7 and Hep3B&#44; LINC01189 was upregulated to investigate its effects on cancer cell proliferation and 5-FU chemoresistance&#46; The competing endogenous RNA &#40;ceRNA&#41; target of LINC01189&#44; human microRNA-155-5p &#40;hsa-miR-155-5p&#41; was probed by dual-luciferase assay and qRT-PCR&#46; Hsa-miR-155-5p was upregulated in LINC01189-overexpessed Huh7 and Hep3B cells to investigate their epigenetic correlation on HCC development regulation&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">LINC01189 is downregulated in HCV-infected HCC tumors and cell lines&#46; LINC01189 overexpression inhibited HCC cancer cell proliferation and 5-FU chemoresistance&#46; Hsa-miR-155-5p was confirmed to be a ceRNA target of LINC01189 in HCC&#46; Upregulating hsa-miR-155-5p reversed the LINC01189-mediated inhibition on HCC proliferation and 5-FU chemoresistance&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">LINC01189 downregulation is associated with HCV infection in HCC&#44; and it has tumor-suppressing effects on HCC development through hsa-miR-155-5p&#46;</p></span>"
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            "titulo" => "Conclusions"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">LINC01189 may be closely associated with HCV infection in HCC&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> Expression of LINC01189 was probed&#44; by qRT-PCR in paired HCC tumor tissues and adjacent non-tumor tissues &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>67&#41; &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In addition&#44; LINC01189 was also probed in a sub-set of HCV-infected HCC tumors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41; &#40;&#42;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> A HCC cell line&#44; HepG2 was infected with HCV virus&#46; After that&#44; HCV RNA expression levels were compared&#44; by qRT-PCR&#44; between infected &#40;HepG2-HCV&#41; and un-infected cells &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> Relative expression of LINC01189 in infected &#40;HepG2-HCV&#41; and un-infected HepG2 cells was probed by qRT-PCR &#40;&#42;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Upregulating LINC01189 reduced proliferation in HCV-infected HepG2 cells&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> HCV-infected HepG2 cells were transfected with a LINC01189 overexpressing vector&#44; pc&#95;1189 or a non-specific overexpression vector&#44; pc&#95;NS&#46; Relative LINC01189 expressions were detected by qRT-PCR &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> HCV-infected HepG2 cells were transfected with a siRNA specifically targeting human LINC01189&#44; si&#95;1189 or a non-specific lncRNA siRNA&#44; si&#95;NS&#46; After that&#44; relative LINC01189 expressions were detected by qRT-PCR &#40;&#916; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> CCK-8 assay was conducted to compare proliferation in HCV-infected HepG2 cells transfected with pc&#95;1189 and those transfected with pc&#95;NS &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Upregulating LINC01189 suppressed HCC proliferation and chemoresistance&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> HCC cell lines&#44; Huh7 and Hep3B cells&#44; were transfected with a LINC01189 overexpressing vector&#44; pc&#95;1189 or a non-specific overexpression vector&#44; pc&#95;NS&#46; After that&#44; relative LINC01189 expressions were detected by qRT-PCR &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> Huh7 and Hep3B cells were transfected with a siRNA specifically targeting human LINC01189&#44; si&#95;1189 or a non-specific lncRNA siRNA&#44; si&#95;NS&#46; After that&#44; relative LINC01189 expressions were detected by qRT-PCR &#40;&#916; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> CCK-8 assay was conducted to compare proliferation in HCC cells transfected with pc&#95;1189 and those transfected with pc&#95;NS &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;D&#41;</span> For Huh7 and Hep3B cells transfected with either pc&#95;1189 or pc&#95;NS&#44; they were incubated with 5-FU at 0&#44; 2&#44; 5&#44; 10 and 20<span class="elsevierStyleHsp" style=""></span>&#956;M for 24<span class="elsevierStyleHsp" style=""></span>h&#46; After that&#44; chemoresistance was compared using a viability assay &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">LINC01189 attaches to hsa-miR-155-5p&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> Two DNA sequences on wild-type LINC01189 3&#8217;-UTR were predicted to attach to hsa-miR-155-5p&#46; The binding sites were then point-mutated&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> The wild type and mutant LINC01189 3&#8217;-UTRs were used to generate two luciferase reporter vectors&#44; WT&#95;1189 and MU&#95;1189&#46; Then&#44; hsa-miR-155-5p mimics &#40;mimics&#95;miR155&#41; or a non-specific miRNA mimics &#40;mimics&#95;NS&#41; were co-transfected with WT&#95;1189 or MU&#95;1189 in human HEK293T cells&#46; And a dual-luciferase activity assay was conducted 48<span class="elsevierStyleHsp" style=""></span>h later&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> In pc&#95;1189- or pc&#95;NS- transfected Huh7 and Hep3B cells&#44; qRT-PCR was performed to compare hsa-miR-155-5p expressions levels &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LINC01189 -mediated HCC proliferation and chemoresistance was regulated by hsa-miR-155-5p&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> Pc&#95;1189-transfected Huh7 and Hep3B cells were double-transfected with a hsa-miR-155-5p mimics &#40;mimics&#95;miR155&#41; or a non-specific miRNA mimics &#40;mimics&#95;NS&#41;&#46; QRT-PCR was used to compare endogenous hsa-miR-155-5p expression levels &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> CCK-8 assay was conducted to compare proliferation in HCC cells transfected with pc&#95;1189 &#47; mimics&#95;miR155 and those transfected with pc&#95;1189 &#47; mimics&#95;NS &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleBold">&#40;C&#41;</span> For double-transfected Huh7 and Hep3B cells&#44; they were incubated with 5-FU at 0&#44; 2&#44; 5&#44; 10 and 20<span class="elsevierStyleHsp" style=""></span>&#956;M for 24<span class="elsevierStyleHsp" style=""></span>h&#46; After that&#44; chemoresistance was compared using a viability assay &#40;&#42; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span> 0&#46;05&#41;&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:27 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "&#91;1&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer statistics&#44; 2019"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            1 => "K&#46;D&#46; Miller"
                            2 => "A&#46; Jemal"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3322/caac.21551"
                      "Revista" => array:7 [
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                        "fecha" => "2019"
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                        "paginaInicial" => "7"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30620402"
                            "web" => "Medline"
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            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "&#91;2&#93;"
              "referencia" => array:1 [
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                    0 => array:2 [
                      "titulo" => "Current cancer situation in China&#58; good or bad news from the 2018 Global Cancer Statistics&#63;"
                      "autores" => array:1 [
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                          "etal" => false
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                            1 => "Y&#46;N&#46; Zong"
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cancer Commun &#40;Lond&#41;"
                        "fecha" => "2019"
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            2 => array:3 [
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              "referencia" => array:1 [
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                      "autores" => array:1 [
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                          "etal" => true
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                            1 => "M&#46; Colombet"
                            2 => "I&#46; Soerjomataram"
                            3 => "C&#46; Mathers"
                            4 => "D&#46;M&#46; Parkin"
                            5 => "M&#46; Pineros"
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                  "host" => array:1 [
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                      "titulo" => "Long noncoding RNAs and human disease"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "O&#46; Wapinski"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.tcb.2011.04.001"
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                        "fecha" => "2011"
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                      "titulo" => "Novel human lncRNA-disease association inference based on lncRNA expression profiles"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "X&#46; Chen"
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                    0 => array:2 [
                      "doi" => "10.1093/bioinformatics/btt426"
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                        "fecha" => "2013"
                        "volumen" => "29"
                        "numero" => "20"
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                      "titulo" => "Human cancer long non-coding RNA transcriptomes"
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                            3 => "G&#46;L&#46; Stewart"
                            4 => "K&#46;M&#46; Lonergan"
                            5 => "J&#46;Y&#46; Kennett"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2020.09.013

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Year/Month	Html	Pdf	Total

2024 November	1	0	1
2024 October	10	1	11
2024 September	9	4	13
2024 August	16	3	19
2024 July	56	2	58
2024 June	13	3	16
2024 May	14	3	17
2024 April	12	6	18
2024 March	23	7	30
2024 February	23	3	26
2024 January	17	8	25
2023 December	14	4	18
2023 November	12	3	15
2023 October	36	9	45
2023 September	35	4	39
2023 August	22	4	26
2023 July	13	1	14
2023 June	29	4	33
2023 May	50	4	54
2023 April	39	1	40
2023 March	29	1	30
2023 February	9	2	11
2023 January	15	6	21
2022 December	14	4	18
2022 November	12	5	17
2022 October	12	7	19
2022 September	17	21	38
2022 August	14	9	23
2022 July	18	7	25
2022 June	13	5	18
2022 May	15	8	23
2022 April	8	9	17
2022 March	8	9	17
2022 February	9	3	12
2022 January	16	8	24
2021 December	15	17	32
2021 November	46	12	58
2021 October	65	11	76
2021 September	27	13	40
2021 August	37	7	44
2021 July	16	19	35
2021 June	22	6	28
2021 May	21	13	34
2021 April	63	24	87
2021 March	16	10	26
2021 February	19	13	32
2021 January	6	6	12
2020 December	7	10	17
2020 November	13	3	16

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