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CEMIP induces TGF-β/Smad signaling to promote keloid development by binding to SPARC
Department of Plastic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
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and chronic intestinal failure who underwent intestinal transplantation in Brazil" "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:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1096 "Ancho" => 3000 "Tamanyo" => 187653 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Clinical course description of SBS-IF patient's timeline from the date of underlying condition to the date of intestinal transplantation per patient (months).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Yuri Longato Boteon, Mariana Hollanda Martins da Rocha, Luciana Haddad, Rafael Antonio Arruda Pecora, Andre Dong Won Lee, Claudia Yang Santos, Amanda Pinter Carvalheiro da Silva Boteon, Igor Calil, Giovana Garcia Rossi, Fernanda Marques, Bianca Facas, Luiz Augusto Carneiro D'Albuquerque" "autores" => array:12 [ 0 => array:2 [ "nombre" => "Yuri Longato" "apellidos" => "Boteon" ] 1 => array:2 [ "nombre" => "Mariana Hollanda Martins da" "apellidos" => "Rocha" ] 2 => array:2 [ "nombre" => "Luciana" "apellidos" => "Haddad" ] 3 => array:2 [ "nombre" => "Rafael Antonio Arruda" "apellidos" => "Pecora" ] 4 => array:2 [ "nombre" => "Andre Dong Won" "apellidos" => "Lee" ] 5 => array:2 [ "nombre" => "Claudia Yang" "apellidos" => "Santos" ] 6 => array:2 [ "nombre" => "Amanda Pinter Carvalheiro da Silva" "apellidos" => "Boteon" ] 7 => array:2 [ "nombre" => "Igor" "apellidos" => "Calil" ] 8 => array:2 [ "nombre" => "Giovana Garcia" "apellidos" => "Rossi" ] 9 => array:2 [ "nombre" => "Fernanda" "apellidos" => "Marques" ] 10 => array:2 [ "nombre" => "Bianca" "apellidos" => "Facas" ] 11 => array:2 [ "nombre" => "Luiz Augusto Carneiro" "apellidos" => "D'Albuquerque" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara017" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">•</span><p id="para0001" class="elsevierStylePara elsevierViewall">Substantial average of hospitalizations (4.3 per patient and 0.5 patient/year).</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">•</span><p id="para0002" class="elsevierStylePara elsevierViewall">The main reasons for intestine transplantation were related to parenteral nutrition.</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">•</span><p id="para0003" class="elsevierStylePara elsevierViewall">Complications related to parenteral nutrition were the main reason for hospitalization.</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">•</span><p id="para0004" class="elsevierStylePara elsevierViewall">High burden of hospitalization and complication with a mean length of stay of 50 days.</p></li><li class="elsevierStyleListItem" id="celistitem0005"><span class="elsevierStyleLabel">•</span><p id="para0005" class="elsevierStylePara elsevierViewall">Median time between SBS-IF diagnosis and transplant indication of 16 months.</p></li></ul></p></span>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593224001984?idApp=UINPBA00004N" "url" => "/18075932/000000790000000C/v123_202411010523/S1807593224001984/v123_202411010523/en/main.assets" ] "itemAnterior" => array:16 [ "pii" => "S1807593224001972" "issn" => "18075932" "doi" => "10.1016/j.clinsp.2024.100520" "estado" => "S250" "fechaPublicacion" => "2024-01-01" "aid" => "100520" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original articles</span>" "titulo" => "The role of metabolic factors in the association between obesity and cholelithiasis: A two-step, two-sample multivariable mendelian randomization study" "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:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1480 "Ancho" => 2500 "Tamanyo" => 172275 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig 1:" "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Estimates of casual effect of body mass index (BMI) on cholelithiasis in MR analysis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Xiangrong Xu, Jiawei Gao, Jun Sun, Ruiwen Liu, Wei Chen" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Xiangrong" "apellidos" => "Xu" ] 1 => array:2 [ "nombre" => "Jiawei" "apellidos" => "Gao" ] 2 => array:2 [ "nombre" => "Jun" "apellidos" => "Sun" ] 3 => array:2 [ "nombre" => "Ruiwen" "apellidos" => "Liu" ] 4 => array:2 [ "nombre" => "Wei" "apellidos" => "Chen" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara005" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">•</span><p id="para0001" class="elsevierStylePara elsevierViewall">Genetic analysis shows HDL mediates 7.3 % of BMI's impact on cholelithiasis risk.</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">•</span><p id="para0002" class="elsevierStylePara elsevierViewall">Triglycerides contribute 3.5 % to BMI's effect on cholelithiasis, according to genetic evidence.</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">•</span><p id="para0003" class="elsevierStylePara elsevierViewall">Targeting HDL & Triglycerides may reduce cholelithiasis risk in individuals with high BMI.</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">•</span><p id="para0004" class="elsevierStylePara elsevierViewall">Study reveals novel insights into BMI-associated cholelithiasis mechanisms.</p></li></ul></p></span>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593224001972?idApp=UINPBA00004N" "url" => "/18075932/000000790000000C/v123_202411010523/S1807593224001972/v123_202411010523/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original articles</span>" "titulo" => "CEMIP induces TGF-β/Smad signaling to promote keloid development by binding to SPARC" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Xinyi Li, Wei Zhang, Xiaojing Li" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Xinyi" "apellidos" => "Li" ] 1 => array:2 [ "nombre" => "Wei" "apellidos" => "Zhang" ] 2 => array:4 [ "nombre" => "Xiaojing" "apellidos" => "Li" "email" => array:1 [ 0 => "Lixiaojing930111@163.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0001" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Plastic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China" "identificador" => "aff0001" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0003" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1953 "Ancho" => 3458 "Tamanyo" => 307910 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">CEMIP binds to SPARC. (A) Coexpedia database revealed that CEMIP was co-expressed with SPARC. (B) The protein level of SPARC in KF transfected with shRNA-CEMIP was detected by western blot. (C) co-IP assay confirmed the binding of CEMIP and SPARC. (D) IP assay predicted that CEMPIP silencing inhibited SPARC precipitation. Data are expressed as mean ± SD (***p < 0.001).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0009" class="elsevierStylePara elsevierViewall">As a benign fibrous tumor of the skin, keloid results from the over-proliferation of fibroblasts as well as excessive deposition of Extracellular Matrix (ECM) in the dermis after skin injury.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> The pathogenesis of keloid is complex, which may be related to genetic, immune as well as cellular signal transduction pathways.<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Keloid scar not only influences beauty, but also contributes to picking pain, pruritus and even cause dysfunction.<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> The treatment approaches to keloid predominantly include surgery, local medication, cryotherapy, and a combination of laser and radiation therapy.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Although keloid is a benign dermal tumor, the treatment outcome of keloid patients is not ideal because of its high recurrence. With an in-depth understanding of the genetic and immune correlation of keloid, other therapeutic methods have been developed, such as gene therapy, targeted therapy, and immunotherapy, but the therapeutic effects of these treatment methods have yet to be verified.<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a></p><p id="para0010" class="elsevierStylePara elsevierViewall">Being an intranuclear protein, Cell Migration-inducing hyaluronidase 1 (CEMIP) is located in human chromosome 15q25.1 with the enzymatic capacity to degrade hyaluronan.<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> An increasing number of studies have demonstrated that CEMIP has abnormal expression in breast cancer, colon cancer, prostate cancer, and other tumors, which can promote the biological process of tumor invasion, metastasis, apoptosis and so on.<a class="elsevierStyleCrossRefs" href="#bib0009"><span class="elsevierStyleSup">9-11</span></a> CEMIP could promote Epithelial-Mesenchymal Transition (EMT) process in colorectal cancer and facilitate mesenchymal transformation shuttling into circulation.<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> Also, another study reported that CEMIP promoted cell invasion and migration and triggered EMT of Non-Small-Cell Lung Cancer (NSCLC) cells through PI3K/AKT pathway.<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> In addition, CEMIP was reported to participate in the enhanced degradation of Hyaluronic Acid (HA) in dermal fibroblast and Wnt/β-catenin signaling pathway.<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> Moreover, it was also evidenced that CEMIP was upregulated in synovial fibroblasts in Rheumatoid Arthritis (RA) or Osteoarthritis (OA) patients.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> All the above-mentioned findings indicate that CEMIP acts as a critical regulator in cell proliferation, invasion, migration and fibrosis, but its role in keloid hyperplasia has not been studied. Thus, this study was designed, aiming to identify the biological roles of CEMIP in keloid hyperplasia and to disclose its potential mechanisms.</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Bioinformatic analysis</span><p id="para0011" class="elsevierStylePara elsevierViewall">Coexpedia database (<a href="https://www.coexpedia.org/search.php">https://www.coexpedia.org/search.php</a>) was used to predict the co-expression of CEMPI and Secreted Protein Acidic and Rich in Cysteine (SPARC). PPA-red (<a href="https://www.iitm.ac.in/bioinfo/PPA_Pred/prediction.html#">https://www.iitm.ac.in/bioinfo/PPA_Pred/prediction.html#</a>) predicted the combination of CEMPI and SPARC.</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell culture and treatment</span><p id="para0012" class="elsevierStylePara elsevierViewall">Keloid Fibroblasts (KF) and normal fibroblasts (NF) that provided by the American Type Culture Collection (Rockville) were cultivated in DMEM (Invitrogen) supplemented with 10% FBS and 1% penicillin-streptomycin with 5% CO<span class="elsevierStyleInf">2</span> at 37 °C.</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Cell transfection</span><p id="para0013" class="elsevierStylePara elsevierViewall">For the knockdown of CEMIP, specific shRNA targeting CEMIP (shRNA-CEMIP-1/2), and corresponding control shRNA (shRNA-NC) were synthesized by Gene Pharma (Shanghai, China). To overexpress SPARC, the pc-DNA 3.1 vector containing the whole length of SPARC (Ov-SPARC) and the empty vector (Ov-NC) were synthesized by Shanghai Genechem Co., Ltd. 100 nM recombinants were transfected into KF utilizing Lipofectamine 2000 (Invitrogen-Life Technologies) in light of standard protocol. After transfection for 48h, KF were collected for ensuing research.</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Cell counting kit-8 (CCK-8) assay</span><p id="para0014" class="elsevierStylePara elsevierViewall">KF with indicated treatment were inoculated into 96-well plates and then cultivated in DMEM with 10% FBS for 24h, 48h and 72h Afterwards each well was added with 10 μL WST-8 (Beyotime) to further incubate the plates for 2h, and then the absorbance was appraised by means of a microplate reader (Bio-Rad) at 450 nm.</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Immunofluorescence staining</span><p id="para0015" class="elsevierStylePara elsevierViewall">The transfected KF were subjected to 4% polyoxymethylene fixation and 0.5% Trition-X100 permeation. Following the block with 10% BSA in PBS, the overnight subjection of KF to primary antibodies against Ki67 and FN was conducted at 4 °C, after which was the cultivation with secondary antibodies for 1h at room temperature. DAPI was applied for the counterstaining of KF and the observation was implemented under a fluorescence microscope (Nikon Eclipse80i).</p></span></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Wound healing assay</span><p id="para0016" class="elsevierStylePara elsevierViewall">KF with indicated treatment were inoculated into 6-well plates and then cultured until 80%–90% cell fusion was reached. With the help of white pipette tips, wound-in cell monolayers were made. Then, the PBS-rinsed cells were cultured in a serum-free medium for 24h at 37 °C. Finally, the wounds were recorded at 0 and 24h utilizing an inverted microscope (Olympus Corp).</p><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Transwell assay</span><p id="para0017" class="elsevierStylePara elsevierViewall">KF with indicated treatment were inoculated into the serum-free medium (200 μL) in the upper chambers pre-coated with Matrigel. RPMI-1640 medium that was decorated with 10% FBS was loaded in the lower chamber. After incubation for 24h, invaded cells on the lower face were subjected to 100% methanol fixation and H&E staining. The images of cells passing through the membranes were captured utilizing an inverted microscope. Five random fields were selected for counting.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Co-immunoprecipitation (co-IP)</span><p id="para0018" class="elsevierStylePara elsevierViewall">Lysates that were prepared from cells using lysis buffer (150 mM NaCl, 10 mM HEPES, pH 7.4, 1% NP-40) were then exposed to HA affinity agarose (Sigma-Aldrich), or CEMIP or SPARC antibody with protein G agarose overnight at 4 °C. Beads containing affinity-bound proteins were washed 6 times by immunoprecipitation wash buffer (150 mM NaCl, 10 mM HEPES, pH 7.4, 0.1% NP-40), following which was the elution with 1 M glycine (pH 3.0). The eluates were then mixed with sample buffer, denatured, and applied for analysis by western blot.</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">RNA extraction and quantitative real-time PCR (qRT-PCR)</span><p id="para0019" class="elsevierStylePara elsevierViewall">Total RNAs that isolated from sample KF with Trizol reagent (Invitrogen) were reverse transcribed into cDNA utilizing PrimeScript RT Master Mix (Perfect Real Time; Takara Bio, Inc.) in light of standard protocol. The templets were amplified on an ABI PRISM 7900 Real-Time system (Applied Biosystems) by virtue of the SYBR Premix ExTaq kit (Takara Bio, Inc.). The primer sequences for PCR are presented as below: CEMIP: 5′-ACCCATCACTCGGTCTCTGA-3′ (forward) and 5′-GAGGTGAGCAGCAGTGTCTT-3′ (reverse); SPARC: 5′-CAAGAAGCCCTGCCTGATGA-3′ (forward) and 5′-TCTTCGGTTTCCTCTGCACC-3′ (reverse); GAPDH: 5′-GGGAAACTGTGGCGTGAT-3′ (forward) and 5′-GAGTGGGTGTCGCTGTTGA-3′ (reverse). Data were demonstrated in the format of fold change (2<span class="elsevierStyleSup">-ΔΔCt</span>), which normalized to GAPDH.</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Western blot</span><p id="para0020" class="elsevierStylePara elsevierViewall">Total proteins that were isolated from sample KF with RIPA buffer (Auragene). Following the separation with 10% SDS-PAGE, the transfer of proteins to PVDF membranes was implemented. Membranes, which were impeded by 5% BSA, were incubated with antibodies targeting CEMIP, Collagen I, α-SMA, FN, SPARC, TGF-β, p-SMAD2, p-SMAD3, SMAD2, SMAD3 and GAPDH at 4 °C overnight. After that, the PBST-rinsed membranes were probed with appropriate secondary antibodies for 1h at room temperature. Finally, the visualization of protein bands was implemented employing an ECL detection system (Beyotime) and ImageJ software (Version 1.49) was adopted to analyze protein density.</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Statistical analysis</span><p id="para0021" class="elsevierStylePara elsevierViewall">Data collected from three independent experiments were displayed in the format of mean ± SD and were analyzed utilizing SPSS 19.0 software (Chicago). For differences between the two groups, Student's <span class="elsevierStyleItalic">t</span>-test was adopted while one-way ANOVA with a post hoc Bonferroni multiple comparison test was employed for the comparisons among multiple groups. P less than 0.05 was viewed to have statistical significance.</p></span></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Results</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Downregulation of CEMIP suppresses KF proliferation, migration and invasion</span><p id="para0022" class="elsevierStylePara elsevierViewall">With the purpose of investigating the role of CEMIP in keloid hyperplasia, CEMIP expression in keloid fibroblasts was initially assessed. As <a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>A‒B demonstrated, the mRNA and protein expressions of CEMIP in KF were conspicuously elevated relative to the Normal Fibroblasts (NF). To identify the biological role that CEMIP played in KF, CEMIP was silenced and qPCR as well as western blot was adopted for the examination of transfection efficiency (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>C‒D). Results obtained from CCK-8 assay depicted that CEMIP silencing remarkably inhibited cell proliferation (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>E). In addition, immunofluorescence staining showed that the level of Ki67 in KF was reduced by CEMIP silencing (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>F). Moreover, the knockdown of CEMIP reduced the rate of cell migration when compared with the shRNA-NC group (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>G). Transwell assay results indicated that the invasive ability in KF was restrained by the knockdown of CEMIP (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>H).</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">CEMIP silencing inhibits ECM deposition in KF</span><p id="para0023" class="elsevierStylePara elsevierViewall">Then, the authors explored the effects of CEMIP silencing on ECM deposition in KF. As shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>A, CEMIP knockdown specifically decreased the protein levels of Collagen I, α-SMA and FN by contrast with the shRNA-NC group. Consistently, data from immunofluorescence staining revealed that the level of FN in cells transfected with shRNA-CEMIP was markedly reduced (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>B).</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">CEMIP binds to SPARC</span><p id="para0024" class="elsevierStylePara elsevierViewall">The authors further explored the mechanism involved in the function of CEMIP in KF. As shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>A, Coexpedia database revealed that CEMIP was co-expressed with SPARC. PPA-red database also showed that CEMIP protein could bind to SPARC and predicted that the value of binding free energy is -15.51 kcal/moL. CEMIP silencing led to downregulated SPARC expression in KF (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>B). Moreover, co-IP assay confirmed the binding of CEMIP and SPARC (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>C). IP experiment also predicted that CEPIP silencing inhibited SPARC precipitation (<a class="elsevierStyleCrossRef" href="#fig0003">Fig. 3</a>D).</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">CEMIP silencing restrains the proliferation, invasion and migration of KF by inhibiting SPARC</span><p id="para0025" class="elsevierStylePara elsevierViewall">To identify the role of SPARC in CEMIP-mediated KF, Ov-SPARC was transfected into KF to elevate SPARC expression. The transfection efficiency of Ov-SPARC was examined utilizing qPCR as well as western blot (<a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>A‒B). As <a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>C depicted, SPARC overexpression elevated the reduced cell proliferation in CEMIP-silenced KF. Similarly, immunofluorescence assay revealed that Ki67 level in shRNA-CEMIP+Ov-NC group was significantly increased after the transfection with Ov-SPARC (<a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>D). Moreover, wound healing and transwell assay displayed that the decreased migration and invasion in shRNA-CEMIP+Ov-NC group were rehabilitated after SPARC was overexpressed (<a class="elsevierStyleCrossRef" href="#fig0004">Fig. 4</a>E‒F).</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">Knockdown of CEMIP ameliorates ECM deposition in KF via binding to SPARC</span><p id="para0026" class="elsevierStylePara elsevierViewall">Next, the authors identify the role of SPARC in ECM deposition of CEMIP-mediated KF. As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>A, CEMIP silencing abated the production of Collagen I, α-SMA and FN in KF compared with those in KF without transfection. However, SPARC overexpression counteracted the impacts of CEMIP silencing on these proteins. Consistently, the immunofluorescence assay revealed that the level of FN in KF was significantly decreased by CEMIP silencing, which was subsequently increased after the transfection with Ov-SPARC (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 5</a>B).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">CEMIP silencing blocks TGF-β/Smad signaling by suppressing SPARC</span><p id="para0027" class="elsevierStylePara elsevierViewall">With the aim of further investigating the function of a downstream pathway of CEMIP in KF, a western blot was implemented. The results showed that CEMIP silencing significantly inhibited the level of TGF-β and the phosphorylation levels of Smad2 and Smad3 in KF, which were then reversed after overexpressing SPARC expression (<a class="elsevierStyleCrossRef" href="#fig0006">Fig. 6</a>).</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Discussion</span><p id="para0028" class="elsevierStylePara elsevierViewall">Keloid is the result of excessive local tissue fibrosis after skin injury and wound healing.<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> It is characterized by aggressive growth of fibroblasts and excessive deposition of ECM.<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Keloid is prone to recurrence and epitaxial growth without comprehensive anti-scar therapy after surgical resection.<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> KF are flat and long spindle-shaped, with an obvious proliferation of spinous cells and increased cell layers in vivo, and are often considered to be the key cells of keloid formation.<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Fibroblasts are the main cell population in the lesional area, which proliferate and secrete a large amount of ECM, resulting in excessive collagen synthesis and deposition.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> Therefore, finding therapies or drugs to inhibit fibroblast proliferation and ECM may be an effective way to treat keloids. In this study, the authors demonstrated the promotive role of CEMIP and its relationship with SPARC in KF.</p><p id="para0029" class="elsevierStylePara elsevierViewall">Previous studies have claimed that CEMIP acts as a stimulator in tumor cell growth, invasion, and spread of the tumors.<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> For example, CEMIP enhanced the proliferative and migrative capabilities of breast cancer and prostate cancer cells.<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> Moreover, CEMIP was reported to be increased in human and mouse inflamed synovial membranes and induce EMT pathway and fibrotic markers.<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Schmaus et al. revealed that Sulfated HA regulated the hyaluronan metabolism, proliferation and differentiation of fibroblasts by suppressing the hyaluronidase CEMIP.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> Deroyer et al. also reported that CEMIP was associated with the dedifferentiation of human chondrocyte into fibroblast-like chondrocytes and that CEMIP promoted α-SMA expression and TGF-β signaling towards the p-Smad2–3/Alk5/PAI-1 pathway.<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> In the present study, the authors found that CEMIP was highly expressed in KF. CEMIP depletion repressed the capabilities of KF to proliferate, invade and migrate as well as suppressed the deposition of ECM.</p><p id="para0030" class="elsevierStylePara elsevierViewall">The matricellular protein SPARC has been proven to participate in scar formation and tissue fibrosis.<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Previous studies have implicated that the depletion of SPARC in mice or rats markedly alleviated dermal, renal, pulmonary, or hepatic fibrotic processes.<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> Lin et al. found that SPARC expression was increased in keloid dermal tissue.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> In addition, SPARC led to an increase in collagen matrix contraction and cell proliferation, thus promoting excessive wound healing and scar formation in human Tenon's capsules after filtration surgery.<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Through the present research, it was discovered that CEMIP can be co-expressed with SPARC and CEMIP can bind to SPARC. With the aim of further confirming the relationship between these two proteins, co-IP was performed to verify the combination of CEMIP and SPARC. It was implicated that SPARC overexpression counteracted the suppressive impacts of CEMIP interference on KF cell proliferation, invasion, migration, as well as ECM deposition.</p><p id="para0031" class="elsevierStylePara elsevierViewall">Transforming Growth Factor-β (TGF-β) is viewed to be a critical fibrotic cytokine.<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> TGF-β1 can directly or indirectly regulate the proliferative or apoptotic capability of fibroblasts, and then affect the formation of fibroblasts.<a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> TGF-β1 can also regulate collagen synthesis and degradation by activating or inhibiting fibroblastic type I and type III collagen promoters.<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> Meanwhile, by down-regulating the secretion of collagenase and promoting the expression of its protein inhibitor, TGF-β1 suppressed the degradation of collagen and other ECM proteins, and stimulated the synthesis of ECM-receptor integrin to make cells adhere to matrix proteins.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a> TGF-β1 phosphorylates intracellular Smad2 and Smad3 by binding to TGF-βI and II receptors on the cell membrane. Activated Smad2/Smad3 complex binds to Smad4 to enter the nucleus, and then affects fibroblast proliferative or apoptotic capabilities, collagen synthesis or degradation through gene regulation.<a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> A current Study has shown that SPARC induced TGF-β signaling promotes pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts.<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> In this study, the authors also explored the effects of CEMIP/SPARC on TGF-β1/Smad in KF. The data showed that CEMIP silencing specifically restrained the expression of TGF-β1 and the levels of p-Smad2 and p-Smad3, which were subsequently reversed by SPARC overexpression.</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Conclusion</span><p id="para0032" class="elsevierStylePara elsevierViewall">In summary, this study disclosed that CEMIP silencing repressed KF proliferative, migrative and invasive capabilities, as well as suppressed ECM deposition, which may rely on the modulation of CEMIP-mediated TGF-β1/Smad pathway. These results may provide novel insights into keloid pathogenesis and develop therapeutic strategies for patients with keloid.</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Availability of data and materials</span><p id="para0033" class="elsevierStylePara elsevierViewall">All data generated or analyzed during this study are included in this published article.</p></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">Ethics approval and consent to participate</span><p id="para0034" class="elsevierStylePara elsevierViewall">Not applicable.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0032">Patient consent for publication</span><p id="para0035" class="elsevierStylePara elsevierViewall">Not applicable.</p></span><span id="sec0026" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0033">Authors’ contributions</span><p id="para0036" class="elsevierStylePara elsevierViewall">Xinyi L and Xiaojing Li designed the study, drafted and revised the manuscript. Xinyi Li and Wei Zhang analyzed the data and searched the literature. All authors performed the experiments. All authors read and approved the final manuscript.</p></span><span id="sec0027" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0034">Funding</span><p id="para0037" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs0001">Natural Science Foundation of Anhui Province</span>, China (<span class="elsevierStyleGrantNumber" refid="gs0001">1908085QH327</span>) and the Scientific research project of colleges and universities in Anhui province (2022AH051191).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2291202" "titulo" => "Highlights" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abss0001" ] ] ] 1 => array:3 [ "identificador" => "xres2291203" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0002" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abss0003" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abss0004" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0005" "titulo" => "Conclusion" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1903463" "titulo" => "Keywords" ] 3 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0002" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "Bioinformatic analysis" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Cell culture and treatment" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Cell transfection" ] 3 => array:2 [ "identificador" => "sec0006" "titulo" => "Cell counting kit-8 (CCK-8) assay" ] 4 => array:2 [ "identificador" => "sec0007" "titulo" => "Immunofluorescence staining" ] ] ] 5 => array:3 [ "identificador" => "sec0008" "titulo" => "Wound healing assay" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0009" "titulo" => "Transwell assay" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Co-immunoprecipitation (co-IP)" ] 2 => array:2 [ "identificador" => "sec0011" "titulo" => "RNA extraction and quantitative real-time PCR (qRT-PCR)" ] 3 => array:2 [ "identificador" => "sec0012" "titulo" => "Western blot" ] 4 => array:2 [ "identificador" => "sec0013" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0014" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Downregulation of CEMIP suppresses KF proliferation, migration and invasion" ] 1 => array:2 [ "identificador" => "sec0016" "titulo" => "CEMIP silencing inhibits ECM deposition in KF" ] 2 => array:2 [ "identificador" => "sec0017" "titulo" => "CEMIP binds to SPARC" ] 3 => array:2 [ "identificador" => "sec0018" "titulo" => "CEMIP silencing restrains the proliferation, invasion and migration of KF by inhibiting SPARC" ] 4 => array:2 [ "identificador" => "sec0019" "titulo" => "Knockdown of CEMIP ameliorates ECM deposition in KF via binding to SPARC" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "CEMIP silencing blocks TGF-β/Smad signaling by suppressing SPARC" ] ] ] 7 => array:2 [ "identificador" => "sec0021" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0022" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0023" "titulo" => "Availability of data and materials" ] 10 => array:2 [ "identificador" => "sec0024" "titulo" => "Ethics approval and consent to participate" ] 11 => array:2 [ "identificador" => "sec0025" "titulo" => "Patient consent for publication" ] 12 => array:2 [ "identificador" => "sec0026" "titulo" => "Authors’ contributions" ] 13 => array:2 [ "identificador" => "sec0027" "titulo" => "Funding" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-11-21" "fechaAceptado" => "2024-10-11" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1903463" "palabras" => array:5 [ 0 => "CEMIP" 1 => "SPARC" 2 => "TGF-β/Smad" 3 => "Keloid Hyperplasia" 4 => "Keloid Fibroblasts" ] ] ] ] "tieneResumen" => true "highlights" => array:2 [ "titulo" => "Highlights" "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara007" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">•</span><p id="para0001" class="elsevierStylePara elsevierViewall">CEMIP silencing suppresses the proliferation, migration, invasion and ECM deposition of KF.</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">•</span><p id="para0002" class="elsevierStylePara elsevierViewall">CEMIP binds to SPARC.</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">•</span><p id="para0003" class="elsevierStylePara elsevierViewall">SPARC overexpression reversed the effects of CEMIP silencing on KF.</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">•</span><p id="para0004" class="elsevierStylePara elsevierViewall">The TGF-β/Smad signaling was associated with the regulation of CEMIP SPARC in KF.</p></li></ul></p></span>" ] "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Background</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Cell Migration Inducing Hyaluronidase 1 (CEMIP) is a protein that plays regulatory functions in a variety of cellular processes in many diseases. Nevertheless, its role and molecular mechanism in keloid hyperplasia are still elusive.</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">Expressions of CEMIP and Secreted Protein acidic and Rich in Cysteine (SPARC) were detected by qRT-PCR and western blot. CCK-8 assay, along with immunofluorescence staining, was applied for the assessment of cell proliferation. The capabilities of cells to migrate and invade were evaluated utilizing wound healing and Transwell, while Extracellular Matrix (ECM) deposition was measured by immunofluorescence and western blot. The interaction of CEMIP and SPARC was predicted by the Coexpedia and PPA-red databases and verified by co-IP. Western blot was adopted for the estimation of TGF-β/Smad pathway-related proteins.</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">The data demonstrated that CEMIP expression was elevated in Keloid Fibroblasts (KF). CEMIP interference suppressed cell proliferative, migrative and invasive capabilities and ECM deposition in KF. Mechanistically, bioinformatics analysis revealed that CEMIP was co-expressed with SPARC and CEMIP protein could bind to SPARC. SPARC expression was reduced in CEMIP-silenced cells. SPARC overexpression counteracted the impacts of CEMIP silencing on cell proliferative, migrative and invasive capabilities and ECM deposition in KF. In addition, the expressions of TGF-β/Smad signaling-related proteins were decreased by CEMIP silencing via the inhibition of SPARC.</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">In summary, this study revealed that CEMIP modulated KF proliferation, migration, invasion and ECM deposition by TGF-β/Smad signaling through binding to SPARC.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0002" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abss0003" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abss0004" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0005" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3070 "Ancho" => 3458 "Tamanyo" => 881799 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Downregulation of CEMIP suppresses KF proliferation, migration and invasion. The mRNA (A) and protein (B) levels of CEMIP in Keloid Fibroblasts (KF) and Normal Fibroblast (NF) were detected by qRT-PCR and western blot. The mRNA (C) and protein (D) levels of CEMIP in KF transfected with shRNA-CEMIP were detected by qRT-PCR and western blot. (E) Cell proliferation was evaluated by CCK-8 assay. (F) Immunofluorescence staining was used to detect the level of Ki67. (G) Cell migration was evaluated by wound healing assay. (H) Cell invasion was evaluated by transwell assay. Data are expressed as mean ± SD (*p < 0.05, **p < 0.01, ***p < 0.001).</p>" ] ] 1 => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3223 "Ancho" => 3468 "Tamanyo" => 1016681 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">CEMIP silencing inhibits ECM deposition in KF. (A) The protein levels of Collagen I, α-SMA and FN in KF transfected with shRNA-CEMIP were assessed by western blot. (B) Immunofluorescence staining was used to detect the level of FN in KF transfected with shRNA-CEMIP. Data are expressed as mean ± SD (*** p < 0.001).</p>" ] ] 2 => array:8 [ "identificador" => "fig0003" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1953 "Ancho" => 3458 "Tamanyo" => 307910 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">CEMIP binds to SPARC. (A) Coexpedia database revealed that CEMIP was co-expressed with SPARC. (B) The protein level of SPARC in KF transfected with shRNA-CEMIP was detected by western blot. (C) co-IP assay confirmed the binding of CEMIP and SPARC. (D) IP assay predicted that CEMPIP silencing inhibited SPARC precipitation. Data are expressed as mean ± SD (***p < 0.001).</p>" ] ] 3 => array:8 [ "identificador" => "fig0004" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1927 "Ancho" => 3458 "Tamanyo" => 654304 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0004" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">CEMIP silencing restrains the proliferation, invasion and migration of KF by inhibiting SPARC. The mRNA (A) and protein (B) levels of SPARC in KF transfected with Ov-SPARC were detected by qRT-PCR and western blot. (C) Cell proliferation was evaluated by CCK-8 assay. (D) Immunofluorescence staining was used to detect the level of Ki67. (E) Cell migration was evaluated by wound healing assay. (F) Cell invasion was evaluated by transwell assay. Data are expressed as mean ± SD (** p < 0.01, *** p < 0.001, # p < 0.05, ## p < 0.01, ### p < 0.001).</p>" ] ] 4 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2912 "Ancho" => 3458 "Tamanyo" => 844695 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">Knockdown of CEMIP ameliorates ECM deposition in KF via binding to SPARC. (A) The protein levels of Collagen I, α-SMA and FN in KF transfected with shRNA-CEMIP with the presence or absence of Ov-SPARC were assessed by western blot. (B) Immunofluorescence staining was used to detect the level of FN in KF transfected with shRNA-CEMIP with the presence or absence of Ov-SPARC. Data are expressed as mean ± SD (*** p < 0.001).</p>" ] ] 5 => array:8 [ "identificador" => "fig0006" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 2282 "Ancho" => 3458 "Tamanyo" => 479706 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0006" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">CEMIP silencing blocks TGF-β/Smad signaling by suppressing SPARC. Western blot was used to measure the levels of TGF-β, Smad2, p-Smad2, Smad3and p-Smad3 in KF transfected with shRNA-CEMIP with the presence or absence of Ov-SPARC. Data are expressed as mean ± SD (*** p < 0.001).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec1" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0001" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. 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