title: Upregulation of the putative oncogene COTE1 contributes to human hepatocarcinogenesis through modulation of WWOX signaling.
abstract: Family with sequence similarity 189, also known as COTE1, has been found to be significantly upregulated in hepatocellular carcinoma (HCC) specimens and cell lines and is associated with tumor size and differentiation. Furthermore, COTE1 contributes to hepatocellular carcinogenesis. The overexpression of COTE1 enhanced in vitro cell viability and colony formation in soft agar, and in vivo tumorigenicity of HCC-derived Focus and Huh7 cells. In contrast, COTE1 knockdown via RNAi markedly suppressed these phenotypes in YY-8103 and WRL-68 HCC cell lines. Mechanistic analyses indicated that COTE1 physically associated with WW domain-containing oxidoreductase (WWOX) and modulated WWOX tyrosine phosphorylation. The ectopic overexpression of COTE1 inhibited the WWOX-p53 signaling pathway by reducing the phosphorylation of WWOX at the Tyr33 residue in Focus cells. Conversely, COTE1 silencing activated tyrosine 33 phosphorylation of WWOX and induced WWOX-p53 mediated mitochondrial apoptosis in WRL-68 cells. In addition, COTE1 upregulation in Huh7 cells blocked the WWOX-cyclin D1 pathway via dephosphorylation of WWOX Tyr287, stimulating cell cycle progression whereas phosphorylation of Tyr287 of WWOX induced by COTE1 silencing resulted in activation of WWOX-cyclin D1 signaling, leading to cell cycle arrest in YY-8103 cells. Together, our findings suggest that the cytoplasmic protein COTE1 contributes to HCC tumorigenesis by regulating cell proliferation through the modulation of WWOX signaling.
authors.affiliation: Department of Hepatobiliary Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, P.R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing 210029, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing 210029, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing 210029, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing 210029, P.R. China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, P.R. China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, P.R. China.
authors.forename: Zeguang
authors.initials: Z
authors.lastname: Han
authors.affiliation: Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing 210029, P.R. China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009857:Oncogenes / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human