title: Down-regulation of PTEN by HCV core protein through activating nuclear factor-κB.
abstract: The hepatitis C virus (HCV) core protein is an important causative agent in HCV related hepatocellular carcinoma (HCC). Tumor suppressor gene PTEN appears to act in the liver at the crossroad of processes controlling cell proliferation. In this study we investigated the effect of the HCV core protein on the PTEN pathway in hepatocarcinogenesis. The HCV core was transfected stably into HepG2 cell. The effect of HCV core on cell proliferation and viability were detected by 3-(4, 5)-dimethylthiahiazo-(-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) assay, clonogenic survival assay and Fluorescence Activating Cell Sorter (FACS) analysis. The expressions of PTEN were detected by real time RT-PCR and/or Western blot analysis, also the mechanism of down-regulation of PTEN was explored by western blot, luciferase assay and RNA interference. We found the HCV core promoted cell proliferation, survival and G2/M phase accumulation. It downregulated PTEN at mRNA and protein level and activated PTEN downstream gene Akt accompanied with NF-κB activation. Furthermore, the inhibition of HCV core by its specific shRNAs decreased the effect of growth promotion and G2/M phase arrest, inhibited the expression of nuclear p65 and increased PTEN expression. The activity of PTEN was restored when treated with NF-κB inhibitor PDTC. By luciferase assay we found that NF-κB inhibited PTEN promoter transcription activity directly in HCV core cells, while PDTC was contrary. Our study suggests that HCV proteins could modulate PTEN by activating NF-κB. Furthermore strategies designed to restore the expression of PTEN may be promising therapies for preventing HCV dependent hepatocarcinogenesis.
authors.affiliation: Department of Radiation Oncology, First Affiliated Hospital of Kunming Medical University Kunming 650032, Yunnan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, First Affiliated Hospital of Kunming Medical University Kunming 650032, Yunnan, China.
authors.forename: Rong-Qing
authors.initials: RQ
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, First Affiliated Hospital of Kunming Medical University Kunming 650032, Yunnan, China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Feng
authors.affiliation: Department of Radiation Oncology, First Affiliated Hospital of Kunming Medical University Kunming 650032, Yunnan, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Kunming General Hospital Kunming 650032, Yunnan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D015536:Down-Regulation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C066229:prolinedithiocarbamate; D011392:Proline; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Core protein; PTEN; hepatitis C virus; hepatocellular carcinoma