title: C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway.
abstract: Hepatitis B virus (HBV) is a major risk factor of chronic liver disease and hepatocellular carcinoma (HCC). Random integration of HBV DNA into the host genome is frequent in HCC leading to truncation of the HBV DNA, particularly at the C-terminal end of the HBV X protein (HBx). C-terminally truncated HBx (HBx-ΔC) has been implicated in playing a pro-oncogenic role in hepatocarcinogenesis. However, the mechanism whereby HBx-ΔC1 contributes to hepatocarcinogenesis remains unclear. In this study, we investigated the functional role of HBx-ΔC1 in regulating liver cancer stem cell (CSC) properties. Using Tet-on inducible system, we found that HBx-ΔC1 enhanced CSC properties including self-renewal, tumorigenicity, chemoresistance, migration and expression of liver CSC markers, when compared with the full-length HBx counterpart and vector control. Interestingly, HBx-ΔC1 conferred resistance in HCC cells towards sorafenib treatment through suppression of apoptotic cascade. In addition, HBx-ΔC1 upregulated a panel of stemness genes, in which Nanog was found to be among the most significant one in both trasnfected cell lines. Consistently, Nanog was upregulated in human HCC samples which had HBx-ΔC1 expression. Furthermore, the induction of CSC properties by HBx-ΔC1 was via the Stat3/Nanog pathway, as administration of Stat3 inhibitor abolished the HBx-ΔC1-induced self-renewing capacity. In conclusion, our data suggest that HBx-ΔC1 enhances liver CSCs properties through Stat3/Nanog cascade, and provide a new insight for the therapeutic intervention for HBV-related HCC.
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Rachel Hiu Ha
authors.initials: RHH
authors.lastname: Ching
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Karen Man Fong
authors.initials: KMF
authors.lastname: Sze
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Eunice Yuen Ting
authors.initials: EYT
authors.lastname: Lau
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Yung-Tuen
authors.initials: YT
authors.lastname: Chiu
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Joyce Man Fong
authors.initials: JMF
authors.lastname: Lee
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Irene Oi Lin
authors.initials: IOL
authors.lastname: Ng
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|Current address: Department of Applied Biology and Chemical Technology, Lee Shau Kee Building, Hong Kong Polytechnic University, Hong Kong.
authors.forename: Terence Kin Wah
authors.initials: TKW
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000970:Antineoplastic Agents; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
keywords: HCC; Stat3; hepatocellular carcinoma; nanog; stemness; truncated HBx