C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway
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Rachel Hiu Ha Ching1,2,*, Karen Man Fong Sze1,2,*, Eunice Yuen Ting Lau1,2,*, Yung-Tuen Chiu1,2, Joyce Man Fong Lee1,2, Irene Oi Lin Ng1,2, Terence Kin Wah Lee1,2,3
1State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
2Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
3Current address: Department of Applied Biology and Chemical Technology, Lee Shau Kee Building, Hong Kong Polytechnic University, Hong Kong
*These authors have contributed equally to this work
Terence Kin Wah Lee, email: firstname.lastname@example.org
Irene Oi Lin Ng, email: email@example.com
Keywords: truncated HBx, Nanog, Stat3, stemness, hepatocellular carcinoma (HCC)
Abbreviations: Hepatitis B virus, HBV; Hepatocellular carcinoma, HCC; HBV X protein, HBx; C-terminally truncated HBx, HBx-ΔC1; cancer stem cell, CSC.
Received: March 17, 2016 Accepted: January 16, 2017 Published: February 08, 2017
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.
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