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.

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

“…34,35 One of the predominant HBV proteins in HCC is HBx, which activates oncogenes, leads to epigenetic modifications, modulates miRNAs and long non-coding RNAs and affects proliferation, apoptosis, metabolism, chemotherapy resistance and metastasis. [36][37][38][39][40][41] Here, we have identified HBxmediated inhibition of ZHX2 via miR-155 as another possible mechanism by which HBV influences HCC progression (Fig. 6c).…”

“…The miR-155 seed site in ZHX2 3 0 UTR was deleted for the 3 0 UTR-del mut. [36][37][38][39][40][41] Here, we have identified HBxmediated inhibition of ZHX2 via miR-155 as another possible mechanism by which HBV influences HCC progression (Fig. The pRL-TK plasmid was transfected into all cells as Renilla luciferase control.…”

BNIP3L-Dependent Mitophagy Promotes HBx-Induced Cancer Stemness of Hepatocellular Carcinoma Cells via Glycolysis Metabolism Reprogramming

“…The link between HBx-expressing and CSCs in HBV-related HCC has gradually become a research hotspots. It has been reported that HBx promoted a CD44 + CD133 + CSCs subset in malignant transformed L-02 cells and Huh7 cells, and HBx regulated tumorigenicity, self-renewal, and drug resistance in HCC cells [4,35,36]. In the present study, we selected two different HCC cells with distinct proportion of ABCG2 + subset, which Huh7 cells had a low ABCG2 + subset ratio and MHCC-97H had a high ABCG2+ subset ratio.…”

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

“…A recent study had shown that HBx-ΔC promoted the appearance of a CD133 hepatic CSC subset and confer cancer and stem cell-like features in HCC [27] . It is associated with cancer cell invasiveness and reduction of apoptotic response, tumorigenicity, chemoresistance, and migration [27,28] .…”