Abstract
Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.
Highlights
Hepatocellular carcinoma (HCC) is a complex and heterogeneous disease involved in multiple-stages and multiple-factors
We found that over-expression of HBxΔ31 decreased the mRNA levels of mammary serine protease inhibitor (Maspin), Rho GDP dissociation inhibitor α (RhoGDIα) and CAPZB in MIHA and HepG2 cells compared with full-length HBx and control vector
Previous studies have shown that HBx gene is frequent and spontaneous mutation in human HCC and leads to C-terminally truncated HBx (Ct-HBx) protein
Summary
Hepatocellular carcinoma (HCC) is a complex and heterogeneous disease involved in multiple-stages and multiple-factors. The high rate of metastasis or post-operation recurrence and the low response rate to chemotherapy are responsible for poor prognosis of HCC patients [1].
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