Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma

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.

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

“…HBx has been well documented with respect to playing an oncogenic role in HCC development. There is evidence available indicating that HBx promoted HCC cell invasion and metastasis by down‐regulating Wnt‐5α and up‐regulating MMP10 (Li et al ., 2016; Sze et al ., 2013). HBx serves as a transcriptional regulator of many oncogenes and tumor suppressor genes.…”

Polymorphisms and expression pattern of circular RNA circ-ITCH contributes to the carcinogenesis of hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) ranks the sixth most common cancer and the third cause of cancer-related mortality worldwide [ 1 , 2 ]. In Asia and sub-Saharan Africa areas, over 5% of the populations suffered chronically infected chronic hepatitis B virus (HBV) infection, which could reflect the elevated prevalence of HCC [ 1 , 3 – 5 ]. In china, the estimated new cases and deaths for HCC were 466.1 and 422.1 thousands, respectively [ 6 ].…”

A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway

“…Previous studies suggested that the random integration of HBV genome may led to the C-terminal truncation of HBx (HBx-ΔC, usually loss the C-terminal 27-30 aa) 28 . The HBx-ΔC frequently expressed in HBV-associated liver tumors, and play a important role in facilitating hepatocarcinogenesis 29 , 30 . Therefore, we further tested the reactivity of 9D11 in detections of natural HBx mutants via Western blot analyses of cell lysates of matched pair tissues derived from 5 additional CHB related HCC patients (patient 4 to 8).…”