Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma
Metrics: PDF 1785 views | HTML 2738 views | ?
Weihua Li1, Man Li2, Dongjiang Liao3, Xinpeng Lu3, Xia Gu4, Qianqian Zhang2, Zhixiang Zhang2, Hui Li2
1Department of Gastroenterology, Zhujiang Hospital of Nanfang Medical University, Guangzhou 510280, China
2Department of Infectious Disease and Hepatology, Hepatitis Research Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
3Pathology Research Room, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510120, China
4Department of Pathology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Weihua Li, email: [email protected]
Keywords: HBV, C-terminal truncated HBx, metastasis-suppressors, transcriptional regulation, hepatocellular carcinoma
Received: February 01, 2016 Accepted: June 17, 2016 Published: July 04, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.