Oncotarget

Research Papers:

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

Weihua Li _, Man Li, Dongjiang Liao, Xinpeng Lu, Xia Gu, Qianqian Zhang, Zhixiang Zhang and Hui Li

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Oncotarget. 2016; 7:55110-55127. https://doi.org/10.18632/oncotarget.10399

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Abstract

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

Correspondence to:

Weihua Li, email: liweihuascu@163.com

Keywords: HBV, C-terminal truncated HBx, metastasis-suppressors, transcriptional regulation, hepatocellular carcinoma

Received: February 01, 2016    Accepted: June 17, 2016    Published: July 04, 2016

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.


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