title: 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.
authors.affiliation: Department of Gastroenterology, Zhujiang Hospital of Nanfang Medical University, Guangzhou 510280, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Infectious Disease and Hepatology, Hepatitis Research Room, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Pathology Research Room, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510120, China.
authors.forename: Dongjiang
authors.initials: D
authors.lastname: Liao
authors.affiliation: Pathology Research Room, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510120, China.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pathology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Infectious Disease and Hepatology, Hepatitis Research Room, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease and Hepatology, Hepatitis Research Room, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease and Hepatology, Hepatitis Research Room, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D051347:CapZ Actin Capping Protein / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics*; D014183:Transplantation, Heterologous; D054334:Viral Regulatory and Accessory Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C569638:ARHGDIA protein, human; C000598253:CAPZB protein, human; D051347:CapZ Actin Capping Protein; C085344:SERPIN-B5; D015843:Serpins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha
keywords: C-terminal truncated HBx; HBV; hepatocellular carcinoma; metastasis-suppressors; transcriptional regulation