COOH-terminal deletion of HBx gene is a frequent event in HBV-associated hepatocellular carcinoma

Liu, Xiaohong; Lin, Jing; Zhang, Shu‐Hui; Zhang, Shunmin; Feitelson, Mark A.; Gao, Hengjun; Zhu, Minghua

doi:10.3748/wjg.14.1346

Cited by 40 publications

(37 citation statements)

References 23 publications

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“…Therefore, COOH-terminal deletion is a major feature of HBx identified in tumor tissue. In addition, a specific integration of HBx at GA-rich region of 17p13 locus (repeat region 56047...56210/ rpt_family = 'GA-rich') was also found in 6 of the 14 HCC patients in our previous study (24).…”

Section: Hbx Gene Sequencing In Hepatocellular Carcinoma Tissues Fromsupporting

confidence: 54%

“…HBx also plays a role in regulating a series of cell-signaling cascades, most notably in the Ras-and Raf-induced mitogen-activated protein kinase pathways, and in inactivation of tumor suppressive genes through promoter hypermethylation (30). Previous studies have demonstrated that HBx deletion, especially the COOHterminal deletion of HBx, is a frequent event in HBV-associated HCC tissues (11,12,24).…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

Liu

Li²,

Zhang³

et al. 2011

Oncol Rep

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Abstract. The carcinogenic role of hepatitis B virus x protein (HBx) in hepatocellular carcinoma (HCC) remains largely unknown. Centromere protein A (CENP-A) has been found to be frequently overexpressed in HCC. In the present study, we aimed to investigate the role of HBx in regulating CENP-A activity in HCC carcinogenesis. CENP-A expression was examined and the HBx gene was sequenced in 20 HBsAgpositive HCC patients and corresponding non-cancerous liver tissues. The influence of HBx mutants on CENP-A expression in HepG2 cells was analyzed by a series of assays. We found that CENP-A expression was significantly elevated in HCC tissues. HBx deletion, especially the COOH-terminal deletion of HBx is a frequent event in HBV-associated HCC tissues. A positive correlation was found between CENP-A expression and HBx COOH mutation in HCC tissues. HBx mutant increased the expression of the CENP-A mRNA and protein compared with full-length HBx. However, HBx did not directly interact with CENP-A. It is concluded that overexpression of CENP-A is closely associated with HBx COOH mutation in HCC. HBx mutant can increase CENP-A expression, probably through a mechanism independent of their physical combination, and thereby it may represent a potential therapeutic strategy for HCC.

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Section: Hbx Gene Sequencing In Hepatocellular Carcinoma Tissues Fromsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

Liu

Li²,

Zhang³

et al. 2011

Oncol Rep

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“…A number of studies have reported that a frequently occurring HBx mutation is the deletion of the COOH-terminus in tissue samples of patients with HCC [3][4][5] . These data suggest that COOH-terminal truncations of HBx may play a critical role in hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…As such, HBx is involved in the regulation of genotoxic stress responses, protein degradation pathways, cell proliferation and apoptosis, immune responses and cell adhesion [2] . It has been reported that COOH-terminal deletions of HBx are frequent events in HBV-associated HCC tissues [3][4][5] . In addition, our previous study found a natural mutant of HBx that had 27 truncated amino acids at the COOH-terminal (termed HBxΔ127) [6] , which was consistent with other reports [3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that COOH-terminal deletions of HBx are frequent events in HBV-associated HCC tissues [3][4][5] . In addition, our previous study found a natural mutant of HBx that had 27 truncated amino acids at the COOH-terminal (termed HBxΔ127) [6] , which was consistent with other reports [3][4][5] . It has been reported that HBx mutants with the COOH-terminal deletion abrogated the antiproliferative effects of wild type HBx [7] .…”

Section: Introductionmentioning

confidence: 99%

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A mutant of HBx (HBxΔ127) promotes hepatoma cell growth via sterol regulatory element binding protein 1c involving 5-lipoxygenase

Wang

Zhang

et al. 2010

Acta Pharmacol Sin

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Aim: Previously, we identified a natural mutant of hepatitis B virus X gene (HBx) with a deletion from 382 to 401 base pairs (termed HBxΔ127), which could potently enhance growth of hepatoma cells. In this study, we further investigated the mechanism of increased hepatoma cell growth that was mediated by HBxΔ127. Methods: We examined the effect of HBxΔ127 on the transcription factor sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS) in a model of HepG2-XΔ127 (or H7402-XΔ127) cells, which was stably transfected with HBxΔ127 gene in a human hepatoma HepG2 (or H7402) cell line. Results: Relative to wild type HBx, HBxΔ127 was able to potently activate SREBP-1c at the levels of promoter activity, mRNA and protein by a luciferase reporter gene assay, RT-PCR and Western blot analysis. Then, using the treatment with MK886, a specific 5-lipoxygenases (5-LOX) inhibitor, (or 5-LOX siRNA) we identified that 5-LOX was responsible for the upregulation of SREBP-1c by luciferase reporter gene assay, RT-PCR and Western blot analysis. Because FAS was a target gene of SREBP-1c, we further showed that HBxΔ127 was able to strongly activate the promoter activity of FAS and upregulated the mRNA expression level of FAS as well, by luciferase reporter gene assay and RT-PCR. In function, flow cytometry analysis revealed that FAS contributed to the growth of hepatoma cells that was mediated by HBxΔ127, using cerulenin (a FAS inhibitor). Conclusion: HBxΔ127 promotes hepatoma cell growth through activating SREBP-1c involving 5-LOX.

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Characterization of occult hepatitis B virus strains in south african blood donors†

et al. 2009

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T he implementation of nucleic acid testing (NAT) in blood donations from areas with high or low prevalence of hepatitis B virus (HBV) infection has resulted in the identification of a small number of infections in the preseroconversion window period (WP) 1 and a considerably larger number of blood units containing no detectable hepatitis B surface antigen (HBsAg) but low levels of HBV DNA associated, in most cases, with anti-HBc, suggesting an established infection. These cases were called occult HBV infection (OBI). 2 In Europe, where HBV genotypes A2 and D are prevalent, OBIs are detected in 1:2,000 to 1:20,000 donations 3,4 and are characterized by occurring in older donors (median age 51), mostly males (90%), and with normal levels of alanine aminotransferase (ALT). Viral load is consistently below 1,000 IU/mL (median, 25 IU/mL) and, compared to the dominance of genotype A2 in HBsAg-positive infections, a significantly higher proportion of OBI genotype D is observed. The remarkably high frequency of multiple amino acid substitutions in the pre-S/S proteins (100% in the major hydrophilic region [MHR] of genotype D OBIs) affecting both humoral and cellular epitopes strongly suggested that OBIs in Europe appears, to a large extent, determined by host immune pressure.

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COOH-terminal deletion of HBx gene is a frequent event in HBV-associated hepatocellular carcinoma

Abstract: AIM:To investigate the hepatitis B virus (HBV) x gene (HBx) state in the tissues of HBV-related hepatocellular carcinoma (HCC) in Chinese patients and whether there were particular HBx mutations.

Cited by 40 publications

References 23 publications

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

A mutant of HBx (HBxΔ127) promotes hepatoma cell growth via sterol regulatory element binding protein 1c involving 5-lipoxygenase

Characterization of occult hepatitis B virus strains in south african blood donors†

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