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Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis.
J Pathol 2015; 237(1):38-49JP

Abstract

Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development.

Authors+Show Affiliations

Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Gastroenterology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25925944

Citation

Zhu, Ranxu, et al. "Truncated HBx-dependent Silencing of GAS2 Promotes Hepatocarcinogenesis Through Deregulation of Cell Cycle, Senescence and P53-mediated Apoptosis." The Journal of Pathology, vol. 237, no. 1, 2015, pp. 38-49.
Zhu R, Mok MT, Kang W, et al. Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis. J Pathol. 2015;237(1):38-49.
Zhu, R., Mok, M. T., Kang, W., Lau, S. S., Yip, W. K., Chen, Y., ... Chan, H. L. (2015). Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis. The Journal of Pathology, 237(1), pp. 38-49. doi:10.1002/path.4554.
Zhu R, et al. Truncated HBx-dependent Silencing of GAS2 Promotes Hepatocarcinogenesis Through Deregulation of Cell Cycle, Senescence and P53-mediated Apoptosis. J Pathol. 2015;237(1):38-49. PubMed PMID: 25925944.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis. AU - Zhu,Ranxu, AU - Mok,Myth T S, AU - Kang,Wei, AU - Lau,Suki S K, AU - Yip,Wing-Kit, AU - Chen,Yangchao, AU - Lai,Paul B S, AU - Wong,Vincent W S, AU - To,Ka-Fai, AU - Sung,Joseph J Y, AU - Cheng,Alfred S L, AU - Chan,Henry L Y, Y1 - 2015/05/28/ PY - 2014/07/17/received PY - 2015/04/15/revised PY - 2015/04/22/accepted PY - 2015/5/1/entrez PY - 2015/5/1/pubmed PY - 2015/11/6/medline KW - GAS2 KW - HBV KW - apoptosis KW - cell cycle KW - hepatocellular carcinoma KW - senescence KW - truncated HBx SP - 38 EP - 49 JF - The Journal of pathology JO - J. Pathol. VL - 237 IS - 1 N2 - Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/25925944/Truncated_HBx_dependent_silencing_of_GAS2_promotes_hepatocarcinogenesis_through_deregulation_of_cell_cycle_senescence_and_p53_mediated_apoptosis_ L2 - https://doi.org/10.1002/path.4554 DB - PRIME DP - Unbound Medicine ER -