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Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression.
Eur J Cancer 2014; 50(15):2560-9EJ

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and chronic hepatitis B virus (HBV) infection is the major risk factor of HCC. The virus encodes HBV X (HBx) protein that plays a critical role in the development of HCC. Studies have revealed numerous HBx-altered genes and signalling pathways that heavily contribute to tumourigenesis of non-tumour hepatocytes. However, the role of HBx in regulating other critical gene regulators such as microRNAs is poorly understood, which impedes the exploration of a complete HBx-associated carcinogenic network. Besides, critical microRNAs that drive the transformation of non-tumour hepatocytes are yet to be identified. Here, we overexpressed C-terminal truncated HBx protein in a non-tumour hepatocyte cell line MIHA, and measured a panel of cancer-associated miRNAs. We observed that oncogenic miR-21 was upregulated upon ectopic expression of this viral protein variant. HBx-miR-21 pathway was prevalent in HCC cells as inhibition of HBx in Hep3B and PLC/PRF/5 cells significantly suppressed miR-21 expression. Subsequently, we showed that the upregulation of miR-21 was mediated by HBx-induced interleukin-6 pathway followed by activation of STAT3 transcriptional factor. The high dependency of miR-21 expression to HBx protein suggested a unique viral oncogenic pathway that could aberrantly affect a network of gene expression. Importantly, miR-21 was essential in the HBx-induced transformation of non-tumour hepatocytes. Inhibition of miR-21 effectively attenuated anchorage-independent colony formation and subcutaneous tumour growth of MIHA cells. Our study suggested that overexpression of miR-21 was critical to promote early carcinogenesis of hepatocytes upon HBV infection.

Authors+Show Affiliations

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37604, USA.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China. Electronic address: frankch@cuhk.edu.hk.

Pub Type(s)

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

Language

eng

PubMed ID

25087183

Citation

Li, Chi Han, et al. "Hepatitis B Virus X Protein Promotes Hepatocellular Carcinoma Transformation Through Interleukin-6 Activation of microRNA-21 Expression." European Journal of Cancer (Oxford, England : 1990), vol. 50, no. 15, 2014, pp. 2560-9.
Li CH, Xu F, Chow S, et al. Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression. Eur J Cancer. 2014;50(15):2560-9.
Li, C. H., Xu, F., Chow, S., Feng, L., Yin, D., Ng, T. B., & Chen, Y. (2014). Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression. European Journal of Cancer (Oxford, England : 1990), 50(15), pp. 2560-9. doi:10.1016/j.ejca.2014.07.008.
Li CH, et al. Hepatitis B Virus X Protein Promotes Hepatocellular Carcinoma Transformation Through Interleukin-6 Activation of microRNA-21 Expression. Eur J Cancer. 2014;50(15):2560-9. PubMed PMID: 25087183.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression. AU - Li,Chi Han, AU - Xu,Feiyue, AU - Chow,Sheungching, AU - Feng,Lu, AU - Yin,Deling, AU - Ng,Tzi Bun, AU - Chen,Yangchao, Y1 - 2014/07/30/ PY - 2014/03/06/received PY - 2014/07/04/revised PY - 2014/07/07/accepted PY - 2014/8/4/entrez PY - 2014/8/5/pubmed PY - 2014/12/17/medline KW - Hepatitis B X protein KW - Hepatitis B virus KW - Hepatocellular carcinoma KW - Interleukin 6 KW - MicroRNA-21 SP - 2560 EP - 9 JF - European journal of cancer (Oxford, England : 1990) JO - Eur. J. Cancer VL - 50 IS - 15 N2 - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and chronic hepatitis B virus (HBV) infection is the major risk factor of HCC. The virus encodes HBV X (HBx) protein that plays a critical role in the development of HCC. Studies have revealed numerous HBx-altered genes and signalling pathways that heavily contribute to tumourigenesis of non-tumour hepatocytes. However, the role of HBx in regulating other critical gene regulators such as microRNAs is poorly understood, which impedes the exploration of a complete HBx-associated carcinogenic network. Besides, critical microRNAs that drive the transformation of non-tumour hepatocytes are yet to be identified. Here, we overexpressed C-terminal truncated HBx protein in a non-tumour hepatocyte cell line MIHA, and measured a panel of cancer-associated miRNAs. We observed that oncogenic miR-21 was upregulated upon ectopic expression of this viral protein variant. HBx-miR-21 pathway was prevalent in HCC cells as inhibition of HBx in Hep3B and PLC/PRF/5 cells significantly suppressed miR-21 expression. Subsequently, we showed that the upregulation of miR-21 was mediated by HBx-induced interleukin-6 pathway followed by activation of STAT3 transcriptional factor. The high dependency of miR-21 expression to HBx protein suggested a unique viral oncogenic pathway that could aberrantly affect a network of gene expression. Importantly, miR-21 was essential in the HBx-induced transformation of non-tumour hepatocytes. Inhibition of miR-21 effectively attenuated anchorage-independent colony formation and subcutaneous tumour growth of MIHA cells. Our study suggested that overexpression of miR-21 was critical to promote early carcinogenesis of hepatocytes upon HBV infection. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/25087183/Hepatitis_B_virus_X_protein_promotes_hepatocellular_carcinoma_transformation_through_interleukin_6_activation_of_microRNA_21_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0959-8049(14)00807-7 DB - PRIME DP - Unbound Medicine ER -