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Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels.
Cancer Lett 2015; 362(1):131-8CL

Abstract

Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumor dedifferentiation, infiltration, and metastasis. However, the underlying mechanism for E-cadherin downregulation in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) is still unclear. In this study, we found that ectopic expression of HCV core protein or infection with HCV in human hepatocytes upregulated the levels of the transcriptional repressors, E12 and E47, resulting in inactivation of the E-cadherin promoter, containing E-box motifs, and subsequent repression of its expression. E12/E47 knock-down almost completely abolished the potential of HCV core protein to repress E-cadherin expression. HCV core protein inhibited ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. E12/E47 upregulation ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered expression levels of EMT markers, including E-cadherin, plakoglobin, and fibronectin, and increased capacity for cell detachment and migration. In conclusion, HCV core protein represses E-cadherin expression by upregulating E12/E47 levels to induce EMT in HCV-associated HCC.

Authors+Show Affiliations

Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: kljang@pusan.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

25817725

Citation

Tiwari, Indira, et al. "Hepatitis C Virus Core Protein Induces Epithelial-mesenchymal Transition in Human Hepatocytes By Upregulating E12/E47 Levels." Cancer Letters, vol. 362, no. 1, 2015, pp. 131-8.
Tiwari I, Yoon MH, Park BJ, et al. Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels. Cancer Lett. 2015;362(1):131-8.
Tiwari, I., Yoon, M. H., Park, B. J., & Jang, K. L. (2015). Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels. Cancer Letters, 362(1), pp. 131-8. doi:10.1016/j.canlet.2015.03.032.
Tiwari I, et al. Hepatitis C Virus Core Protein Induces Epithelial-mesenchymal Transition in Human Hepatocytes By Upregulating E12/E47 Levels. Cancer Lett. 2015 Jun 28;362(1):131-8. PubMed PMID: 25817725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels. AU - Tiwari,Indira, AU - Yoon,Min-Ho, AU - Park,Bum-Joon, AU - Jang,Kyung Lib, Y1 - 2015/03/27/ PY - 2015/01/22/received PY - 2015/03/21/revised PY - 2015/03/23/accepted PY - 2015/3/31/entrez PY - 2015/3/31/pubmed PY - 2015/6/19/medline KW - E-cadherin KW - E12/E47 KW - Epithelial–mesenchymal transition KW - Hepatitis C virus core protein KW - Hepatocellular carcinoma SP - 131 EP - 8 JF - Cancer letters JO - Cancer Lett. VL - 362 IS - 1 N2 - Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumor dedifferentiation, infiltration, and metastasis. However, the underlying mechanism for E-cadherin downregulation in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) is still unclear. In this study, we found that ectopic expression of HCV core protein or infection with HCV in human hepatocytes upregulated the levels of the transcriptional repressors, E12 and E47, resulting in inactivation of the E-cadherin promoter, containing E-box motifs, and subsequent repression of its expression. E12/E47 knock-down almost completely abolished the potential of HCV core protein to repress E-cadherin expression. HCV core protein inhibited ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. E12/E47 upregulation ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered expression levels of EMT markers, including E-cadherin, plakoglobin, and fibronectin, and increased capacity for cell detachment and migration. In conclusion, HCV core protein represses E-cadherin expression by upregulating E12/E47 levels to induce EMT in HCV-associated HCC. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/25817725/Hepatitis_C_virus_core_protein_induces_epithelial_mesenchymal_transition_in_human_hepatocytes_by_upregulating_E12/E47_levels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(15)00224-4 DB - PRIME DP - Unbound Medicine ER -