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Wang Z, Ceniccola K, Florea L, et al. Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma. Infect Agent Cancer. 2015;10:19doi: 10.1186/s13027-015-0014-0.
Wang, Z., Ceniccola, K., Florea, L., Wang, B. D., Lee, N. H., & Kumar, A. (2015). Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma. Infectious agents and cancer, 1019. https://doi.org/10.1186/s13027-015-0014-0
Wang, Zhao, et al. "Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma." Infectious agents and cancer vol. 10 (2015): 19. doi: https://doi.org/10.1186/s13027-015-0014-0
Wang Z, Ceniccola K, Florea L, Wang BD, Lee NH, Kumar A. Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma. Infect Agent Cancer. 2015 Jul 08;10:19. doi: 10.1186/s13027-015-0014-0. eCollection 2015. PMID: 26157476; PMCID: PMC4495692.
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Infect Agent Cancer. 2015 Jul 08;10:19. doi: 10.1186/s13027-015-0014-0. eCollection 2015.

Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma.

Infectious agents and cancer

Zhao Wang, Kristin Ceniccola, Liliana Florea, Bi-Dar Wang, Norman H Lee, Ajit Kumar

Affiliations

  1. Department of Biochemistry, The George Washington University, Washington, DC USA.
  2. Department of Pharmacology, and Program in Molecular Oncology, The George Washington University, Washington, DC USA.
  3. McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD USA.

PMID: 26157476 PMCID: PMC4495692 DOI: 10.1186/s13027-015-0014-0

Abstract

BACKGROUND: Hepatitis C virus (HCV) infection is an established cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC); however, it is unclear if the virus plays a direct role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is critical determinant of epithelial architecture and hepatic development; depletion of HNF4α is correlated with oncogenic transformation. We explored the viral role in the inhibition of HNF4α expression, and consequent induction of tumor-promoting genes in HCV infection-associated HCC.

METHODS: Western blot analysis was used to monitor the changes in expression levels of oncogenic proteins in liver tissues from HCV-infected humanized mice. The mechanism of HNF4α depletion was studied in HCV-infected human hepatocyte cultures in vitro. Targeting of HNF4α expression by viral non-coding RNA was examined by inhibition of Luciferase HNF4α 3'-UTR reporter. Modulation of invasive properties of HCV-infected cells was examined by Matrigel cell migration assay.

RESULTS: Results show inhibition of HNF4α expression by targeting of HNF4α 3'-UTR by HCV-derived small non-coding RNA, vmr11. Vmr11 enhances the invasive properties of HCV-infected cells. Loss of HNF4α in HCV-infected liver tumors of humanized mice correlates with the induction of epithelial to mesenchymal transition (EMT) genes.

CONCLUSIONS: We show depletion of HNF4α in liver tumors of HCV-infected humanized mice by HCV derived small non-coding RNA (vmr11) and resultant induction of EMT genes, which are critical determinants of tumor progression. These results suggest a direct viral role in the development of hepatocellular carcinoma.

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