Interferon regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma

Autor: Dan Li, Gulam Waris, Erdene Baljinnyam, Neerja Kaushik-Basu, Ozge Cevik, Betsy J. Barnes, Dinesh Manvar, Erica Maria Pimenta
Přispěvatelé: [Cevik, Ozge -- Li, Dan -- Baljinnyam, Erdene -- Manvar, Dinesh -- Pimenta, Erica M. -- Barnes, Betsy J. -- Kaushik-Basu, Neerja] Rutgers Biomed & Hlth Sci, Dept Microbiol Biochem & Mol Genet, Newark, NJ 07103 USA -- [Cevik, Ozge] Cumhuriyet Univ, Fac Pharm, Dept Biochem, TR-58140 Sivas, Turkey -- [Li, Dan -- Pimenta, Erica M. -- Barnes, Betsy J.] New Jersey Med Sch Canc Ctr, Rutgers Biomed & Hlth Sci, Newark, NJ 07103 USA -- [Li, Dan -- Barnes, Betsy J.] Northwell Hlth, Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA -- [Waris, Gulam] Rosalind Franklin Univ Med & Sci, Chicago, IL 60064 USA -- [Kaushik-Basu, Neerja] NIH, Infect Dis & Microbiol Integrated Review Grp, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA
Rok vydání: 2017
Předmět:
Zdroj: The Journal of biological chemistry. 292(52)
ISSN: 1083-351X
Popis: WOS: 000419013000041
PubMed ID: 29079574
Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
National Institutes of Health [CA153147, CA191903]; International Postdoctoral Research Fellowship Program by the Scientific and Technological Research Council of Turkey (TUBITAK) [2219]
This work was supported by National Institutes of Health Grants CA153147 (to N. K.-B.) and CA191903 (to B. J. B.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Supported by the International Postdoctoral Research Fellowship Program provided by the Scientific and Technological Research Council of Turkey (TUBITAK) 2219.
Databáze: OpenAIRE
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