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Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes

Si, Y and Liu, X and Cheng, M and Wang, M and Gong, Q and Yang, Y and Wang, T and Yang, W (2011) Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS ONE, 6 (5).

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Abstract

Liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) are commonly induced by chronic hepatitis C virus (HCV) infection. We aimed to identify and characterize the involvement of previously screened cytokine GDF15 in HCV pathogenesis. We examined the GDF15 expression after HCV infection both in vitro and in vivo. Cultured JFH-1 HCV was used to determine the GDF15 function on virus propagation. GDF15 overexpression and RNA interference were employed to profile the GDF15-regulated genes, signaling pathways and cell biology phenotypes. The mRNA expression and protein secretion of GDF15 was dramatically increased in HCV-infected hepatoma cells, which maybe a host response to viral proteins or infection-induced cell stress. Patients infected with HCV had an average 15-fold higher blood GDF15 level than that of healthy volunteers. Three HCC individuals in the HCV cohort showed extremely high GDF15 concentrations. Transfection or exogenously supplied GDF15 enhanced HCV propagation, whereas knockdown of endogenous GDF15 resulted in inhibition of virus replication. Overexpressed GDF15 led to Akt activation and the phosphorylation of Akt downstream targeted GSK-3β and Raf. Several HCC-related molecules, such as E-cadherin, β-catenin, Cyclin A2/B1/D1, were up-regulated by GDF15 stimulation in vitro. Overexpression of GDF15 in hepatoma cells resulted in increased DNA synthesis, promoted cell proliferation, and importantly enhanced invasiveness of the cells. In conclusion, these results suggest that an elevated serum GDF15 level is a potential diagnostic marker for viral hepatitis, and GDF15 may contribute to HCV pathogenesis by altering the signaling and growth of host cells. © 2011 Si et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Si, Y
Liu, X
Cheng, M
Wang, M
Gong, Q
Yang, Y
Wang, T
Yang, W
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorJang, Sung KeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 27 May 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0019967
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Refereed: Yes
MeSH Headings: Carcinoma, Hepatocellular--genetics; Cell Line, Tumor; Gene Expression Regulation, Neoplastic--physiology; Growth Differentiation Factor 15--biosynthesis; Hepatitis C--physiopathology; Humans; Liver Neoplasms--genetics
Other ID: NLM PMC3100307
PubMed Central ID: PMC3100307
PubMed ID: 21625435
Date Deposited: 30 Aug 2012 15:01
Last Modified: 02 Feb 2019 13:58
URI: http://d-scholarship.pitt.edu/id/eprint/13860

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