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.
Highlights
Hepatitis C virus (HCV) is an important human pathogen affecting an estimated 170 million people worldwide [1]
We demonstrate that growth differentiation factor 15 (GDF15) is an HCV (HBV) induced host circulating biomarker and may play important roles during liver pathogenesis by regulating specific pathways and hepatocellular carcinomas (HCC)-related genes
In order to elucidate which viral protein may be causing this upregulation, the selected individual HCV proteins were transiently transfected into Huh7.5.1 cells, and the secreted GDF15 protein was determined by ELISA
Summary
Hepatitis C virus (HCV) is an important human pathogen affecting an estimated 170 million people worldwide [1]. Chronic HCV infection is often clinically asymptomatic but can frequently progress to liver fibrosis, cirrhosis and hepatocellular carcinomas (HCC). Both viral proteins and dysregulated immunocytes have been implicated for causing liver diseases, the knowledge about HCV infection induced hepatopathogenesis is still limited. Non-invasive serum predictors of HCV infection and knowledge of their potential roles during disease progression are urgently needed to help adjust treatment regimens and understand pathogenic mechanisms. Our previous work screened the possible involvement of growth differentiation factor 15 (GDF15) during HCV infection [2]
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