Growth Differentiation Factor 15 Is Induced by Hepatitis C Virus Infection and Regulates Hepatocellular Carcinoma-Related Genes

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.

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…19,20,34,48 Recent studies have also shown that the in vitro proliferation of ESCC cell lines was reduced by inhibition of PI3K or MEK1/2. 49,50 Here we demonstrated that GDF15 increased the growth of ESCC cell lines dose-dependently.…”

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…69 GDF-15 is strongly upregulated in hepatocellular carcinoma and other liver diseases, such as fibrosis or cirrhosis induced by hepatitis C virus. 70 GDF-15 autocrine signaling of transformed or infected hepatocytes then induces Akt, GSK-3/b catenin, Raf phosphorylation and other downstream targets, such as cell-cycle regulators (cyclins A2, E1 and D2) or adhesion molecules (E-cadherin). Interestingly, impairing GDF-15 can inhibit viral replication.…”

“…Interestingly, impairing GDF-15 can inhibit viral replication. 70 In malignant melanomas, GDF-15 is highly overexpressed, 71 and it is able to mimic VEGF in the neovascularization in the tumor site. 72 Similarly, in malignant glioblastomas, GDF-15 is upregulated as a reaction to anoxia, suggesting more general involvement in vascularization development.…”

Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration

“…GDF-15 is also found to be induced by hepatitis C virus and in hepatocellular carcinoma, where the GDF-15 autocrine signaling of infected hepatocytes mediates GSK-3/β catenin, Akt and Raf phosphorylation (Si et al, 2011). This is followed by cell-cycle regulation by e.g.…”

“…This is followed by cell-cycle regulation by e.g. cyclins A2, D2 and E1, or cell adhesion molecules, such as E-cadherin (Si et al, 2011). In malignant glioblastomas, GDF-15 is upregulated following anoxia, indicating its role in angiogenesis (Boyle et al, 2009;Huh et al, 2010).…”