HCV core-mediated activation of latent TGF-β via thrombospondin drives the crosstalk between hepatocytes and stromal environment

Abstract

The mechanisms by which fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) develop during chronic hepatitis C virus (HCV) infection are not fully understood. We previously observed that HCV core protein induced a TGF-β-dependent epithelial mesenchymal transition, a process contributing to the promotion of cell invasion and metastasis by impacting TGF-β1 signalling. Here we investigated HCV core capacity to drive increased expression of the active form of TGF-β1n transgenic mice and hepatoma cell lines. We used an in vivo model of HCV core expressing transgenic mice. We observed that about 50% of genes deregulated by core protein expression were TGF-β1 target genes. Active TGF-β levels were increased in HCV core transgenic mouse livers. Overexpression of core protein in hepatoma cells increased active TGF-β levels in culture supernatants and induced Smad2/3 phosphorylation, thus reflecting activation of the TGF-β signaling pathway. Moreover, our data showed the implication of thrombospondin-1 in core-dependent TGF-β activation. Finally, hepatoma cells expressing HCV core could activate stellate cells in co-culture and this activation was TGF-β dependent. Collectively, these data delineate a novel paradigm where HCV may be related to liver pathogenesis through its ability to induce a local, intrahepatic TGF-β activation. They argue for a dual impact of HCV core on liver fibrosis and liver carcinogenesis: HCV core could act both as autocrine and paracrine factor modulating TGF-β responses within hepatocytes and in stromal environment through TGF-β activation.