Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-β pathway

Abstract

Hepatitis C virus (HCV) is a major risk factor for human hepatocellular carcinoma (HCC) but the mechanisms underlying HCV-induced carcinogenesis are still poorly understood. We have hypothesized that viral variants, selected during long-term infection, might contribute to cellular transformation. To address this issue, we have investigated the effect of natural HCV core variants isolated from liver tumors (T), or their non-tumor (NT) counterparts, on the tumor growth factor-b (TGF-b) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-b reporter gene activity with the expression of core sequences isolated from liver tumors. In contrast, moderate or no effects were observed with non-tumor mutants or a core reference sequence. The molecular mechanisms have been characterized and involved the inhibition, by tumor-derived cores, of the DNA-binding activity of the Smad3/4 transcription factors complex. This inhibition occurs through a direct interaction between the central domain (amino acids 59-126) of tumor-derived core and the MH1 DNA-binding domain of Smad3, thus preventing its binding to DNA. We have therefore identified a new cell-signaling pathway targeted by HCV core and inhibited by tumor-derived core sequences. These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-b antiproliferative effects. Oncogene (2005) 24, 6119-6132.

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…In addition, transgenic mice overexpressing a dominant negative TBRII exhibit significant increase in incidence, size and multiplicity of preneoplastic lesions and of HCCs (Tang et al, 1998;Kanzler et al, 2001). Also, in chronic hepatitis C infection, HCV-derived core protein associates with the Smad3 MH1 domain inhibiting its DNA-binding activity (Pavio et al, 2005). Smad2 and Smad4 gene mutations have also been identified in 5-10% HCCs (Yakicier et al, 1999;Longerich et al, 2004).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Smad2 mutations (o5%) and loss of Smad4 expression (10%) are infrequent molecular events (Yakicier et al, 1999;Longerich et al, 2004). Smad3 mutations have not been described in human hepatocarcinogenesis yet; however, recently published data clearly show a physical interaction between Smad3 and the HCV core protein, consequently antagonizing DNA-binding capacity of Smad3 and therefore reducing TGFb-dependent signaling (Cheng et al, 2004;Pavio et al, 2005). Furthermore, the inhibitory Smad7 has been found to be upregulated in about 60% of advanced HCCs, but not in dysplastic nodules and early HCCs (Park et al, 2004).…”

Viral hepatitis and liver cancer: the case of hepatitis C

“…Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-b pathway (Pavio et al, 2005), suggesting that during chronic infection, viral variants that promote cell transformation by providing clonally expanding cells with resistance to TGF-b antiproliferative effects are actively selected. Indeed, HCV exists as quasi-species in patient sera or tissues and the switch from acute to chronic infection has been associated with a wider variety of viral quasispecies (Thimme et al, 2002).…”

“…To reconcile these apparently conflicting findings, it has been proposed that HCV core might have a dual action on the TGF-b system depending on the phase of the disease. Early in HCV infection, HCV core would contribute to fibrogenesis by increasing TGF-b synthesis, and then, after long-term of fibrosis and inflammation and in the context of cirrhotic livers, HCV core variants that contribute to clonal cell expansion and cellular transformation by inhibiting TGF-b-dependent antiproliferative pathways may arise and be selected (Pavio et al, 2005).…”