Liver Cancer-Derived Hepatitis C Virus Core Proteins Shift TGF-Beta Responses from Tumor Suppression to Epithelial-Mesenchymal Transition

Abstract

BackgroundChronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-β is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-β signaling.Principal FindingsWe provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-β responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-β was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-β responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-β growth inhibitory effects to tumor promoting responses.Conclusion/SignificanceOur data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-β, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-β responses from cytostatic effects to EMT development.

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

“…[51][52][53] The role of EMT in fibrosis was established in lung and kidney and, in the liver, transition of hepatocytes, biliary cells and HSC has also been already reported. [22][23][24][25][26] TGFb, which we found secreted by LPC, is a well-known EMT inducer 22,23,25 that could trigger LPC transition by an autocrine/paracrine pathway and provide a new potential mechanism of fibrosis. However, we could not demonstrate the expression of mesenchymal markers (ie aSMA, desmin and FSP1) in CK19-positive LPC cells from AAF/CCl 4 -treated rats in vivo.…”

“…21 Among the large variety of factors secreted by myofibroblasts, transforming growth factor-b (TGFb), the most potent fibrogenic cytokine, is also a well-established mediator of epithelial-mesenchymal transition (EMT), which contributes to fibrosis following injury in several organs including the liver. [22][23][24][25][26] To investigate the fibrogenic potential of LPC, we established a new model in the rat in which persistent LPC expansion induced by a chronic 2-acetylaminofluorene (AAF) treatment was combined to the well-established model of liver fibrosis using chronic carbon tetrachloride (CCl 4 ) injection. 1 Metabolism of CCl 4 into highly reactive CCl 3 radicals by cytochrome P450 is responsible for centrilobular hepatocellular necrosis, which triggers matrix deposition starting around the central veins, with gradual formation of septa bridging neighboring central veins, without any ductular reaction.…”

“…We also investigated whether LPC may directly participate to fibrogenesis and serve as a source of myofibroblasts through EMT as reported for hepatocytes and biliary cells. [22][23][24][25][26] …”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…A link with insulin has also been found for HBV (see above). Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition which is discussed below [41] .…”

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

“…Indeed, evidence indicates that fetal rat hepatocytes are refractory to the apoptotic effects of TGF-b during epithelial-mesenchymal transition (EMT), showing characteristics of HCC cells, including higher levels of active AKT and Bcl-xL (Valde´s et al, 2002(Valde´s et al, , 2004. Moreover, the HCC-derived hepatitis-C virus core protein is capable of shifting TGF-b responses from cytostatic effects in hepatocytes to tumor-promoting responses with the development of EMT (Battaglia et al, 2009).…”