HCV infection exerts pro-oncogenic and pro-fibrotic effects, maybe interfering with relevant biological cellular processes 
. Moreover, HCV-dependent liver damage involves several indirect mechanisms, including chronic inflammation, fibrosis, oxidative stress and their physiopathological consequences. Thus, HCV infection may exert differential effects on liver cell populations: i.e. inflammatory response of macrophages, the activation and proliferation of mesenchymal cell populations (HSCs), and the capacity to induce hepatocyte transformation 
. In particular, during HCV infection, disturbances of the equilibrium between parenchyma and ECM, leading to a disproportionate increase in the deposition of the newly formed connective tissue components (fibrosis), is a common sequel of chronic active liver diseases with serious clinical consequences, such as cirrhosis and HCC development 
. Significant progress has been made in recent years in the analysis of the structural composition of ECM in normal and fibrotic liver and in the dissection of the molecular and cellular mechanisms involved in ECM alterations 
. However, up to now, no one has considered the possible existence of a direct link between the HCV-related ECM alterations, hepatic fibrosis and HCC occurrence. On these grounds, we investigated the effect of HCV infection in the activity and expression of principal proteins involved in intercellular and cell-ECM interactions.
We observed that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. These effects were accompanied by an increased FAK activation that physically interacted and phosphorylated paxillin and alpha-actinin. Our results are consistent with previous studies that demonstrated that paxillin and FAK overexpression, as well as their phosphorylation, were associated with low differentiation in the presence of portal vein thrombosis, along with extra-hepatic metastasis, all synonyms of high malignancy in HCC 
. However, few studies connect the expression of these proteins with HCV-dependent HCC 
. In addition, the HCV-dependent membrane to cytosol alpha-actin translocation could be the direct result of its increased phosphorylation by FAK; the increased expression of paxillin remains to be elucidated. Paxillin overexpression in HCC cells under different stimuli could be dependent on the activation of EMMPRIN(CD147)-mediated activation of FAK signaling pathways 
. Reversal effects of FAK silencing emphasize the role of this kinase enzyme in HCV-dependent effects on hepatocyte-like cells. Therefore, HCV seems to be implicated in inducing FAK activity, which in turn affects adhesiveness and the migratory ability of infected cells interfering with cytoskeleton re-organization.
Recently, it has been suggested that transformed hepatocytes, bearing HCV, are particularly active in stimulating neighboring cells, particularly HSCs, and in exerting paracrine effects 
. Our results demonstrated that increased HCV-dependent FAK activation may be a link among fibrosis, tumorigenesis and tumor progression by inducing ECM deregulation. Our idea is supported by the fact that FAK alterations may characterize both fibrosis and malignancy. In fact, the activation of FAK in Huh7.5.1 cells is associated with an increased cell proliferation, expression of alpha-SMA and HA release. Activation of HSCs may be cytokine-driven. During HCV infection, hepatocyte damage causes activation of Kupffer cells and consequent release of several different cytokines including TNF-alpha. This systemic inflammation coupled with the HCV-dependent enhancement of TNF-alpha production in hepatocyte, may be responsible of fibrogenesis and eventually hepatocarcinogenesis 
. This hypothesis is supported by previous studies demonstrating that circulating levels of TNF-alpha increase during HCV infection, and that this elevation correlates with severity of fibrosis and tissue-damage 
. Accordingly, we observed that HCV infection induced TNF-alpha production and release by hepatocytes suggesting that TNF-alpha should be further investigated as one of the crucial circulating factors that mediate HSCs activation during HCV infection 
. Furthermore, we found that the silencing of FAK significantly enhances the HCV-dependent apoptosis in LX-2, improving their ability to spontaneously resolve fibrogenesis.
In conclusion, we demonstrated that HCV infection, besides modifying the ECM network in hepatoma cells, stimulates mesenchymal cell proliferation and activation; in fact, the HCV infection causes the inappropriate indirect induction of HSCs, the main player in liver fibrosis occurrence, which in turn, greatly enhances the risk of subsequent cancer development.
Control of focal adhesion may represent not only a strategy to manage liver fibrosis, but also a novel therapeutic strategy for the control of HCC progression. This connection provides a new perspective on the investigation of biomolecular markers of HCC development and progression, as well as a new indication for anti-fibrotic and anti-oncogenic therapeutic targets.