INVASIVENESS OF HEPATOCELLULAR CARCINOMA INDUCED BY HEPATITIS VIRUSES

Primary hepatocellular carcinoma is one of the most common cancers and the third leading cause of death from cancer worldwide. High vascular invasion, metastasis potential and recurrence after surgical resection contribute to the poor prognosis of patients with HCV or HBV related HCC. While different studies have established a causative effect of HCV on EMT in cancer cells, no data exists regarding HCV and HBV involvement in regulation of invadopodia, specialized actin-based membrane protrusions, which are key features of invasive cancer. We aimed to explore the influence of HCV and HBV infection on invadopodia formation and activation in hepatoma cells. Moreover, since significant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV infections, we aimed to evaluate the hypothesis that HCV and HBV infection have a different effect on migrative-invasive cell properties. We demonstrate that HCV and HBV promote hepatocytes invasion, matrix degradation and invadopodia formation in the infected cells. Expression of genes involved in migration-invasion and invadopodia related pathways are upregulated in Hepatitis infected cells on both transcriptional and translational levels. Our results suggest that the non-structural oncogenic HCV protein, NS3, is involved in invadopodia inducing pathways. Moreover it appears that HCV induces genes involved in invadopodia formation and maturation that are different from those induced by HBV.

Exploring the nature of molecular paths that start with Hepatitis viruses infection and finalize with cell motility and invasiveness may allow us to identify novel targets for metastatic HCC personalized-therapies and prognosis according to etiology.