Role of Osteopontin in Hepatocellular Carcinoma

This project aims to dissect the molecular mechanisms whereby Osteopontin (OPN) drives hepatocellular carcinogenesis and progression, to fill the gap in our knowledge on the pathogenesis of hepatocellular carcinoma (HCC). Our main hypothesis was that OPN signals via CD44 to inhibit DNA repair, apoptosis and the cell cycle by reducing p53 signaling. Our results we have shown that both overexpression and ablation of OPN in hepatocyte drive the onset of HCC. In mice lacking OPN, we observed DNA hyper-methylation and reduction of the response to the DEN chemical carcinogen, followed by increased cancer stem cells (CSCs) at 5 months. In mice overexpressing OPN in hepatocytes, we did not find an increase in the number of CSCs at 5 months, suggesting that high levels of OPN would rather stimulate the progression of CSCs to HCC. The last reporting period will address this hypothesis. Finally, we showed that the impact of OPN on HCC was independent from CD44.