Understanding the role of cholesterol and the effects of statins and ezetimibe for the prevention and treatment of hepatocarcinogenesis

We hypothesize that an altered intracellular cholesterol metabolism facilitates cell proliferation of hepatocellular carcinoma (HCC), as result of modifications in expression of key-regulators of cell functions, such the “switch genes”.

Hence, pharmacologic interventions aimed to correct the altered intracellular cholesterol metabolism may be beneficial.We aim: i) to improve the understanding of the alterations in intracellular cholesterol metabolism promoting HCC; and to ii) to unravel key genes that “switch” the hepatocyte phenotype toward a tumoral one.

Liver tumors and normal counterpart (from HCC patients and from a study in which patients were treated with simvastatin and ezetimibe) and cell models better resembling human hepatic cholesterol metabolism, will be used.

New therapeutic targets will be identified, and the effects of the new treatments will be evaluated using network analysis, enabling the generation of networks of interactions between data of different types (e.g., methylome, transcriptome, biochemical parameters).

This project has great value for patients because the outcomes may indeed rapidly translate into a better management of HCC, being most of the drugs tested already approved and in use. Hence the knowledge gained may constitute the basis of mechanism-based intervention and drug repurposing.

Beyond the clinical research and healthcare related values, the project has also a strategic value because will strengthen the collaboration between Vita-Salute San Raffaele University, Milan, and the Karolinska Institutet/Karolinska University Hospital, which are two partners of the European University Hospital Alliance.