Grant: Project Grant

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of death by cancer worldwide. This disease is still poorly understood, and the treatment options are limited. Consequently, the prognosis of HCC in general is not good, with only one out of five patients surviving more than five years after diagnosis. HCC etiology has a strong environmental component, which could potentially make half of the cases preventable. Indeed, the major known causes of the disease are infections with hepatitis viruses (B or C) or exposure to toxins such as alcohol and aflatoxin B1. Other important risk factors are diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism(s) by which NAFLD or other type of hepatitis can progress to HCC are far from being fully understood. Previous studies suggest that vitamin K deficiency might be implicated in the development of NAFLD and HCC. The current project focuses on one enzyme called VKORC1L1 which is implicated in the recycling of vitamin K in the liver. Our preliminary results support an important role for VKORC1L1 in preventing NAFLD and HCC in pre-clinical animal models. This project will investigate the molecular and cellular mechanisms by which VKORC1L1 and vitamin K are protecting the liver from oxidative stress. We will also assess in animal models the therapeutic potential of vitamin K and VKORC1L1 to prevent NAFLD and HCC. Finally, we will use human hepatocytes to test the relevance of our finding to humans, with the ultimate objective to develop more targeted treatments for NAFLD and HCC.