Grant: Project Grant

The liver carries out many vital functions such as metabolism of dietary nutrients, storage of vitamins and iron, synthesis of blood proteins and formation of bile. Besides, the liver purifies blood to prevent toxic substances from reaching other vital organs. Hepatocytes, which are the main cell type in the liver, detoxify and eliminate toxic substances that enter blood. During this process, hepatocytes may get injured and undergo death, which prompts adjacent normal cells to proliferate regenerate a functional liver mass. However, repeated/persistent assaults (e.g., alcohol abuse, hepatitis virus infection) induce chronic inflammation and liver 'fibrosis', leading to 'cirrhosis' - characterized by replacement of loss of liver tissue with fibrous tissue, resulting in reduced liver functions. In livers with cirrhosis, hepatocytes undergo recurrent proliferation to restore liver functions. This causes the formation of liver nodules, within which cells accumulate genetic lesions and may become cancerous. While liver failure caused by cirrhosis ranks among the top 10 causes of death in the western world, liver cancer remains the 3rd leading cause of cancer death. Understanding the molecular basis of abnormal hepatocyte proliferation following liver injury is essential to develop more efficient treatments for liver cancer. The key mediators of hepatocyte proliferation are cytokines and growth factors. Normally, their actions are tightly controlled by diverse mechanisms, one of which is mediated by the 'Suppressor Of Cytokine Signaling' (SOCS) family of proteins. The genes coding for SOCS1 and SOCS3 proteins are frequently inactivated in liver cancer biopsies, indicating that they play important roles in preventing hepatocytes from becoming cancerous. Our goal is to understand how these SOCS proteins function in the liver using mouse models of liver cancer so that this knowledge could be used to develop rational strategies to treat liver cancer.