Regulation of Stemness and Metabolic Networks by Polycomb Repressive Complex 2 in Hepatitis B Virus mediated Liver Cancer
Abstract
Chronic Hepatitis B Virus (HBV) infection results in liver cancer. Although effective vaccines are available to prevent HBV infection, current treatment options for 240 million people worldwide who are chronic carriers of HBV are inadequate. Moreover, there is extremely high risk of HBV infection to a newborn if the mother is a chronic carrier of the virus. New therapeutic approaches targeting key molecules involved in liver cancer as well as cancer stem cells is required to prevent liver cancer pathogenesis. In my first study, I investigated the mechanisms involved in the formation of hepatic cancer stem cells (hCSCs). hCSCs are one of the reasons for relapse of cancer after treatment. Understanding how these hCSCs form would enable development of therapeutic strategies to prevent their formation. Using human and mouse liver cancer cell lines and tissue samples, I showed that PolyComb Repressive Complex 2 (PRC2) regulates pluripotency in hepatocytes. Loss of PRC2 function during HBV infection results in re-expression of several molecules including EpCAM. EpCAM undergoes regulated intramembrane proteolysis to generate intracellular domain, EpICD. EpICD activates Wnt signaling, resulting in the expression of several cancer stem cell markers and pluripotency genes. The re-expression of these genes could pave the way for the formation of hCSCs. Hence, stabilizing the PRC2 complex will likely affect development of hCSCs. In my second study, I researched the metabolic deregulation that occurs during HBV infection. It is well known that cancer cells alter metabolic pathways to meet their unrestricted proliferative requirements. Employing RNA Seq studies in HBV infected hepatocytes, I identified downregulation of cholesterol metabolism genes, nuclear encoded mitochondrial genes as well as upregulation of amino acid transporters and purine biosynthesis genes. I am currently working on understanding how these changes promote liver cancer and how they can be rectified. Targeting metabolic pathways would restore metabolic regulation and induce metabolic stress in cancer cells which could eventually induce apoptosis. To conclude, my research has identified a novel mechanism by which hCSCs could develop in liver cancer and identified PRC2 as a key molecule that has therapeutic potential. My ongoing research will enable us to understand how HBV brings about metabolic deregulation in coordination with induction of hCSC genes.
Degree
Ph.D.
Advisors
Andrisani, Purdue University.
Subject Area
Molecular biology|Oncology
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