Hepatocellular carcinoma (HCC) has become the second leading cause of cancer-related death worldwide. The up trending of HCC prevalence in the United States (especially in the State of Texas) is at least partially due to obesity epidemic with an estimate of 42.4% of the US population considered obese. Obesity-induced HCC is the terminal stage of non-alcoholic fatty liver disease (NAFLD)-a spectrum of chronic liver disorders originating from benign fatty liver that can further progress into more advanced forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even HCC. Scientific studies in the past decade have suggested that obesity-induced chronic inflammation in the liver is th...

Read More

Hepatocellular carcinoma (HCC) has become the second leading cause of cancer-related death worldwide. The up trending of HCC prevalence in the United States (especially in the State of Texas) is at least partially due to obesity epidemic with an estimate of 42.4% of the US population considered obese. Obesity-induced HCC is the terminal stage of non-alcoholic fatty liver disease (NAFLD)-a spectrum of chronic liver disorders originating from benign fatty liver that can further progress into more advanced forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even HCC. Scientific studies in the past decade have suggested that obesity-induced chronic inflammation in the liver is the key switch mediating the transition from benign fatty liver to NASH and eventually HCC. Thanks to the close collaboration between clinical oncologists and bench scientists, we now know that uncontrolled hyperactivation of a host immune sensor-called the NLRP3 (Nod-like receptor pyrin domain containing 3) inflammasome-is responsible for initiating chronic liver inflammation. However, how the NLRP3 inflammasome becomes hyperactivated in the liver remains unknown, thus making it a big hurdle for anti-HCC drug development. Our research group recently discovered that a nucleotide enzyme, called SAMHD1, functions as a key homeostatic regulator in immune cells to restrict overactivation of the NLRP3 inflammasome, thereby preventing chronic inflammation in the liver. However, we also discovered that dietary obesity causes inactivation of SAMHD1 in liver immune cells, leading to the removal of a key cellular "brake" that keeps NLRP3 inflammasome activity in check. In this proposal, we plan to utilize multiple cutting-edge approaches and technologies to comprehensively and vigorously investigate the role of SAMHD1 in pathogenesis of obesity-induced HCC. The experimental results coming out of this study will guide future design of anti-liver cancer therapies.

Read Less