The Role of Necroptosis-mediated Inflammation in Hepatocellular Carcinoma

Non-alcoholic hepatosteatosis (NASH) due to metabolic syndrome or diabetes mellitus has been identified as the fastest growing cause of hepatocellular carcinoma (HCC), the fourth leading cause of cancer related deaths in the world. Therapeutic options for HCC are limited, and survival after diagnosis is poor (>10%). Thus, a better understanding of the mechanisms that drive the progression of NASH to HCC is critical in developing new strategies to prevent/treat HCC. Chronic inflammation is a key player in the pathogenesis of HCC, however, pathways that drive chronic hepatic inflammation in NASH-driven HCC is not known. Necroptosis is a regulated mode of cell death that causes inflammation and is activated in the livers of patients with NASH. Therefore, we tested whether necroptosis-mediated inflammation plays a role in the progression of NASH to HCC in a mouse model of NASH-induced HCC. Overall design: For our study, we used wild type (WT) mice and mouse models where necroptosis is blocked (Ripk3 or Mlkl knockout mice). Mice were fed with normal chow diet (control diet) or choline deficient low or high fat diet (CD-LFD or CD-HFD) for 6 months. End point analyses was done for checking inflammation, tumor incidence and signalling pathway components. Transcriptomic analysis was done to understand the change in gene expression between the study groups. The results indicate that several genes invloved in HCC development are modulated in the WT group fed a CD-HFD , which gets reversed when necroptosis is blocked.