Protein Kinase ??/?? suppresses liver cancer by repressing autophagy and oxidative phosphorylation in hepatocytes [RD]

Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during the generation of reactive oxygen species (ROS), and how ROS promotes tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) ??/?? loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC cell autonomously and non-autonomously. Although PKC?/? promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKC??/?? levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer. Overall design: Hepatic mRNA profiles of 28-week old wild-type (Prkcif/f) and hepatocyte-specific Protein Kinase ??/??-KO (Prkcif/fAlbCre) mice fed with regular chow