The role of p62/SQSTM1 and other autophagy receptors in liver homeostasis and hepatocarcinogenesis

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Chronic cell death is a key event in liver disease promoting inflammation and development of hepatocellular carcinoma (HCC). Autophagy maintains liver homeostasis by preventing death of hepatocytes, but it can also favour tumorigenesis by promoting survival and metabolic fitness of cancer cells. The pro-survival role of autophagy is mediated through the selective clearance of dysfunctional organelles or toxic cytoplasmic aggregates and is facilitated by autophagy receptors, such as p62/SQSTM1. Yet, p62 is a multifunctional protein that also regulates various signalling pathways. Aberrant p62 accumulation in autophagy-deficient hepatocytes was shown to drive cell death, inflammation and hepatocarcinogenesis by overactivating the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. It is unclear, however, if the p62/Nrf2 pathway drives tumour formation indirectly by promoting liver damage or through distinct functions.Preliminary evidence from genetic mouse models suggests that p62 regulates hepatocyte survival and liver tumourigenesis through different functional interactions. This project aims to determine the prevalence of p62-linked Nrf2 overactivation in liver cancer cells and mouse and human HCCs, and to identify a molecular signature that is specifically associated with activation of this pathway. Moreover, the contribution of various p62 functions in survival of non-transformed hepatocytes and tumourigenic potential of HCC cells will be delineated in an unbiased way. To validate the results, p62 mutant mice will be generated and subjected to liver injury models.In addition, our preliminary data support the proposed notion that extensive functional redundancies exist between p62 and other autophagy receptors, which is a relatively unexplored aspect of liver biology. The second part of the project is therefore intended to unravel autophagy receptors with overlapping functions that are relevant for survival of normal hepatocytes and liver cancer cells under conditions that induce selective autophagy. Differences between hepatocytes competent or incompetent for autophagy will be examined.Altogether, the proposed study will elucidate the molecular roles of p62 that are critically regulating hepatocyte survival and hepatocarcinogenesis, while it will identify autophagy receptors that are relevant for liver physiology and disease. Translational implications of these results could include a better stratification and design of combinatorial therapeutic strategies for liver disease and HCC patients.