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

慢性细胞死亡是肝脏疾病中的一个重要事件，促进了肝细胞癌的炎症和发展。自噬通过防止肝细胞死亡来维持肝脏的动态平衡，但它也可以通过促进癌细胞的存活和新陈代谢适应来促进肿瘤的发生。自噬的促生存作用是通过选择性清除功能障碍的细胞器或有毒的细胞质聚集体来实现的，并由自噬受体如p62/SQSTM1促进。然而，p62是一种多功能蛋白质，也调节各种信号通路。自噬缺陷肝细胞中p62的异常积聚被证明通过过度激活核因子红系2相关因子2(NRF2)转录因子而导致细胞死亡、炎症和肝癌的发生。然而，目前还不清楚p62/Nrf2通路是通过促进肝损伤间接驱动肿瘤形成，还是通过不同的功能促进肿瘤形成。来自遗传小鼠模型的初步证据表明，p62通过不同的功能相互作用调节肝细胞存活和肝脏肿瘤的发生。该项目旨在确定P62相关的Nrf2在肝癌细胞以及小鼠和人类肝癌中的过度激活的流行率，并确定与这一途径的激活特别相关的分子特征。此外，各种p62功能在未转化的肝细胞存活和肝癌细胞的致瘤潜能中的贡献将以公正的方式被勾画出来。为了验证结果，我们将产生p62突变小鼠并进行肝损伤模型。此外，我们的初步数据支持p62和其他自噬受体之间存在广泛的功能冗余的观点，这是肝脏生物学中相对未被探索的一个方面。因此，该项目的第二部分旨在解开具有重叠功能的自噬受体，这些受体与正常肝细胞和肝癌细胞在诱导选择性自噬的条件下的生存相关。这项拟议的研究将阐明p62在调节肝细胞存活和肝癌发生中的分子作用，同时它将确定与肝脏生理和疾病相关的自噬受体。这些结果的翻译含义可能包括对肝病和肝细胞癌患者进行更好的分层和设计组合治疗策略。

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.