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促进炎症和肝细胞癌（HCC）发展的关键事件。自噬通过防止肝细胞死亡来维持肝脏稳态，但它也可以通过促进癌细胞的存活和代谢适应性来促进肿瘤的发生。自噬的促生存作用是通过选择性清除功能失调的细胞器或有毒的细胞质聚集体介导的，并由自噬受体（如p62/SQSTM1）促进。然而，p62是一种多功能蛋白，也调节各种信号通路。p62在自噬缺陷肝细胞中的异常积累被证明通过过度激活核因子红系2相关因子2 （Nrf2）转录因子来驱动细胞死亡、炎症和肝癌的发生。然而，目前尚不清楚p62/Nrf2通路是否通过促进肝损伤或通过不同的功能间接驱动肿瘤形成。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。该项目旨在确定肝癌细胞、小鼠和人类hcc中p62相关Nrf2过度激活的患病率，并确定与该途径激活特异性相关的分子特征。此外，各种p62功能在非转化肝细胞的存活和HCC细胞的致瘤潜能中的贡献将以公正的方式描述。为了验证结果，将生成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功能冗余的观点，这是肝脏生物学中一个相对未被探索的方面。因此，该项目的第二部分旨在揭示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存活有关。肝细胞的自噬能力和不能力的差异将被检查。总之，本研究将阐明p62在调节肝细胞存活和肝癌发生中的关键分子作用，同时它将确定与肝脏生理和疾病相关的自噬受体。这些结果的翻译意义可能包括更好的分层和设计肝脏疾病和HCC患者的联合治疗策略。

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.