Role of CMA failure in NASH progression to Hepatocellular Carcinoma

摘要 本研究旨在探讨蛋白质稳态（proteostasis）的维持缺陷在 脂肪肝，发展为肝细胞癌（HCC）。系统中的干扰， 在HCC中观察到维持肝脏蛋白质稳态，但在HCC中蛋白质稳态丧失的程度 脂肪肝是否构成HCC发展的危险因素仍不清楚。我们会专注于监护人- 介导的自噬（CMA），一种蛋白质质量控制系统，介导细胞质的选择性降解， 溶酶体中的蛋白质。肝脏CMA缺陷导致肝脏脂肪变性，原因是肝脏葡萄糖改变 和脂质代谢以及整体能量学。我们最近对CMA和 肿瘤发生的研究表明：（I）CMA具有抗肿瘤作用，因为CMA失败，如 在衰老、糖尿病或脂肪肝中观察到， 阻断发展自发性肿瘤;（II）CMA是转化细胞维持肿瘤生长所必需的，因为： (i)转化细胞最大程度地上调CMA，（ii）转化细胞中CMA的阻断降低增殖 并诱导细胞死亡，以及（iii）阻断预形成的肿瘤中的CMA抑制肿瘤生长并导致 肿瘤缩小 我们认为：（1）脂肪变性肝脏中CMA的逐渐下降促进了脂肪变性肝脏的恶性转化。 背景下的促癌刺激和2）干预，以恢复正常的CMA活性，在脂肪变性 肝脏将阻止或减缓HCC的进展。 为了验证这一假设，我们打算：1）确定CMA失败对致癌转化的贡献 2）确定CMA失败对HCC进展的肝脏和免疫细胞类型特异性贡献; 3） 评估CMA的化学和遗传上调作为预防措施的可能有益影响 针对NASH至HCC进展的干预。 意义：本研究将阐明CMA的功能障碍如何导致肝脏病理学改变， 增加脂肪肝患者发生HCC的风险。我们的发现可以帮助开发新的方法来保护 脂肪变性肝脏稳态和功能，并降低其发生HCC的风险。

ABSTRACT This proposal investigates the contribution of defective maintenance of protein homeostasis (proteostasis) in the steatotic liver, to the progression to hepatocellular carcinoma (HCC). Disturbances in the systems that maintain liver proteostasis have been observed in HCC, but the extent to which loss of proteostasis in the steatotic liver constitutes a risk factor for development of HCC remains unknown. We will focus in chaperone- mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic proteins in lysosomes. Defective CMA in liver leads to hepatosteatosis due to alterations in hepatic glucose and lipid metabolism and in overall energetics. Our recent studies on the interplay between CMA and oncogenesis have shown that: (I) CMA has an anti-oncogenic effect since failure of CMA, such as that observed in aging, diabetes or the steatotic liver, favors malignant transformation, and mice with hepatic CMA blockage develop spontaneous tumors; (II) CMA is required in transformed cells to sustain tumor growth since: (i) transformed cells maximally upregulate CMA, (ii) blockage of CMA in transformed cells reduces proliferation and induces cell death and (iii) blockage of CMA in pre-formed tumors inhibits tumor growth and results in tumor shrinkage. We propose that 1) the gradual decline of CMA in the steatotic liver facilitates malignant transformation in the context of a pro-oncogenic stimulus and that 2) interventions to restore normal CMA activity in the steatotic liver will prevent or slow down progression to HCC. To test this hypothesis, we intend to: 1) determine the contribution of CMA failure to oncogenic transformation in HCC; 2) identify the liver and immune cell type-specific contribution of CMA failure to HCC progression; 3) evaluate the possible beneficial impact of chemical and genetic upregulation of CMA as a preventive intervention against NASH to HCC progression. Significance: This study will elucidate how functional impairment of CMA contributes to liver pathology and if it increases HCC risk in steatotic liver. Our findings could help in developing new approaches to preserve steatotic liver homeostasis and function and reduce its risk to HCC.