肝癌中ARID1A对自噬的调控研究

Recent studies have revealed close relationship between autophagy and hepatocellular carcinoma (HCC). Although autophagy is commonly seen as a set of cytoplasmic events, in recent years, compelling evidence has revealed that nucleus is actually a major regulator of autophagy. However, it remains largely unknown about the nuclear regulation of autophagy. As a central component of SWI/SNF chromatin remodeling complex, ARID1A exhibits high mutation rates and decreased expression in HCC, acting as a tumor suppressor. In the preliminary study, we found that ARID1A overexpression led to suppressed autophagy, while autophagy was enhanced in ARID1A knockout (KO) HCC cells. Moreover, we found that ARID1A could interact with mTOR, a fundamental molecule in nutrient sensing and autophagy regulation. These findings suggest that ARID1A may participate in the regulation of autophagy. In this project, we will confirm the relationship between autophagy and ARID1A in HCC, disclose the mechanism of autophagy regulation by ARID1A, as well as the significance and underlying mechanism of this regulation in the development of HCC. This study will not only improve the understanding of ARID1A in physiology and pathology, but also provide information for developing novel therapeutic strategy targeting autophagy for HCC.

近年来研究表明自噬与肝癌的发生发展有着密切的关系。虽然自噬的大部分事件都发生在细胞质中，但是近来认为细胞核才是自噬的主要调控者，然而对自噬的核内调控仍有许多未知。ARID1A作为染色质重塑复合物SWI/SNF的核心成员，在肝癌中显示出高突变率和表达下调，是重要的抑癌基因。前期研究中，我们发现ARID1A过表达抑制肝癌细胞的自噬，而在ARID1A knockout（KO）的细胞中自噬则明显增强。此外，ARID1A和自噬的关键调控分子mTOR相互作用，这都提示ARID1A很可能参与了肝癌中自噬的调控。因此，在本项研究中，我们将明确肝癌中ARID1A和自噬的关系，探索ARID1A对于自噬的调控机理以及这一调控在肝癌发生发展中的作用和机制。本项研究将揭示ARID1A对自噬的调控机制，这是对ARID1A生理病理功能的全新认识。此外，我们的研究还将为发展新的针对自噬的肝癌治疗策略提供有价值的参考。

近年来研究表明自噬与肝癌的发生发展有着密切的关系。虽然自噬的大部分事件都发生在细胞质中，但是近来认为细胞核才是自噬的主要调控者，然而对自噬的核内调控仍有许多未知。ARID1A作为染色质重塑复合物SWI/SNF的核心成员，在肝癌中显示出高突变率和表达下调，是重要的抑癌基因。前期研究中，我们发现ARID1A过表达抑制肝癌细胞的自噬，而在ARID1A knockout（KO）的细胞中自噬则明显增强。在本项目中，我们从细胞、动物和临床水平确立了ARID1A和自噬在肝癌中的关系；揭示了ARID1A对自噬的调控机制；研究了ARID1A对自噬的调控对肝癌发生发展的影响及相关机制。我们发现，ARID1A和自噬的关系与肝癌发展进程密切相关。正常肝脏细胞中ARID1A KO能促进自噬，抑制肝癌的发生。ARID1A通过USP9X调控AMPKα的一个isoform PRKAA2的水平，调控了自噬，影响了肝癌细胞对葡萄糖剥夺的耐受性。我们的研究为ARID1A突变的肝癌患者提供了靶向USP9X-PRKAA2的治疗策略。