SALL4及其相互作用蛋白对肝癌治疗抗性的调控功能研究

More recently, SALL4 has been suggested as a marker of liver cancer stem cell and involve in proliferation, apoptosis, invasion and self-renewal of hepatocellular carcinoma cells. SALL4 was thought to be a potential therapeutic target for liver cancer. Several studies have shown that SALL4 can affect drug resistance of cancer cells, while how it regulate radiotherapy and chemotherapy resistance of liver cancer and its underlying mechanism remains unclear. Our previous study show that SALL4 physically interact with Ku80 and induce Ku80 ubiquitination and degradation. In this study, we explore mechanisms related to the biological function of SALL4-Ku80 interaction. To study the function of SALL4 on DNA damage repair and treatment resistance of liver cancer, and explore the dependency on Ku80 ubiquitination and degradation induced by SALL4. In addition, this project will also investigate whether Ku80 affects the transcription of SALL4 downstream target genes, and regulate the proliferation, apoptosis and self-renew of liver cancer cells. The results from this study will extend the signal transduction networks of SALL4 and Ku80, and strongly support new mechanisms in occurrence, progression and treatment resistance of liver cancer, and provide new targets for prognosis and therapy of liver cancer.

SALL4蛋白作为近年来新发现的肝癌干细胞标志物，参与调控肝癌的增殖、凋亡、侵袭和自我更新等过程，是一个潜在的肝癌治疗靶点。虽然有个别研究表明SALL4能够影响肿瘤的耐药，但是SALL4如何调控肝癌对放疗和化疗的抵抗及其分子机制尚不明确。我们的前期研究发现SALL4能够与Ku80蛋白相互结合并诱导Ku80的泛素化降解，因此，本项目拟以SALL4与Ku80相互结合的生物学功能为突破口，研究SALL4诱导Ku80泛素化降解是否影响Ku80介导的DNA损伤修复，并通过该通路发挥调控肝癌治疗抗性的功能；另外，本项目还将探讨Ku80结合SALL4是否影响SALL4对其下游靶基因的转录，以及因此影响肝癌的增殖、凋亡和自我更新等过程。本项目的研究将有助于扩展SALL4和Ku80的信号调控网络，加深对肝癌发生发展和治疗抗性的新机制的认识，为制定更有效的肝癌治疗策略，提供新的思路。

SALL4作为最近发现的新的肝癌干细胞标志物，在肝癌的发生发展过程中发挥重要功能，因此扩展SALL4相关的信号通路研究和以SALL4为靶点的抗肿瘤药物研发是目前肝癌靶向治疗的重要研究方向。本项目通过蛋白质组学筛选和后续CO-IP和免疫荧光染色实验验证，首次发现了SALL4与Ku80蛋白之间的相互作用。本研究进一步明确了SALL4-Ku80相互作用的具体区段。后续的研究发现，一方面Ku80通过竞争结合SALL4促进OCT4溶酶体降解来抑制OCT4蛋白表达，从而抑制HCC细胞的自我更新和转移。另一方面，SALL4通过促进Ku80范素化降解下调Ku80表达，进而发挥抑制DNA双链断裂修复的功能。本研究扩展了SALL4和Ku80相关信号通路和功能的研究，为靶向该相互作用的抗肿瘤药物研发提供了理论基础。