m6A修饰介导的HSF1通过p75(NTR)增强肝细胞癌循环肿瘤细胞失巢凋亡抵抗特性的研究

肝细胞癌（HCC）患者循环肿瘤细胞（CTC）可发生失巢凋亡抵抗促使HCC的复发转移，抑制CTC失巢凋亡抵抗是治疗HCC的重要途径。申请人前期研究发现HSF1在CTC中存在m6A甲基化修饰的高表达，其高表达可增强CTC的失巢凋亡抵抗，并发现HSF1可调控p75(NTR)的表达及其信号调节通路，同时p75(NTR)存在DNA甲基化修饰。申请人在上述基础上拟深入研究：（1）细胞水平研究m6A修饰介导的HSF1可结合DNA甲基转移酶DNMT3a，抑制p75(NTR)的DNA甲基化并下调其表达水平，增强HCC中CTC失巢凋亡抵抗特性。（2）动物水平研究m6A修饰介导的HSF1通过p75(NTR)调控HCC中CTC失巢凋亡抵抗。（3）临床标本资料研究HSF1、p75(NTR)及调节通路分子与CTC的相关性。本项目拟探明HSF1增强HCC患者CTC失巢凋亡抵抗特性的作用及机制，为治疗HCC提供新的靶点。

Circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC) can develop anoikis resistance to promote the recurrence and metastasis of HCC. Inhibition of anoikis resistance of CTC is an important way to treat HCC. The applicant's previous study found that HSF1 had high expression of M6A methylation modification in CTC, and its high expression could enhance the anoikis resistance of CTC. It was also found that HSF1 could regulate the expression of p75(NTR) and its signal regulation pathway, while p75(NTR) had DNA methylation modification.The applicant intends to conduct further research on the above basis: (1) Studies at the cellular level that M6A modified HSF1 can bind DNA methyltransferase DNMT3A, inhibit DNA methylation of p75(NTR) and down-regulate its expression level, thus enhancing the anoikis resistance of CTC in HCC. (2) At the animal level, M6A modification-mediated HSF1 regulates CTC anoikis resistance in HCC through p75(NTR). (3) To study the correlation between HSF1, p75(NTR), regulatory pathway molecules and CTC in clinical specimens.This project aims to explore the role and mechanism of HSF1 in enhancing the anoikis resistance of CTC in HCC patients, so as to provide a new target for the treatment of HCC.