肿瘤相关巨噬细胞调控GSTM1相关自噬介导肝癌耐药的机制研究

The resistance to anticancer drug is the main cause of the chemotherapy failure in treatment of hepatocellular carecinoma (HCC) and this circumstance has added urgency to the need to explore the mechanisms of it and the way to reverse. As people pay more and more attention to tumor microenvironment induced chemoresistance, it may be a key factor in inducing tumor drug-resistance. Tumor associated macrophage (TAM) is an vital role in HCC microenvironment and our preliminary experiments suggested that TAM could up-regulate the expression of GSTM1 in HCC which resulted in enhanced ability of chemoresistance and GSTM1 was probably correlated with chemotherapy-related autophagy. As a member of the Glutathione S-transferase (GST) family, GSTM1 has extremely close relationship with tumors occurrence and drug resistance, and is considered to be one of the key factors that mediates chemoresistance in HCC. However, it is still unclear that how TAM regulates it and then induces drug-resistance. This project will clarify TAM could induce the chemoresistance of HCC by up-regulating GSTM1 in HCC via molecules that carry chemical signals between cells resulted in activation of GSTM1-related autophagy. We hope to illustrate the role of tumor microenvironment in HCC drug-resistance and it may provide new ideas and theoretical basis in looking for new therapeutic target of reversing chemoresistance of HCC.

肝细胞癌耐药的产生是导致化疗失败的主要原因，急需我们对其产生机制及逆转措施进行研究。肿瘤微环境介导的耐药越来越被人们重视，很可能是诱导肿瘤耐药的关键因素。肿瘤相关巨细胞（TAM）是肝癌微环境中的重要一员，预实验结果提示TAM可上调肝癌细胞谷胱甘肽转硫酶M1（GSTM1）表达并增加其耐药性，且GSTM1与化疗相关细胞自噬有关。而GSTM1作为GST家族中与肿瘤发生和耐药极为密切的一员，被认为是介导肝癌耐药的核心因素之一，但其如何受到TAM调控并影响自噬进而介导耐药的机制尚不明确。本研究拟通过诱导建立TAM与肝癌细胞共培养模型、检测肝癌细胞相关蛋白和基因以及体内外实验和机制研究，拟阐明TAM可通过细胞间分子信号诱导肝癌细胞GSTM1表达，从而调控GSTM1相关细胞自噬，介导肝癌耐药的机制。借此阐释肿瘤微环境在肝癌耐药中的作用方式，并为逆转肝癌耐药新靶点的寻找提供新思路和理论依据。

肝细胞癌耐药的产生是导致化疗失败的主要原因，急需我们对其产生机制及逆转措施进行研究。肿瘤微环境介导的耐药越来越被人们重视，很可能是诱导肿瘤耐药的关键因素。肿瘤相关巨细胞（TAM）是肝癌微环境中的重要一员，本研究通过诱导建立TAM与肝癌细胞共培养模型、检测肝癌细胞相关蛋白和基因以及体内外实验和机制研究，阐明自噬激活可介导GSTM1相关肝癌耐药，而肿瘤相关巨噬细胞可通过介导肝癌细胞发生自噬增加对奥沙利铂的耐药；在肝癌中 MicroRNA-30a可抑制自噬介导的失巢凋亡抵抗与肿瘤转移。本研究阐释肿瘤微环境在肝癌耐药中的作用方式，并为逆转肝癌耐药新靶点的寻找提供新思路和理论依据。