AT1R拮抗剂ARB逆转HER2+乳腺癌细胞曲妥珠耐药及分子机制研究

Recent studies have shown a critical role of EMT and cancer stem cell (CSC) in trastuzumab resistance of HER2+ breast cancer cells, and an important role of IL6-mediated inflammatory signal pathway in the induction and maintenance of EMT and CSC. Meanwhile, AT1R antagonist ARB has been extensively used in the treatment of cardiovascular disease through the inhibition of multiple inflammation-related signaling.Our previous research found that AT1R was significantly over-expressed in trastuzumab-resistant HER2-positive breast cancer cell line SKBR3/R as compared with parental SKBR3 cells,and notablely, the increased expression of AT1R was tightly associated with high level of IL6 secretion in SKBR3/R cells. Hence,we further study, in the project, the role and molecular signal mechanism of AT1R in the induction and maintenance of EMT and CSC and the resulted trastuzumab resistance of SKBR3/R cells.Furthermore,we study the potential role and molecular signal mechanism of AT1R antagonist in inhibiting the induction and maintenance of EMT and CSC and overcoming trastuzumab resistance of SKBR3/R cells. At last, we analyse in vivo the effect of ARB on trastuzumab resistance of SKBR3/R. Our project trys to demonstrate a new molecular mechanism of trastuzumab resistance of HER2-positive breast cancer, and provides a innovative strategy and subclinical evidence to overcome resistance to trastuzumab therapy of HER2-positive breast cancer.

近期研究显示EMT和肿瘤干细胞（CSC）在HER2+乳腺癌细胞曲妥珠抵抗中起着关键性的作用，而最新研究发现IL-6炎症信号通路在肿瘤细胞EMT和CSC生成中具有重要地位，结合AT1R拮抗剂ARB能通过抑制多条炎症信号通路的活性广泛应用于心血管疾病的治疗，以及我们前期发现AT1R显著过表达于HER2+曲妥珠耐药细胞株SKBR3/R且与炎症因子IL-6的表达密切相关，因此，本项目拟在SKBR3/R细胞株中研究AT1R在介导SKBR3/R细胞EMT、CSC生成及后续的曲妥珠耐药中的作用及分子信号机制，深入研究AT1R特异性拮抗剂ARB在抑制SKBR3/R细胞EMT、CSC生成及逆转曲妥珠耐药性中的作用，最后从动物移植瘤模型中验证ARB在体内逆转SKBR3/R曲妥珠耐药性的效果，不仅从新的角度阐明HER2+乳腺癌的曲妥珠抵抗机制，且为曲妥珠抵抗HER2+乳腺癌的临床治疗提供新的思路和重要科学依据。

根据先前研究显示EMT和肿瘤干细胞（CSC）在HER2+乳腺癌细胞曲妥珠抵抗中起着极为关键的作用以及最新发现IL6炎症信号通路在介导肿瘤细胞EMT和CSC的重要地位，结合AT1R拮抗剂ARB通过抑制多条炎症相关信号通路的活性广泛应用于心血管疾病的治疗以及我们前期发现AT1R显著过表达于HER2+曲妥珠耐药细胞株SKBR3/R且与炎症因子IL6的表达密切相关，本项目拟在SKBR3/R细胞株中研究AT1R在介导SKBR3/R细胞EMT、CSC产生和维持及后续的曲妥珠耐药中的作用及分子信号机制，进一步深入研究AT1R特异性拮抗剂ARB在抑制SKBR3/R细胞EMT、CSC生成及逆转曲妥珠耐药中的作用。我们的工作不仅研究了曲妥珠耐药与乳腺癌干细胞的关系、AngII受体拮抗剂坎地沙坦在逆转乳腺癌HER2+细胞曲妥珠单抗耐药中的作用以及调节细胞内信号通路的分子机制，而且深入分析了介导肿瘤细胞自分泌AngII的分子机制，阐明了肿瘤细胞内AngII的产生并不依赖传统的肾素-血管紧张素酶（Renin-ACE）生成途径，而是通过糜蛋白酶（Chymase）依赖的途径生成，进一步发现肿瘤细胞内糖酵解代谢产物乳酸在介导肿瘤细胞内糜蛋白酶依赖的AngII生成途径中介导着重要作用，肿瘤乏氧微环境显著促进了肿瘤细胞内葡萄糖的糖酵解代谢活性，促使肿瘤细胞内乳酸的大量积累，导致糜蛋白依赖的AngII生成活性在乏氧肿瘤细胞表现得更加活跃，从而AngII能优先存在于肿瘤的乏氧微环境中；我们的研究为克服HER2-阳性乳腺癌的曲妥珠耐药提高了新的策略，而且揭示了肿瘤内局部通过乳酸-糜蛋白酶途径肿瘤细胞可自身产生AngII从而介导肿瘤细胞重要生物学行为的调节。