西黄丸对乳腺癌荷瘤小鼠肿瘤微环境调节性T细胞AP-1相关信号通路调控的分子机制

It is one of important mechanisms for immune escaping of tumor cells that Treg cells assemble and has immune inhibition. Our preliminary studies showed that Xihuang pills had anti-breast cancer effect by downregulating the numbers of CD4+CD25+ Treg cells and IL-6, IL-10 and TGF-β levels. However, the regulatory mechanism of Xihuang pills for Treg cells in tumor microenvironment remains unknown. This study will investigate that Xihuang pills inhibit proliferation of Treg cells in tumor microenvironment by downregulating PI3K/AKt/AP-1 and MEKK1/SEK1/JNK1/AP-1 expression as well as promote apoptosis of Treg cells in tumor microenvironment by downregulating the expressions of BclxL and XIAP proteins. Furthermore, We will confirm that Xihuang pills regulate promoter of IL-10, TGF-β, BclxL and XIAP by inhibiting PI3K/AKt/AP-1and MEKK1/SEK1/JNK1/AP-1pathway and inhibiting the combination of AP-1 with relevant DNA sequence. This study will provide new understanding for Xihuang pills to regulat transcription of IL-10, TGF-β, BclxL and XIAP. It is great significance for treating breast cancer.

Treg细胞在肿瘤微环境中聚集并发挥免疫抑制作用，是肿瘤免疫逃逸的重要机制之一。我们前期实验发现西黄丸通过减少外周血CD4+CD25+ Treg细胞数量，降低IL-6、IL-10、TGF-β水平发挥抗乳腺癌作用，但其对肿瘤微环境中Treg细胞的调控及其分子机制尚不清楚。本研究拟探讨西黄丸通过下调PI3K/AKt/AP-1和MEKK1/SEK1/JNK1/AP-1表达来抑制肿瘤微环境中Treg细胞增殖，通过下调BclxL和XIAP表达促进肿瘤微环境中Treg细胞凋亡。特别是明确西黄丸通过抑制PI3K/AKt/AP-1和MEKK1/SEK1/JNK1/AP-1通路以及抑制AP-1与相应DNA序列结合来调控IL-10、TGF-β、BclxL、XIAP启动子活性。研究结果将为西黄丸调控Treg细胞IL-10、TGF-β、BclxL、XIAP转录的分子机制提供新认识，对西黄丸治疗乳腺癌具有重要意义。