HBXIP通过GM-CSF调控乳腺癌MDSCs募集与活化的作用及其机制研究

髓源性抑制细胞(Myeloid-derived suppressor cells，MDSCs)在肿瘤部位的募集和活化是肿瘤免疫逃逸的关键。随着以MDSCs为靶点的抗肿瘤治疗作用凸显，MDSCs受到广泛关注，但其在肿瘤中显著募集和活化的分子机制尚不清楚。本项目前期研究发现癌蛋白HBXIP可促进乳腺癌荷瘤小鼠肿瘤组织中MDSCs募集与活化，并通过稳定MDSCs募集活化关键因子GM-CSF的mRNA上调GM-CSF的表达促进其分泌。本项目拟在前期工作基础上，应用小鼠乳腺癌模型深入研究HBXIP调控乳腺癌MDSCs募集活化促进肿瘤发展的作用；通过RNA免疫共沉淀结合高通量测序、qPCR等技术重点阐明HBXIP通过N6-甲基腺嘌呤(m6A)增加GM-CSF的mRNA稳定性进而上调GM-CSF表达的分子机制。该项目将阐释乳腺癌MDSCs募集与活化的新机制，为乳腺癌治疗提供新靶点。

Recruitment and activation of myeloid derived suppressor cells (MDSCs) in tumor sites is responsible for tumor immune escape. With the prominent effect of anti-MDSCs cancer therapy, MDSCs receive worldwide attention. However, the mechanism by which MDSCs are recruited and activated in tumor sites is elusive. Primarily, mouse breast cancer model revealed that oncoprotein HBXIP could enhance the recruitment and activation of MDSCs in the tumor sites of breast tumor-bearing mice. Furthermore, HBXIP could stabilize the mRNA of GM-CSF, which is responsible for the accumulation and activation of MDSCs, and as a result, upregulate GM-CSF expression and promote it secretion. This project, based on the primary findings, will first demonstrate the promotion of tumor progress enhanced by HBXIP through upregulating the recruitment and activation of MDSCs using mouse breast cancer model. This project will illustrate the molecular mechanism by which HBXIP stabilized the mRNA of GM-CSF through m6A methylation and upregulated the expression of GM-CSF. This project will give insights into the mechanism of MDSCs accumulation and activation in breast cancer, and also provide target(s) for breast cancer therapy.