核受体ERRα上调乳腺癌细胞中趋化因子CCL2表达的分子机制及其在肿瘤炎性微环境中的作用

Inflammatory tumor microenvironment plays very important roles in facilitating the malignant development of breast cancer. The chemokine CCL2 is one of the most important effective factors that constitute inflammatory breast tumor microenvironment. CCL2 can serve as a breast tumor stimulator through re-educating several kinds of effective cells of breast tumor microenvironment. It has been generally accepted that CCL2 in breast tumor microenvironment is originated from breast cancer cells. However, the mechanisms underlying the up-regulation of CCL2 expression in breast cancer cells are unclear. ERRα is a nuclear receptor emerging as a novel biomarker of breast cancer. Nowadays, a large number of researches are dedicated to exploring the mechanisms through which ERRα participates in the development of breast cancer. The studies uncovering the relationship between ERRα and native immunity or inflammation implied the possibility that ERRα may be involved in the tumor associated inflammation. Our previous studies indicated that there is an ERRα-CCL2 positive regulatory pathway existed in breast cancer cells. Moreover, there are several potential response elements located in the promoter region of human CCL2 gene, through which ERRα can directly or indirectly regulate the expression of CCL2. Our program aims at demonstrating that CCL2 expression is under the control of ERRα in breast cancer cells, elucidating the mechanism underlying the regulation of CCL2 gene expression by ERRα, and evaluating the effect of this regulatory pathway on inflammatory breast tumor microenvironment. We hope these work linking breast cancer cells to its inflammatory microenvironment will help us to better recognize the pathogenesis of breast cancer.

肿瘤炎性微环境对乳腺癌的发生发展有极大促进作用。趋化因子CCL2是乳腺肿瘤炎性微环境中最重要的效应分子之一，能驯化肿瘤微环境中的多种细胞以推动乳腺癌的恶性发展。乳腺肿瘤微环境中的CCL2最早来源于乳腺癌细胞，但导致CCL2在乳腺癌细胞中表达上调的具体机制并不十分清楚。核受体ERRα是一个新型的乳腺癌肿瘤标志物，其参与乳腺癌进程的具体机制备受关注。而其在天然免疫及炎症中的作用暗示ERRα具有参与肿瘤相关炎症的潜能。我们前期的研究提示，在乳腺癌细胞中存在ERRα——CCL2正向调控通路。而且在人CCL2启动子区存在着供ERRα直接或间接作用的调控元件。本项目拟在此基础上明确ERRα对乳腺癌细胞中CCL2的表达调节作用，详细解析ERRα上调CCL2表达的分子机制，并初步探索这种调控作用对乳腺肿瘤炎性微环境的影响，以期望从联系乳腺癌细胞和其肿瘤炎性微环境的角度加深对乳腺癌发病机制的认识。

肿瘤炎性微环境对乳腺癌的发生发展有极大促进作用。趋化因子CCL2是乳腺肿瘤炎性微环境中最重要的效应分子之一。乳腺肿瘤微环境中的CCL2最早来源于乳腺癌细胞，但导致CCL2在乳腺癌细胞中表达上调的具体机制并不十分清楚。核受体ERRα是一个新型的乳腺癌肿瘤标志物，其参与乳腺癌进程的具体机制是研究热点。而其在天然免疫及炎症中的作用暗示ERRα具有参与肿瘤相关炎症的潜能。目前，我们的研究提示，在各种乳腺癌细胞株中，ERRα与单核细胞趋化因子CCL2的表达存在显著的相关性；功能缺失/获得实验证实ERRα能够正向调控CCL2的表达。而在人CCL2启动子区--820bp~-2800bp的区域极有可能存在直接的ERRα调控元件。此外，我们利用蛋白芯片技术对不同类型乳腺癌细胞的炎性细胞因子表达谱进行了鉴定，并在高侵袭性乳腺癌细胞株MDA-MB-231中发现了多个疑似的新型ERRα调控靶点，这些研究结果将从构筑肿瘤炎性微环境的角度加深我们对核受体ERRα促进乳腺癌发展机制的认识。