钙卫蛋白S100A8/A9通过激活MCAM/HIF-1α/LOXL4信号通路促进乳腺癌肺转移前微环境形成的作用及机制研究

乳腺癌肺转移是导致乳腺癌死亡率居高不下的重要原因，其具体分子机制尚未完全阐明。“肿瘤转移前微环境（PMN）”学说为乳腺癌肺转移的研究提供新思路。我们前期研究显示，细胞外钙卫蛋白S100A8/A9与乳腺癌细胞膜MCAM受体结合后促进LOXL4表达，而LOXL4可引起癌细胞黏附能力增强。进一步通过基因芯片结果筛选出MCAM下游转录因子HIF-1α，发现其可与LOXL4启动子结合。有鉴于此，我们推测：S100A8/A9通过MCAM/HIF-1α/LOXL4信号通路增强乳腺癌细胞LOXL4分泌，LOXL4通过体循环到达肺组织后促进肺PMN形成，为后续乳腺癌肺转移提供有利“土壤”。本项目拟建立在临床乳腺癌样本相关性分析基础上，通过结合乳腺癌原位移植动物模型及3D共培养体外模型，阐明S100A8/A9促进肺PMN形成的分子机制，为今后晚期乳腺癌肺转移的治疗提供新的理论基础与研究靶点。

Metastatic breast cancer in the lungs refers to high mortality in breast cancer patients worldwide. Unfortunately, to date, the precise molecular mechanisms are still elusive. However, “Pre-metastatic niche (PMN)” theory provides novel viewpoints for lung metastatic of breast cancer. Our previous studies demonstrated that calprotein S100A8/A9 promoted the expression of LOXL4 through binding to the membrane receptor MCAM of breast cancer cells in order to enhance the adhesion capacity of lungs. Further, the in-depth microarray data showed that the expression of LOXL4 is highly associated with the activation of its transcription factor HIF-1α induced by the S100A8/A9 and MCAM binding. Therefore, we hypothesized that S100A8/A9 enhances the LOXL4 secretion of breast cancer cells by activating HIF-1α signaling pathway. Next, LOXL4 transported to the lung through systemic circulation induces PMN formation, which offers the favorable “soil” for breast cancer lung metastasis. Eventually, the progression of lung metastatic breast cancer is dramatically accelerated by the whole cross-talking process reported above. Overall, the present project is designed for investigating the molecule mechanisms of PMN formation induced by S100A8/A9, especially the role of MCAM/HIF-1α/LOXL4 in both 3D co-cultured in-vitro model and orthotopic metastatic mouse model of breast cancer, which is compared with the relevance analysis of breast cancer patient samples. Our finding might shed a new light on a novel theoretical basis and promising intervention targets for the therapeutics of lung metastatic breast cancer in future.