RNA结合蛋白MSI2促进乳腺癌骨转移的分子机制

骨骼是乳腺癌最常见的转移部位，乳腺癌细胞与骨髓微环境的相互作用与骨转移倾向性密切相关。然而，乳腺癌如何调控自身与骨转移微环境互作的机制仍不清楚。我们前期研究发现：RNA结合蛋白MSI2在骨转移性乳腺癌组织中扩增并高表达，与患者骨转移事件发生密切相关。进一步预实验显示：MSI2可结合并增强GLG1、PTHrP和PTPN1的mRNA稳定性，①通过GLG1/E-selectin轴促进乳腺癌细胞与骨髓血窦内皮细胞之间黏附而定植骨髓；②并激活PTHrP/RANKL信号通路诱导破骨细胞分化；③同时，PTPN1诱导IFNAR1去磷酸化被内吞而抑制I型干扰素通路的激活，使肿瘤细胞实现免疫逃逸而存活；最终促进乳腺癌骨转移。然而，其具体分子机制仍有待阐明。本项目将深入探讨MSI2促进乳腺癌细胞骨转移的生物学功能及其详细分子机制，为乳腺癌骨转移提供新的理论依据；并探讨MSI2在骨转移性乳腺癌临床诊治中的意义。

Bone is the most common site of metastasis in breast cancer. The metastatic tendency of breast cancer cells is closely linked to the interaction between breast cancer cells and the bone marrow microenvironment. However, the regulatory mechanism is still largely unclear. Recently, we found that RNA binding protein MSI2 was highly expressed in bone metastatic breast cancer tissues, and overexpression of MSI2 was negatively correlated with bone metastasis-free survival in breast cancer patients. Furthermore, we observed that: ① MSI2 enhanced the mRNA stability of GLG1, an E-selectin ligand, and induced metastatic colonization in bone of disseminated breast cancer cells through enhancing the GLG1/E-selectin axis; ②MSI2 enhanced the mRNA stability of PTHrP, coding a parathyroid hormone-related protein, and induced the differentiation and maturity of osteoclast through enhancing the PTHrP/RANKL signaling; ③ Meanwhile, MSI2 increased the mRNA stability of PTPN1, coding a protein tyrosine phosphatase, and then promoted breast cancer cells survival through immune escape by inhibiting the type I interferon response. Finally, MSI2 promoted breast cancer metastasis to the bone in vivo. In this project, we will combine both in vitro and in vivo experiment systems, as well as analysis of clinical samples, in order to investigate the biological functions and detailed molecular mechanism of MSI2 in the regulation of bone metastases in breast cancer. Our work would provide a novel prognostic biomarker and therapeutic target against bone metastatic breast cancer.