EYA2通过与PAX6相互作用调控乳腺癌侵袭和转移的机制研究

Transcription co-factor EYA2 and transcription factor PAX6 are highly conserved proteins, which are regulated by each other. Previous studies show that EYA2 and PAX6 mediate invasion and metastasis of breast cancer via TGF-β-Smad induced epithelial-mesenchymal transition and are associated with poor prognosis, respectively. Our preliminary data reveal that EYA2 interacts with PAX6, co-expression of EYA2 and PAX6 correlates with decreased expression of key factors in TGF-β-Smad signaling pathway and shortened survival, suggesting that the interaction of EYA2 and PAX6 promotes invasion and metastasis of breast cancer. However, it remains unknown how invasion and metastasis are regulated by the interaction between EYA2 and PAX6, and the underlying mechanisms. Based on these findings, we aims to employ Co-IP, CRISPR/Cas9 induced gene knockout, tumor invasion and migration assays, and in vivo metastasis assay to define the domain that regulates the interaction between EYA2 and PAX6, and investigate the molecular mechanisms of PAX6-induced breast cancer invasion and metastasis regulated by EYA2 via TGF-β-Smad induced epithelial-mesenchymal transition. Our research will lay the foundation for developing novel anti-cancer agents targeting EYA2-PAX6 complex to improve the treatment of breast cancer.

EYA2和PAX6是具有相互调节关系的两个保守蛋白，对EYA2或PAX6研究发现，两者均可通过TGF-β-Smad信号通路调节的上皮-间质转化参与乳腺癌侵袭和转移，且与患者不良预后有关。本项目组前期研究发现，EYA2能与PAX6结合，共同高表达可使TGF-β-Smad信号通路中关键因子表达升高、患者生存率显著降低，提示EYA2通过与PAX6相互作用促进乳腺癌侵袭和转移。但是，两者如何共同调控以及调控机制尚未明确。在此基础上，本项目拟利用Co-IP、CRISPR/Cas9介导的基因敲除技术，通过细胞侵袭和迁移实验和构建移植瘤模式动物等，探索EYA2-PAX6相互作用的结构基础；研究EYA2与PAX6相互作用对TGF-β-Smad信号通路调节的上皮-间质转化等影响并阐述其调控乳腺癌侵袭和转移的分子机制，为开发抑制EYA2-PAX6结合的抗癌药物提供研究基础，为有效地防治乳腺癌提供新思路。

EYA2和PAX6是具有相互调节关系的两个保守蛋白，对EYA2或PAX6研究发现，两者均可通过TGF-β-Smad信号通路调节的上皮-间质转化参与乳腺癌侵袭和转移，且与患者不良预后有关。本项目组前期研究发现，EYA2能与PAX6结合，共同高表达可使TGF-β-Smad信号通路中关键因子表达升高、患者生存率显著降低，提示EYA2通过与PAX6相互作用促进乳腺癌侵袭和转移。但是，两者如何共同调控以及调控机制尚未明确。在此基础上，本项目拟利用Co-IP、CRISPR/Cas9介导的基因敲除技术，通过细胞侵袭和迁移实验和构建移植瘤模式动物等，探索EYA2-PAX6相互作用的结构基础；研究EYA2与PAX6相互作用对TGF-β-Smad信号通路调节的上皮-间质转化等影响并阐述其调控乳腺癌侵袭和转移的分子机制，为开发抑制EYA2-PAX6结合的抗癌药物提供研究基础，为有效地防治乳腺癌提供新思路。