Hedgehog-Gli信号通路调控"EMT 转化"驱动前列腺癌干细胞形成并致恶性进展的实验研究

cancer stem cells (CSCs) are the root causes of the malignant progress，but its mechanism has not been elucidated. Epithelial - mesenchymal transition process (EMT) is a key driving force for promoting the malignant progression of tumor. Does EMT be closely related with the generation and maintenance of CSCs ? Our preliminary studies show that EMT of prostate cancer(Pca) promote tumor invasion and metastasis, and the PCa cells suffered from EMT display cancer stem cell-like properties. Based on this, this study will interfere with Hedgehog-Gli signaling pathway of PCa cells induced / reversal the EMT to observe the changes of the CSCs properties; and then isolate and identify CSCs from PCa whose EMT characteristic changed, contrast the invasion and tumorigenicity of them in vivo and in vitro ，to verify that CSCs in the key role in the malignant progression of tumors。This project may provide new clues for PCa malignant progression mechanism, lay the theoretical and experimental basis to curb PCa invasion and metastasis.

侵袭转移是前列腺癌(PCa)难治并导致死亡的根本原因，机制尚不清楚。EMT可能是重要机制，肿瘤干细胞(CSCs)理论也为研究带来新思路。EMT 是否和PCa CSCs特性的获得密切相关？在前期项目资助下，我们成功分离并确认了PCa CSCs的免疫表型，发现CSCs中Hedgehog-Gli通路被显著激活，且EMT程度不同的PCa细胞中CSCs的比率有显著差异。据此，我们推测Hedgehog-Gli通路可能调控PCa细胞发生EMT 转化获得CSCs特性，进而侵袭转移。拟利用现代生物技术，探讨激活和封闭Hedgehog-Gli通路是否可诱导或抑制PCa EMT转化和CSCs特性改变，从而揭示Hedgehog-Gli通路在PCa EMT 转化和CSCs理论中的作用，为将来阻断PCa EMT 转化和CSCs形成，进而为遏制PCa侵袭转移奠定理论和实验依据。

应用前列腺癌组织芯片检测前列腺癌干细胞表面标记物表达，发现前列腺癌恶性进展与癌干细胞特性相关。对前列腺癌EMT细胞模型检测分析，发现前列腺癌细胞EMT转化可导致癌干细胞特性的获得。在前期实验结果的基础上，通过封闭Hedgehog-Gli信号通路，检测分析EMT及癌干细胞特性的变化，发现Hedgehog-Gli信号通路的激活可诱导EMT转化，并可促使前列腺癌细胞获得干细胞样特性。因此，本课题初步揭示Hedgehog-Gli信号通路可诱导前列腺癌细胞发生EMT转化并调控前列腺癌干细胞特性获得，从而提高其体外及体内的侵袭、转移能力；同时验证前列腺癌干细胞的恶性表型转化驱动前列腺癌侵袭转移理论。