Hedgehog/Gli1信号通路调控STMN1表达在胃癌EMT转化和侵袭转移过程中的作用及机制研究

The tumor invasion and metastasis are basic characteristics of malignant tumors, and become the most important prognostic factors in gastric cancer. The Hedgehog (Hh) signaling pathway and Stathmin1 (STMN1) are considered to be involved in the molecular mechanism of the invasion and metastasis of the tumors. Our previous study found that the Hh signal pathway is actived in gastric cancer, and the expression pattern of STMN1 is similar to Gli1 in gastric cancer specimens. The STMN1 expression is regulated by Hh signaling in gastric cancer cells. Moreover, STMN1 expression is upregulated in gastric cancer, and its expression is associated with malignant phenotype of gastric cancer.When the expression of stathmin1 was knocked down using siRNA, the migration and invasion of gastric cancer cells in vitro were significantly inhibited and is associated with EMT.Above all, we speculate that Hh signaling regulates the EMT of gastric cancer cells by regulating the expression od STMN1. In this research project, we first ivestigate the expression of Hh signaling pathway members and STMN1 in gastric cancer specimens. Then we examined whether the STMN1 expression is regulated by Hh signaling, and how Hh signaling regulates invasion and metastasis of gastric cancer cells.Finally, knockdown of STMN1 expression by RNA interference,we further explore the mechanism of Hh signaling regulation of STMN1 to change the biological characteristics of gastric cancer.The study will reveal the molecular mechanism of Hh signaling mediated tumor invasion and metastasis of gastric cancer.

肿瘤侵袭和转移是影响胃癌预后的主要因素，EMT可能是重要机制。研究报道Hedgehog（Hh）信号通路、STMN1与肿瘤的侵袭转移过程密切相关。我们前期研究发现Hh/Gli1通路在胃癌中异常激活，阻断Hh通路后STMN1表达下降，并能抑制胃癌细胞的迁移侵袭；而STMN1的异常表达与胃癌的恶性表型密切相关，敲减STMN1表达可抑制胃癌EMT转化和迁移侵袭。据此我们提出“Hh/Gli1通路通过调控STMN1表达，干扰微管稳态，从而促进胃癌发生EMT转化及侵袭转移”这一研究假说。本课题利用现代生物技术，通过激活和封闭Hh/Gli通路活性，并结合干扰Gli1和STMN1表达，分析Hh通路对STMN1的调控机制，揭示Hh/Gli1-STMN1途径在胃癌细胞EMT转化和侵袭转移过程的作用及机制。本研究将有助于揭示Hh通路在胃癌侵袭转移中的作用，为胃癌靶向治疗、遏制侵袭转移提供新的理论依据和实验支持。

胃癌是全球最常见的恶性肿瘤之一，我国由于缺乏有效的筛查，大多数患者确诊时已属于中晚期，肿瘤的侵袭和转移是影响胃癌预后的重要因素。因此，研究胃癌的侵袭转移机制和探索阻断方法，对提高疗效、改善胃癌预后具有重要意义。研究报道Hedgehog（Hh）信号通路、STMN1与肿瘤的侵袭转移过程密切相关。本课题通过调控Hh/Gli通路活性，分析Hh通路对STMN1的调控机制，揭示Hh/Gli1-STMN1途径在胃癌细胞EMT转化和侵袭转移的作用及机制。本研究通过检测胃癌组织和癌旁组织中STMN1蛋白、Hh信号通路蛋白以及EMT标志物的表达，结果提示胃癌组织中Hh信号通路存在异常活化，与STMN1、EMT相关蛋白表达相关。细胞学实验证实Hh/Gli1通路、STMN1与胃癌细胞的迁移及侵袭能力，并且参与胃癌EMT转化调控。进一步研究表明Hh信号通路中的转录因子Gli1可以与STMN1的启动子区直接结合，直接调控STMN1的表达。研究结果证实STMN1参与调节Hh/Gli1信号通路诱导的EMT转化和侵袭转移过程，其作用机制可能与调控微管稳定状态有关。本课题为揭示了Hh/Gli1信号通路调控STMN1表达在胃癌EMT转化中的作用，为遏制侵袭转移提供新的理论支持。