CHIP/EGFR信号通路调控胰腺癌转移的分子机制研究

肿瘤转移是影响胰腺癌患者预后的重要因素，胰腺癌转移的分子过程尚不明确。文献报道EGFR可以通过调控肿瘤干细胞（CSCs）特性和上皮间质转化（EMT）促进肿瘤转移，但其上游调控机制有待进一步探索。我们前期的研究表明泛素E3连接酶CHIP可能通过降解EGFR抑制胰腺癌的转移，但其具体机制尚不明确。本研究应用截断体和突变体，寻找CHIP与EGFR的结合位点，阐明CHIP降解EGFR的分子机制；然后通过体外实验,探索CHIP/EGFR信号通路对胰腺癌细胞转移、干细胞特性及上皮间质转化的调控作用及其机制；最后利用稳转细胞株建立裸鼠原位移植瘤模型，观察胰腺癌转移情况及相关分子的表达，探索CHIP阻断胰腺癌转移的机制，从而明确CHIP是否通过"CHIP/EGFR-CSCs-EMT"这一网络调控胰腺癌的转移。本课题有望深入探索胰腺癌的转移机制，可能为阻断胰腺癌转移进程、治疗转移灶提供新的分子靶点。

Tumor metastasis is the main factor affecting the prognosis of pancreatic cancer, and pancreatic cancer metastasis mechanism is unclear. Literature reported EGFR can control tumor stem cells (CSCs) features and transformation of epithelial mesenchymal (EMT), promote tumor metastasis.Our previouse study indicated that ubiquitin E3 ligase CHIP may inhibit pancreatic cancer metastasis by degradating EGFR, but its specific mechanism is unclear. This study first explore the molecular mechanism of CHIP degradation of EGFR;Then by in vitro experiments illustrate CHIP/EGFR signaling pathways in pancreatic cancer cells, stem cells and EMT phenotypic regulation function and its mechanism;Finally applying Nude mouse orthotopic transplantation tumor model, observing pancreatic cancer metastasis, to verify whether CHIP inhibit pancreatic cancer metastasis by "CHIP/EGFR-CSCs-EMT " network.This study is expected to reveal the mechanism of pancreatic cancer metastasis, to establish the CHIP as a novel targets in treatment of pancreatic cancer provide certain scientific basis.