自噬体-溶酶体膜融合关键蛋白STX17调控整合素α5β1内吞循环在胰腺癌侵袭转移中的作用及机制研究

肿瘤转移是导致胰腺癌临床治疗失败的主要原因。研究表明自噬在肿瘤转移过程中发挥了重要作用，但自噬与胰腺癌转移之间的关系和调控机制至今鲜有报道。我们的近期研究发现，自噬强弱与胰腺癌侵袭转移能力密切相关，自噬体-溶酶体膜融合关键蛋白STX17在胰腺癌中高表达，并能促进胰腺癌的侵袭和转移；下调STX17能减弱α5β1整合素内体循环和粘着斑（FAP）的解聚能力，但其分子调控机制尚未明确。基于以上发现，我们推测STX17在胰腺癌中可能作为选择蛋白介导自噬相关的内体活动，进而参与整合素内吞循环过程和加速FAP解聚，最终促进胰腺癌的转移。在本项目中，我们拟利用临床胰腺癌标本、自发胰腺癌小鼠模型、肝转移动物模型和分子生物学技术等，探讨STX17介导的自噬过程在胰腺癌侵袭转移中的作用，并阐明STX17促进胰腺癌转移的调控机制，为胰腺癌的临床治疗提供新的思路和方法。

Tumor metastasis is the main reason for the failure of clinical treatment of pancreatic cancer (PC). Studies have shown that autophagy plays a critical role in tumor metastasis, but the relationship and regulatory mechanism between autophagy and metastasis of PC remains unclear. Our recent studies have found that autophagy is closely related to the invasion and metastasis of PC, while STX17, a key protein of autophagosome-lysosomal membrane fusion, is highly expressed in PC and can promote the invasion and metastasis of PC. Down-regulation of STX17 could attenuate the endocytosis of α5β1 integrin and the depolymerization of focal adhesion (FAP), but its molecular mechanism has not yet been elucidated. Based on the above clues, we speculate that STX17 can act as a sorting protein in PC to mediate autophagy-associated endosome activities, and then participate in the endocytosis of integrin and accelerate the depolymerization of FAP, ultimately promoting the metastasis of PC. In this project, we intend to explore the role of STX17-mediated autophagy in the invasion and metastasis of PC by using clinical specimens, spontaneous PC mouse models, liver metastasis animal models and molecular biology technology, and clarify the regulatory mechanism of STX17 in promoting the metastasis of PC, so as to provide new ideas and methods for the clinical treatment of PC.