miR-138-5p调控SIRT1-FOXO1-Rab7通路抑制缺氧诱导的胰腺癌细胞自噬和侵袭转移

高侵袭转移特性是胰腺癌临床治疗效果、预后不佳的重要原因。普遍观点认为胰腺癌细胞处于缺氧环境中，通过自噬流维持了细胞内环境稳态。而细胞自噬的发生与肿瘤细胞的恶性生物学特性密切相关。申请人前期研究发现：缺氧诱导胰腺癌细胞发生自噬，miR-138-5p在原发性胰腺癌组织及胰腺癌细胞系中呈低表达，并与其侵袭转移密切相关。文献表明：SIRT1-FOXO1-Rab7信号通路参与调控细胞自噬。生物信息学分析提示：miR-138-5p靶向负调控SIRT1的表达。因此，提出研究假设：miR-138-5p靶向调控SIRT1-FOXO1-Rab7信号通路抑制缺氧诱导的胰腺癌细胞自噬进而影响其侵袭转移。本项目拟从细胞、分子生物学水平、结合动物模型及胰腺癌临床病例资料，验证miR-138-5p在低氧条件下调控胰腺癌细胞自噬，探索其影响胰腺癌细胞侵袭转移的分子机制，为胰腺癌的治疗和预后提供新的分子靶点。

Pancreatic cancer is high invasion and metastasis, which induce poor prognosis disease. The general opinion is that pancreatic tumor cells are in a hypoxia micro-environment and maintain the homeostasis through autoghagy, what is more, the cell autophagy is related to the malignant tumor. Our previous study revealed that hypoxia aroused the autophagy of pancreatic cancer cells, and the expression of miR-138-5p decreased in primary pancreatic cancer tissue and cell line, which was closely correlated to the high invasion and metastasis. It was repeated that SIRT1-FOXO1-Rab7 signaling pathway was involved in cell autophagy. Likewise, bioinformation analysis illustrates that miR-138-5p targets SIRT1 to negatively regulate it. Therefore, it’s supposed that miR-138-5p inhibits the hypoxia-induced autophagy of pancreatic cancer cells through SIRT1-FOXO1-Rab7 signaling pathway to influence the cancer invasion and metastasis. Hence, in the current project, we aim to employ the cell and molecular biology, animal model and clinical assays in both in vivo and in vitro system to further investigates the mechanisms of miR-138-5p regulated autophagy under hypoxia in pancreatic cancer, and explored the impact and molecular mechanism of miR-138-5p on pancreatic cancer invasion and metastasis, which might identify novel diagnostic markers and therapeutic targets for pancreatic cancer.