外泌体源miRNAs介导胰腺癌中糖代谢紊乱/胰岛素抵抗的发生及机制探讨

胰腺癌有独特的代谢重构现象，与外周组织间发生着基于胰岛素抵抗的代谢交互作用，可导致全身代谢紊乱，其引起的糖代谢障碍及胰岛素抵抗（IR）则又与肿瘤增殖、转移、耐药等密切相关。基于项目组胰腺癌相关糖尿病的系列研究以及前期预实验，我们发现胰腺癌源外泌体处理骨骼肌细胞后，导致IRS1/PI3K/Akt信号传导受损，Glut4蛋白表达下降，出现胰岛素抵抗；通过筛选、验证，发现外泌体中的miR-450b-3p 、miR-151-3p可影响胰岛素信号通路，而其角色及具体机制尚不明确。基于此，本项目拟进一步探讨外泌体源miR-450b-3p 及miR-151-3p 是否在胰腺癌介导的IR发生过程中发挥关键作用，并阐明其具体分子机制，同时探讨靶向外泌体miRNA的治疗是否可改善IR及代谢紊乱状态。本项目研究结果将为临床提供用以纠正胰腺癌患者代谢紊乱、改进诊疗的潜在干预靶点。

Pancreatic cancer (PC) has a characteristic of metabolic reprogramming, including metabolic crosstalk between PC and peripheral tissues, with a pathological basis of insulin resistance (IR) underlying. It causes systemic metabolic disorder，including glucose intolerance and IR, which shows a closely correlation to tumor proliferation, metastasis and chemotherapy resistance. Based on the researches of pancreatic cancer associated new-onset diabetes (PC-DM) and previous work, we discovered that: In skeletal muscle cells, PC-exosomes induce inhibition of IRS1/PI3K/Akt signaling, decrease of Glut4 protein expression, and IR. Further screening and validation indicated that exosomal miR-450b-3p and miR-151-3p can disturb the signaling transduction. However, the specific function and mechanism is unknown. In this project, we intend to observe the function and elucidate the mechanism of exosomal miR-450b-3p and miR-151-3p in the course of PC-associated IR, and evaluate the possibility of targeting miR-450b-3p and miR-151-3p in the treatment of PC-associated IR/metabolic disorder. The results would contribute to discover potential targets for correcting metabolic disorders and improving diagnosis/treatment in the context of PC.