KRAS突变调控TMOD3促进Warburg效应介导胰腺癌增殖及侵袭转移的机制研究

KRAS是胰腺癌中突变最早且几率最大的关键驱动基因。研究表明: KRAS突变介导的有氧糖酵解(Warburg)效应是胰腺癌快速增殖及高侵袭性的重要原因之一，但分子机制仍不清楚。申请人前期研究发现：①原肌球调节蛋白（TMOD3）在胰腺癌中高表达，并与胰腺癌KRAS突变、临床理病参数、总生存率密切相关。②TMOD3可在体外促进胰腺癌细胞增殖及侵袭转移能力。③TMOD3调控葡萄糖转运体（Glut1）的表达及膜定位④TMOD3可参与调控细胞骨架及F-actin聚集。因此提出研究假说：KRAS突变调控TMOD3促进F-actin介导的Glut1循环回膜，增加胰腺癌细胞葡萄糖摄入，从而促进胰腺癌细胞Warburg效应、增殖及侵袭转移能力。本研究将以TMOD3为研究对象，深入了解KRAS突变介导Warburg效应，增殖及侵袭转移的分子机制，为胰腺癌的治疗提供可能的靶点。

KRAS is the key driver gene in pancreatic cancer with the earliest mutation and the highest probability. Studies have shown that: KRAS mutation-mediated aortic glycolysis (Warburg) effect is one of the important reasons for the rapid proliferation and high invasiveness of pancreatic cancer, but the molecular mechanism remains unclear. The previous study of the applicant found that: ① TMOD3 is highly expressed in pancreatic cancer, and is closely related to KRAS mutation, clinical pathological parameters and overall survival rate of pancreatic cancer. ②TMOD3 promotes pancreatic cancer cell proliferation and invasion and migration in vitro. ③TMOD3 regulates glucose transporter (Glut1) expression and membrane localization ④TMOD3 could be involving in the cytoskeleton regulation and F-actin aggregation. Therefore, the hypothesis is proposed: KRAS mutation induced TMOD3 to promote F-actin aggregation-mediated Glut1 recyling and glucose uptake increasing, thereby promoting Warburg effect, proliferation and invasion and metastasis of pancreatic cancer cells. The study will focus on TMOD3 to explore the molecular mechanism of KRAS mutation-mediated Warburg effect, proliferation and invasion and metastasis, and provide a potential therapeutic target for the treatment of pancreatic cancer.