MYC/let-7/LAT2通路通过谷氨酰胺代谢和糖酵解调控胰腺癌化疗耐药的机制研究

化疗耐药是限制胰腺癌患者预后的重要因素，因此，深入研究调控胰腺癌化疗耐药的分子机制，对于改善胰腺癌患者预后具有重要的意义。近年研究表明，能量代谢重塑已成为调控化疗耐药的重要机制之一。转录因子MYC和miRNA在胰腺癌谷氨酰胺代谢、糖酵解和化疗耐药调控中均发挥重要作用。课题组前期通过生物信息学分析提示MYC和let-7可以相互作用并构成MYC-let-7反馈环；进一步实验结果表明，LAT2为let-7的靶基因，LAT2/mTOR通路可通过调控糖酵解和谷氨酰胺代谢诱导胰腺癌化疗耐药。因此，本研究拟采用XF能量代谢平台、ChIP-seq、液相色谱质谱联合分析等技术，基于人源肿瘤异种移植瘤模型和KPC小鼠胰腺癌模型，在体外、体内水平系统地探索MYC/let-7/LAT2通路通过谷氨酰胺代谢和糖酵解调控胰腺癌化疗耐药的作用及其分子机制，从而为逆转胰腺癌化疗耐药并寻找化疗联合治疗靶点提供依据。

Chemoresistance is an important factor resulting in poor prognosis of patients with pancreatic cancer. Therefore, exploring the molecular mechanism regulating chemoresistance is of great significance for improving the prognosis of patients with pancreatic cancer. Energy metabolism reprogramming has become one of the important mechanisms for the regulation of chemoresistance. Recent studies have shown that transcription factor MYC and miRNA play important roles in the regulation of glutamine metabolism, glycolysis and chemoresistance in pancreatic cancer. Bioinformatics analysis results of our research group showed that MYC and let-7 can combine and interact with each other, forming a feedback loop of myc-let-7. The preliminary results revealed that LAT2 was the target gene of let-7, LAT2/mTOR pathway could induce chemoresistance in pancreatic cancer by regulating glycolysis and glutamine metabolism. Therefore, this study will systematically explore the role of MYC/let-7/LAT2 pathway on glutamine metabolism, glycolysis and chemoresistance in pancreatic cancer and the potential molecular mechanisms by using series of technologies including XF energy metabolism analizer, ChIP-seq and liquid chromatography-mass spectrometry, and based on the patient derived xenograft and KPC model. This study will lay a foundation for the reversal of chemoresistance and exploration of new target increasing chemosensitivity in pancreatic cancer.