SUMO3介导清热化湿中药调控糖酵解增加吉西他滨药物敏感性的机制研究

化疗耐药是胰腺癌治疗难点。课题组提出"湿热蕴结"是胰腺癌发病核心病机和耐药内因。针对该病机组方的清热化湿中药联合化疗治疗胰腺癌临床疗效优于常规化疗；中药在体内外可增强吉西他滨对胰腺癌耐药细胞抑制作用，然而其机制不明。课题组预实验中:1.转录组测序筛选出小泛素相关修饰蛋白SUMO3可能介导清热化湿中药化疗增敏作用；2.液相色谱-质谱分析发现SUMO3可结合TLE3，继而活化β-catenin；3.清热化湿中药可显著抑制胰腺癌β-catenin及糖酵解。文献提示阻断糖酵解可提高肿瘤对吉西他滨化疗敏感性，而β-catenin是调控肿瘤细胞糖代谢的重要通路。中药是否通过调控SUMO3及其下游TLE3/β-catenin而抑制糖酵解、逆转胰腺癌化疗耐药？其参与的具体机制如何？课题组拟通过体内外实验及临床病例分析，明确清热化湿中药调控SUMO及其下游耐药相关通路、提高胰腺癌化疗敏感性的作用机制。

Chemotherapy resistance is of great difficulty in clinical practice of pancreatic cancer. The research group put forward that accumulation of dampness and heat is the core pathogenesis of pancreatic cancer and the basis of chemotherapy resistance. Researches indicated that based on the above core pathogenesis, clinical effect of heat-and-dampness-clearing (QingReHuaShi, QRHS) herbs in combination with chemotherapy was significantly better than the latter alone. Experimental studies revealed that the herbs could increase the effect of gemcitabine in inhibiting the growth of chemotherapy resistant human pancreatic cancer cells in vitro and in vivo. At present, the mechanism of the effect is not clear. Our preliminary research indicated the following facts: 1. Transcriptome sequencing showed that the small ubiquitin related modifying protein SUMO3 may mediate the sensitization effect of QRHS herbs when combined with chemotherapy. 2. LC-MS analysis indicated that SUMO3 could bind to TLE3 and then activate β-catenin pathway. 3. QRHS herbs could significantly inhibit the glycolysis level of pancreatic cancer cells. According to literature, blocking glycolysis can improve the chemosensitivity of tumor to gemcitabine. And β-catenin is one of the important pathways to regulate the glycometabolism of tumor cells. Is the sensitization effect of QRHS herbs for chemotherapy in pancreatic cancer related to regulation of SUMO3 and its downstream TLE3/β-catenin pathway and glycolysis inhibition? What is the mechanism underlying? To answer the above questions, the project plans to investigate the effect of QRHS herbs in increasing chemosensitivity, and modulating SUMO3 and its downstream signal pathways related to drug resistance, through in vitro and in vivo experiments and clinical analysis.