抑制胃癌保护性自噬对化疗敏感性影响机制的研究

Abstract: The gastric cancer morbility and mortality of China account for 46.8% and 47.8% of the world respectively, and the 5-year survival rate was about 30%. Beyond standardization of the operation, looking for effective chemotherapeutics which can reduce the rate of drug resistance of gastric cancer is the key to improve patient’s survival rate. In recent years, the closed relationship between autophagy pathway and chemoresistance was raised by many researchers for the reason that autophagy can affect the apoptosis pathway through remodeling the tumor cell energy metabolism. We previously found that inhibition of lactate dehydrogenase leaded to anti-tumor nutrient deficiency and protective autophagy at the same time. How to adjust the relationship between autophagy and apoptosis pathway, interfere tumor cell energy metabolism, and  terminate protective autophagy to promote tumor cell necrosis and apoptosis is a hot issue of research recently. Our study focus on the mechnisms of reverse Warburg effect and autophagy in the development of gastric cancer chemoresistance, studying the mechnism of autophagy in developing gastric cancer chemotherapy resistance and the relationship between autophagy and apoptosis by knocking out ATG-5 gene in gastric cancer cell lines. Through genome-wide high-throughput sequencing of the tissues from patients sensitive or resistant to the neoadjuvant chemotherapy, we try to search for molecular markers in chemoresistance related to autophagy. It is of great significance to study the relationship among autophagy ，energy metabolism and apoptosis in gastric cancer cells with chemoresistance and elucidate the effect of autophagy in chemotherapy and the mechanism of protective autophagy .

我国胃癌发病率和死亡率分别占全球的46.8%和47.8%，5年生存率30%左右。推广规范化手术后，寻找有效的化疗药物，降低胃癌细胞耐药率是提高生存率的关键。近年发现自噬途径与肿瘤细胞耐药有密切关系，可重构肿瘤细胞能量代谢，影响凋亡途径。我们前期研究发现，抑制乳酸脱氢酶，导致肿瘤细胞营养匮乏，可诱导肿瘤细胞保护性自噬。如何调节自噬、凋亡途径的关系，干扰肿瘤细胞能量代谢，解除保护性自噬，促进肿瘤细胞坏死和凋亡，是对肿瘤细胞耐药研究的热点问题。本实验研究反Warburg效应和自噬抑制剂联合化疗药在胃癌化疗耐药中的分子机制，siRNA敲除ATG-5基因构建胃癌自噬基因缺陷细胞株，研究自噬在胃癌化疗耐药中作用及自噬与凋亡的关系。对新辅助化疗耐药及非耐药组织进行全基因组高通量测序，寻找自噬在胃癌化疗耐药中分子标志物。研究自噬、能量代谢及凋亡与胃癌耐药的关系，阐明耐药分子机制，对胃癌治疗具有重要意义。

我国胃癌发病率和死亡率分别占全球的46.8%和47.8%，5年生存率30%左右。推广规范化手术后，寻找有效的化疗药物，降低胃癌细胞耐药率是提高生存率的关键。胃癌保护性自噬与耐药密切相关，为此我们开展了以抑制胃癌自噬增加化疗敏感性研究。包括：（1）根据自噬通路，构建设计针对ATG4B相关抑制剂，并筛选出活性较高的W356，通过体外实验验证W356能有效抑制自噬，同时抑制胃癌细胞的增殖，增加胃癌细胞的凋亡，将进一步进行体内实验；（2）为进一步探讨自噬在胃癌中的作用机制，开展了胃癌中核受体与胃癌自噬相关性探讨，筛选出胃癌中高表达的核受体ROR-γ，研究发现ROR-γ与能量代谢及线粒体密切相关，而能量代谢异常是诱导自噬产生的重要因素，相关体内外实验均证明ROR-γ抑制剂F18、GSK805能有效抑制肿瘤生长，我们将进一步验证其对转移性肿瘤的治疗效果；（3）通过核受体ROR-γ与自噬相关性，筛选了洋橄榄叶素，并证实了其在前列腺癌中具有良好的抗肿瘤作用，相关论文已完成并投稿；. 同时在本项目的资助下，研究探讨了消化道肿瘤（结直肠癌和胃癌）的发病机制，并发表高质量SCI论文4篇。为寻找更多有效的抗肿瘤药物，我们筛选了天然海洋产物并从青霉素菌中提取了一类新型环烷酮类化合物，为抗肿瘤药物提供新选择的同时发表SCI论文1篇。. 为此本团队在抑制胃癌自噬增加化疗敏感性，消化道肿瘤发病机制及新的抗肿瘤药物探寻方面提供了新的思路和理论基础。