FOXO3a通过上调JMJD1C促进DNA损伤修复导致弥漫型胃癌对奥沙利铂耐药的机制研究

Gastric cancer can be classified into diffuse type and intestinal type by Lauren classification. It has been found that diffuse-type gastric cancer is less sensitive to oxaliplatin than intestinal type in clinical trials, but the mechanism has not been elucidated. We found that the expression of nuclear transcriptional factor FOXO3a is significantly higher in diffuse-type gastric cancer than that of intestinal type in our previous study, and that FOXO3a promoted resistance to oxaliplatin in diffuse-type gastric cancer cell lines. Further study found that FOXO3a promoted the expression of JMJD1C, and JMJD1C knockout can reduce resistance to oxaliplatin in diffuse-type gastric cancer cell lines. Based on this results, we speculate that FOXO3a may promote DNA repair by up-regulating JMJD1C, leading to resistance to oxaliplatin in diffuse-type gastric cancer. This study aimed to confirm the mechanism by which FOXO3a regulated JMJD1C and clarify the relationship between JMJD1C-mediated DNA damage repair and oxaliplatin-resistance by in vitro and in vivo research, and the effect of FOXO3a-JMJD1C axis on the prediction of oxaliplatin treatment would also be clarified by animal model and gastroscope specimens of advanced gastric cancer. Our results will not only reveal the new mechanism of resistance to oxaliplatin in diffuse-type gastric cancer, but also provide new theoretical basis for individualized therapy and drug development of gastric cancer.

胃癌按Lauren分型分为弥漫型和肠型，临床研究发现弥漫型胃癌对奥沙利铂的敏感性低于肠型胃癌，但机制尚未阐明。申请者在前期研究中发现核转录因子FOXO3a在弥漫型胃癌中的表达显著高于肠型胃癌，且促进了弥漫型胃癌细胞株对奥沙利铂耐药。进一步研究证实FOXO3a可能促进JMJD1C的表达，而敲除JMJD1C可降低弥漫型胃癌细胞株对奥沙利铂的耐药性。据此，我们推测“FOXO3a可通过上调JMJD1C促进DNA损伤修复导致弥漫型胃癌对奥沙利铂耐药”。本课题拟通过体内和体外实验进一步明确FOXO3a对JMJD1C表达的调控机制，阐明JMJD1C介导的DNA损伤修复与奥沙利铂耐药的关系；同时，结合动物模型和晚期胃癌患者标本检测，探讨FOXO3a-JMJD1C信号轴对奥沙利铂疗效的影响和预测作用。所得结果不仅可揭示弥漫型胃癌对奥沙利铂耐药的新机制，还可为胃癌的个体化治疗和新药研发提供新的理论依据。

在本课题的资助下，我们建立了胃癌数据库，并完成了2项回顾性队列研究：1）通过比较XELOX方案与SOX方案在胃腺癌患者术后辅助化疗中的疗效，我们发现两组方案疗效相当；2）通过比较奥沙利铂在不同Lauren分型的胃腺癌患者术后辅助化疗中的作用，我们发现Lauren分型为弥漫型的患者无法从含奥沙利铂的辅助化疗方案中获益。我们利用公开的基因芯片数据，通过LASSO方法分析高通量信使RNA的表达差异，构建了一个由19个mRNA组成的预测胃癌术后复发转移的模型。最后，我们通过体内和体外实验发现了胃癌对5-FU的耐药新机制，即胃癌细胞转录因子HIF1响应5-FU的处理，通过促进HMGB1的转录和表达招募肿瘤相关巨噬细胞进入肿瘤，浸润的巨噬细胞产生大量的GDF15而促进了肿瘤细胞的脂肪酸氧化作用，最终增强了胃癌细胞对5-FU的耐药性。上述结果共计发表SCI论著4篇，协助培养了1名硕士研究生和1名博士研究生，完成课题设定目标。