1,25(OH)2D3协同顺铂通过RASAL2调控RAS信号转导通路抑制胃癌进展

项目名称： 1,25(OH)2D3协同顺铂通过RASAL2调控RAS信号转导通路抑制胃癌进展

项目编号： No.81502087

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 包安裕

作者单位： 武汉大学

项目金额： 18万元

中文摘要： 胃癌是我国最常见的消化道恶性肿瘤，临床以进展期胃癌为主。顺铂为进展期胃癌的基本化疗药，因毒副作用大常与其他药物联用以降低毒副作用，但临床效果欠佳。前期研究发现，1,25(OH)2D3可协同顺铂抑制胃癌细胞增殖，促进胃癌细胞凋亡，此作用与RAS-ERK信号转导通路有关; 继而通过基因芯片筛选发现RASAL2基因在1,25(OH)2D3与顺铂联合作用胃癌细胞时呈现显著高表达。为明确1,25(OH)2D3的协同抑癌机制，本项目将通过沉默和过表达RASAL2基因，研究1,25(OH)2D3和（或）顺铂对胃癌细胞增殖与凋亡、迁移与侵袭的影响；分析RAS活性及RAS/RAF/MEK/ERK信号转导通路受到的调控；并建立人胃癌裸鼠移植瘤模型，在体研究1,25(OH)2D3协同顺铂对胃癌进展的抑制。本项目预期将进一步揭示1,25(OH)2D3协同顺铂抑制胃癌进展的机制，深入认识维生素D的抗癌功效。

中文关键词： 胃肿瘤；1；25(OH)2D3；RASAL2；顺铂

英文摘要： Gastric cancer is the most common malignant tumor with high incidence and mortality in China. Advanced gastric cancer ranks mainly in clinical diagnosed patients. Cisplatin is widely used in the chemotherapy of advanced gastric cancer, while it is often combined used with other drugs because of its serious side effects. However, the clinical therapeutic effect is limited. It is indicated by our previous studies that 1,25(OH)2D3 played a synergistic role with cisplatin in promoting cell apoptosis and inhibiting cell proliferation in gastric cancer cells. With the help of microarray analysis, we found that RASAL2 was up-regulated in combined treatment cells by 1,25(OH)2D3 and cisplatin. In order to clarify the mechanism of 1,25(OH)2D3's synergistic anticaner effects, we designed this project. The project plans to silence or over-express RASAL2 gene and then explore the influences of combined treatment on cellular proliferation, apoptosis, migration and invasion of gastric cancer cells. Importantly, we will analyze the activity of RAS and RAS/RAF/MEK/ERK signal pathway after the combined treatment with 1,25(OH)2D3 and cisplatin. Gastric cancer nude mice xenograft model is to be established for studying the influence of 1,25(OH)2D3 and cisplatin on gastric cancer progress and to reveal the regulation of RAS signal pathway in this course. The project is predicted to further clarify the possible mechanism of 1,25(OH)2D3's synergistice anticancer role with cisplatin, which will be benefit for realize the anticancer effects of vitamin D.

英文关键词： gastric cancer;1;25-dihydroxyvitamin D3;RASAL2;cisplatin