miR-490-3p调控剂(ANOS)抗幽门螺旋杆菌诱发胃癌的作用研究

MicroRNAs function as oncogenes or tumor suppressors by regulating gene expression and represent promising therapeutic targets for cancer. Small molecules modulating microRNAs expressions would thus constitute potential anticancer agents. In our previous study, we found that microRNA-490-3p (miR-490-3p) functioned as a tumor suppressor and was downregulated in Helicobacter pylori （Hp） induced gastric cancer. The mechanism of the role of miR-490-3p in Hp induced gastric cancer was also well elucidated. Since overexpression of miR-490-3p exhibited high anti-gastric cancer efficency, small molecule activating miR-490-3p expression would thus constitute potential anti-Hp induced gastric cancer agent. In our previous studies, by comparing and analyzing the microarray data from miR-490-3p treated gastric cancer cells and 1309 compounds treated cells, we found that a small molecule termed ANOS activiated miR-490-3p expression in a dose dependant manner. ANOS exhibited anti-gastric cancer activity both in in vitro and in vivo. In this project, we will focus on the function of ANOS on prevention,delay and inhibition of Hp induced gastric cancer and try to illustrate the detailed mechanism on how ANOS activates the expression of miR-490-3p.

microRNA通过调节众多基因表达来行使致癌或抑癌功能，使得microRNA在肿瘤治疗中常成为有效靶标。调节microRNA表达的小分子化合物被视为潜在的抗癌药物。申请人前期研究详细阐述了miR-490-3p作为抑癌基因在幽门螺旋杆菌(Hp)诱发胃癌中的作用机制。过表达miR-490-3p抑制胃癌效应显著。因此，激活miR-490-3p表达的调控剂可成为抗Hp诱发胃癌的潜在药物。我们通过生物信息学方法比对miR-490-3p模拟物处理胃癌细胞和1309种小分子化合物分别处理细胞得到的人类全基因芯片数据，发现了一个呈剂量依赖激活miR-490-3p表达的小分子化合物。该化合物被命名为ANOS。初步的体内、体外实验显示ANOS具有明显的抗胃癌活性。本研究旨在探索ANOS是否具有预防、延迟和抑制Hp诱发胃癌的效果及探讨ANOS调控miR-490-3p表达的作用机制。

microRNA通过调节众多基因表达来行使致癌或抑癌功能，使得microRNA在肿瘤治疗中常成为有效靶标。调节microRNA表达的小分子化合物被视为潜在的抗癌药物。项目负责人在前期研究详细阐述了miR-490-3p作为抑癌基因在幽门螺旋杆菌(Hp)诱发胃癌中的作用机制（Xiao et al, cancer research, 2014）。过表达miR-490-3p抑制胃癌效应显著。因此，激活miR-490-3p表达的调控剂可成为抗Hp诱发胃癌的潜在药物。..在该项目中，我们通过生物信息学方法比对miR-490-3p模拟物处理胃癌细胞和1309种小分子化合物分别处理细胞得到的人类全基因芯片数据，发现了一个呈剂量依赖激活miR-490-3p表达的小分子化合物。该化合物被命名为ANOS。体内、体外实验显示ANOS具有明显的抗胃癌活性。同时，本研究发现：ANOS具有抑制Hp诱发胃癌的效果；机制研究发现，ANOS特异激活miR-490-3p的表达是进过抑制miR-490-3p启动子DNA甲基化来完成的。..在该研究中，我们筛选出的小分子化合物ANOS，是我们以 Hp 诱发的胃癌模型研发抗胃癌药物正是基于现有药物的不足，密切联系我国胃癌与 Hp 并发感染的实情，寻求新的突破中发现的一个有意义的发现，是研发针对Hp诱发胃癌的潜在理想候选药物，值得我们对其进行更加深入的研究。