miR-490-3p在结直肠癌中调控长链非编码RNA（lncRNA） 的作用机制及靶点研究

MicroRNAs (miRNAs) function as oncogenes or tumor suppressors by regulating gene expression and represent promising therapeutic targets for cancer. Small molecules modulating miRNAs expressions would thus constitute potential anticancer agents. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor samples and 123 adjacent tumor samples, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. The expression of miR-490-3p was downregulated in most of these digestive cancers, especially in colorectal cancer. In our preliminary study, we found that miR-490-3p functioned as a tumor suppressor in colorectal cancer. According to the long non-coding RNA(lncRNA) microarray profile of colorectal cancer cells in which the miR-490-3p was over expressed, we found a direct target of miR-490-3p, termed RP11-317M11.1. Both in vitro and in vivo studies showed that RP11-317M11.1 exhibited strong carcinogenic activity. We also found that RP11-317M11.1 physically bond to DGCR8, a key regulator of miRNA biogenesis. we will focus on the role of miR-490-3p-RP11-317M11.1-DGCR8 axis in colorectal cancer pathogenesis. Meanwhile, using bioinformatics tool and experiment validation, we also screened a small molecule termed ANOS which can activate miR-490-3p expression in a dose dependant manner. Anti-gastric cancer activity of ANOS in colorectal cancer was also proved in in vitro and in vivo studies. In this project, Illustrating the detailed mechanism on how miR-490-3p regulates RP11-317M11.1-DGCR8 complex and investigating the molecular mechanism of ANOS on activating the expression of miR-490-3p in colorectal cancer will set the theoretical basis for anti-cancer drug development in digestive cancers.

microRNA (miRNA)具有致癌或抑癌功能，使其成为肿瘤治疗中潜在的有效靶点。申请者分析1765例消化道癌及123例癌旁样本的miRNA二代测序数据发现：各消化道癌miRNA表达谱具有相关性；miR-490-3p在消化道癌中普遍下调，在结直肠癌中尤为明显。实验证明miR-490-3p具有抗结直肠癌活性；通过人全lncRNA芯片分析及实验验证鉴定出miR-490-3p直接调控的lncRNA，该lncRNA可与调控miRNA生物合成的蛋白DGCR8结合。我们也筛选出激活miR-490-3p表达而具抑癌活性的小分子化合物ANOS。本项目将在结直肠癌中研究miR-490-3p的抑癌效应否通过lncRNA-DGCR8调控miRNA生物合成的路径实现；明晰ANOS、miR-490-3p、lncRNA以及下游靶蛋白之间相互作用的分子机制，为靶向miR-490-3p抗癌药物研发提供理论依据。

miRNA具有致癌或抑癌功能，且miRNA能同时靶向不同类型的靶点从而降低其赖药性，使其成为肿瘤治疗中潜在的理想靶点。在该项目中，分析1765例消化道癌及123例癌旁样本的miRNA二代测序数据发现各消化道癌miRNA表达谱具有相关性；miR-490-3p在消化道癌中普遍下调，在结直肠癌中尤为明显。实验证明miR-490-3p具有抗结直肠癌活性；通过人全lncRNA芯片分析及实验验证鉴定出miR-490-3p直接调控的lncRNA: RP11-317M11.1, 该lncRNA可与调控miRNA生物合成的蛋白DGCR8结合。我们也筛选出激活miR-490-3p表达而具抑癌活性的小分子化合物ANOS。本项目的研究证实：在结直肠癌中miR-490-3p的抑癌效应通过lncRNA-DGCR8信号路径实现；初步明确了ANOS、miR-490-3p、RP11-317M11.1以及下游靶蛋白之间的相互关系。为靶向miR-490-3p抗癌药物研发提供理论依据。