miR-663抑制结肠癌转移作用及其机制

Recently we found that miR-663, the only given miRNA in centromere regions, was significantly upregulated in colon carcinomas, but downregulated in gastric carcinomas. These indicate that expressions and functions of miR-663 may be tissue/cancer-specific. Clinicopathologic association analysis also showed that colon carcinomas with high miR-663 expression are metastasis-resistant and that these cancer patients had a significant longer overall survival than those with low miR-663 expression. Moreover, we found that enforced overexpression of miR-663 inhibited proliferation and migration of cancer cells, while downregulation of miR-663 expression promoted migration of cancer cells, but did not affect their proliferation in vitro. These results suggest that miR-663 may be a metastasis suppressor for colon cancer. Right now, we have found that among a set of tested target genes, TTC22V1 expression inversely correlates with miR-663 level in multiple cell lines and colon tissues, suggesting TTC22V1 to be one of target genes of miR-663 in the colon. In the present project, we are going to confirm the relationship between miR-663 expression and metastasis of colon carcinomas in an independent cohort and its metastasis supression function in experimental xenograft mouse models. Then,we will explore the possible mechanisms of upregulation of miR-663 in colon carcinomas through DNA demethylation, corresponding lncRNA transcription, and histone modifications. The feasibility of miR-663 overexpression for prevention of colon cancer will be explored. Direct effect of miR-663 on expression of TTC22 and other miR-663 target genes will also be investigated. These studies will be useful for illustration of miR-663 as a metastasis suppressor and its clinical application potential.

我们前期研究发现：<1>miR-663在结肠癌组织中表达明显上调，在胃癌中则表达下调，说明其表达变化存在肿瘤特异性；<2>miR-663表达水平高的结肠癌不易转移，患者总生存时间长；<3>上调miR663的表达抑制结肠癌等细胞的生长和运动迁移，而下调其表达则仅提高癌细胞的运动能力。据此，我们提出miR-663为结肠癌转移抑制基因的假说。进一步在多种细胞系和结肠癌组织中对一组miR-663潜在靶基因进行筛选发现：TTC22V1表达与miR-663表达存在明显负相关。在本项目中，我们拟对miR-663高表达抑制结肠癌转移的作用进行独立队列验证，开展离体和在体抑制癌转移功能研究，探索结肠癌组织中miR-663高表达的成因及其在干预结肠癌转移方面的用途，初步确定miR-663下游靶基因，研究它们在miR-663抑制结肠癌转移中的作用，对揭示miR-663抑制结肠癌转移的机制和临床应用潜能有意义。