The mir-503 cluster is coordinately under-expressed in endometrial cancer

The microRNA-503 cluster, composed of six microRNAs (miR-424, miR503, miR-542, miR-450a-1, miR450a-2 and miR-450b), is located on the human X-chromosome at Xq26. This location is very near the gene encoding placenta-specific protein 1 (PLAC1) that we have shown is significantly over-expressed in several gynecologic cancers. We examined expression of the miR-503 cluster in a panel of endometrial endometrioid adenocarcinomas (EEAs) and found that all of the miRNAs are significantly under-expressed compared with benign tissue. Expression of the miRNAs is highly correlated suggesting that they are regulated from a single promoter. We have used DNA editing (CRISPR) of the miR-503 cluster promoter to down-regulate the entire cluster together. Additionally, known and validated targets of cluster members include a number of important oncogenes. Thus, suppression of miR-503 cluster members contributes to the establishment and maintenance of endometrial cancer. We further suggest that decreased miR-503 cluster expression is due to hyper-methylation of the promoter in tumor cells. Thus, we conclude that the miR-503 cluster is a potential therapeutic target in endometrial cancer.