Endometrial cancer (EC) is the most common gynecologic malignancy in western counties. Generally, a five-year survival of patients with localized disease remains at approximately 96% and this rate drops to 67% and 17% for the patients suffering from regional and distant metastasis, respectively. Therefore, an improved understanding of the molecular mechanisms in metastasis of endometrial cancer has the potential to significantly impact the outcomes for this disease. Studies has outlined the essential roles for miR-449a in regulating pathogenesis of cancers. A number of reports have identified the role of microRNAs in EC, but little is known about miR-449a in it.
FISH was used to detect the expression of miR-449a in the 55 tissues and IHC was performed to measure the NDRG1 expression in the above samples. The alterations of NDRG1 gene were analyzed by cBioPortal for Cancer Genomics online. The human EC cell lines were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin in a humid atmosphere incubator with 5% CO2 at 37 °C. The expression of miR-449a and NDRG1 were assayed by quantitative real time-PCR Wound healing assay, migration and invasion assays were performed to detect the ability of migration and invasion in EC cells. NDRG1 and PTEN/AKT pathway were detected by immunoblotting.
In this study, our analysis found that miR-449a expression is inversely correlated with the stage of endometrial cancer. Overexpression of miR-449a in human EC cells alleviated cell invasion and metastasis in vitro. Conversely, miR-449a knock-down promoted migration and invasion of EC cells. Moreover, we identified N-myc Downstream-Regulated Gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression NDRG1 in 55 endometrial cancer specimens were inversely correlated with that of miR-449a. In addition to this, further studies show that down-regulation of NDRG1 inhibited migration and invasion of EC cells through PTEN/AKT pathway.
miR-449a suppresses metastasis of EC cells by directly targeting NDRG1 gene and activation of miR-449a may represent an effective therapeutic strategy in endometrial cancer.
Clinical trial identification
Legal entity responsible for the study
Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, China.
National Natural Science Foundation of China (81272884).
The author has declared no conflicts of interest.