MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1

Abstract

MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3′ untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC.

Microparticles in cancer: A review of recent developments and the potential for clinical application

“…This finding supported previous observations of reduced migration and invasion following transfection of miR-503 in hepatocellular carcinoma cells [27], acute myeloid leukemia cells [28], chronic myelogenous leukemia cells [29], osteosarcoma cells, colon cancer cells [30], head and neck carcinoma cells [31] and in endometrioid endometrial cancer cells [32].…”

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

“…Our previous studies (Llobet-Navas et al 2014a,b) and the new data shown here have revealed that this miRNA cluster modulates the expression of at least three well-known oncogenes (CDC25A, BCL-2, and IGF1R) in human and mouse primary breast cancers. Others have also shown that, in other cell types, this cluster targets additional genes involved in cell cycle progression (Nakashima et al 2010;Xu et al 2013b), angiogenesis (Ghosh et al 2010;Nakashima et al 2010), immune response (Xu et al 2016), cell metabolism (Long et al 2013), and cell adhesion (Chong et al 2014). Thus, we propose that aberrant high levels of these targets due to loss of miR-424(322)/ 503 support multiple hallmarks of cancer leading to tumorigenesis (Fig.…”

miRNA-503 Promotes Tumor Progression and Is Associated with Early Recurrence and Poor Prognosis in Human Colorectal Cancer

“…miR-503 is downregulated in several types of cancer including oral, hepatocellular, gastric and endometrial [12,13,14,15,16] cancer, suggesting that it plays a tumor-suppressive role in carcinogenesis. In contrast, it is overexpressed in parathyroid carcinoma, retinoblastoma and adrenocortical carcinoma [17,18,19], and upregulation of miR-503 is associated with a shorter overall survival (OS) rate among patients with adrenocortical carcinoma [19].…”