Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication

Abstract

The aberrant expression of human microRNA-181a-1 (hsa-miR-181a) has been implicated in the pathogenesis of various cancers, serving as an oncogene or a tumor suppressor. However, the role of hsa-miR-181a in the pathogenesis of endometrial carcinoma (EC) and its clinical significance are unclear. This study aimed to search for the molecular targets of hsa-miR-181a using bioinformatic tools and then determine the expression levels of hsa-miR-181a in normal, hyperplasia, and EC samples from humans. To predict the targets of hsa-miR-181a, ten different algorithms were used, including miRanda-mirSVR, DIANA microT v5.0, miRDB, RNA22 v2, TargetMiner, TargetScan 6.2, PicTar, MicroCosm Targets v5, and miRWALK. Two algorithms, TarBase 6.0 and miRTarBase, were used to identify the validated targets of hsa-miR-181a-5p (a mature product of hsa-miR-181a), and the web-based Database for Annotation, Visualization and Integrated Discovery (DAVID) 6.7 was used to provide biological functional interpretation of the validated targets of hsa-miR-181a-5p. A total of 78 formalin-fixed, paraffin-embedded tissue specimens from 65 patients and 13 healthy subjects were collected and examined, including normal endometrium (n=13), endometrial hyperplasia (n=18), and EC (37 type I and 10 type II EC cases). Our bioinformatic studies have showed that hsa-miR-181a might regulate a large number of target genes that are important in the regulation of critical cell processes, such as cell fate, cell survival, metabolism, and cell death. To date, 313 targets of hsa-miR-181a have been validated, and 22 of these targets are cancer genes. The precision of predictions by all the algorithms for hsa-miR-181a-1’s targets was low. Many of these genes are involved in tumorigenesis of various cancers, including EC, based on the DAVID and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In comparison with normal endometrial tissue, the expression level of hsa-miR-181a was significantly increased in type I and type II EC (P<0.05), and type II EC exhibited a significant higher expression level of hsa-miR-181a than that in type I EC (P<0.05). In addition, there was a significant increase in the expression level of hsa-miR-181a in type II EC compared with endometrial hyperplasia (P<0.05). Taken together, these results suggest that hsa-miR-181a may serve as an oncogene in endometrial tumorigenesis and that hsa-miR-181a might be used as a new biomarker in the prediction of prognosis of EC in clinical practice. More functional and mechanistic studies are needed to validate the role of hsa-miR-181a in the development, progression, and metastasis of EC.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…A recent study suggested oncogenic role for hsa-miR-181a in endometrial tumorigenesis and its critical role in tumor metastasis of advanced EC (He et al 2015).…”

Loss of miR-101-3p Promotes Transmigration of Metastatic Breast Cancer Cells through the Brain Endothelium by Inducing COX-2/MMP1 Signaling

“…To understand the molecular mechanisms underlying miR-101-3p effect on the trans-endothelial migration ability of BC cells, we searched for its potential pro-metastasis target genes using six prediction databases including mirTarBase 7.0, miRanda-mirSVR (microRNA.org), PicTar, miRDB, TargetScan 7.2 and TarBase v7.0 [ 31 , 32 ]. In our search, we focused on the genes involved in transmigration of BC through the brain endothelium, particularly, HBEGF, PTGS2 and ST6GALNAC5.…”

“…In silico bioinformatics analysis was carried out to identify miR-101 target genes that are involved in transmigration of cancer cells through the brain endothelium. Initially, we searched for the targets of miR-101-3p using 6 prediction databases including mirTarBase 7.0, miRanda-mirSVR (microRNA.org), PicTar, miRDB, TargetScan 7.2 and TarBase v7.0 [ 31 ]. The target genes identified in more than 3 databases were retained.…”

Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells

“…In silico bioinformatics analysis was carried out to identify micro-RNAs that directly target the 3'-UTR of MMP1. We searched for the micro-RNAs using four databases: mirTarBase 7.0, miRanda-mirSVR (microRNA.org), and miRDB, TargetScan 7.2 [42].…”

“…To identify the micro-RNAs that are specifically involved in the upregulation of MMP-1 in brain metastatic breast cancer cells, we analyzed the clinical micro-RNA array cohort data (GSE37407) which contains global microRNA profiling performed on primary breast tumor samples from 10 patients and their corresponding paired brain metastatic tumors [36]. Analysis with the GEO2R tool of the top 250 microRNAs differentially expressed between the primary and brain metastatic breast tumors revealed that five microRNAs are downregulated in brain metastatic tumors compared to breast primary tumors and also predicted to target MMP1 using four prediction databases: mirTarBase 7.0, miRanda-mirSVR (microRNA.org), and miRDB, TargetScan 7.2 [42]: miR-202-3p, miR-326, miR-623, let-7c, and miR-145 (S1 Table). Three of these micro-RNAs (miR-202-3p, miR-623 and miR-145) are validated to target MMP1 [26,32,45].…”