Oncogene database

406958

MIR182

microRNA 182;MIR182;microRNA 182

hsa-mir-182

7q32.2

ncRNA

The FOXO1 transcription factor orchestrates the regulation of genes involved in the apoptotic response, cell cycle checkpoints, and cellular metabolism. FOXO1 is a putative tumor suppressor, and the expression of this gene is dysregulated in some cancers, including prostate and endometrial cancers. However, the molecular mechanism resulting in aberrant expression of human FOXO1 in cancer cells is poorly understood. We show here that FOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue. Silencing of the microRNA processing enzymes, Drosha and Dicer, led to an increase in FOXO1 expression. We also identified functional and specific microRNA target sites in the FOXO1 3 -untranslated region for miR-27a, miR-96, and miR-182, microRNAs that have previously been linked to oncogenic transformation. The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low. Antisense inhibitors to each of these microRNAs led to a significant increase in endogenous FOXO1 expression and to a decrease in cell number in a manner that was blocked by FOXO1 siRNA. Overexpression of FOXO1 resulted in decreased cell viability because of inhibition of cell cycle traverse and induction of cell death. We have identified a novel mechanism of FOXO1 regulation, and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells.

Onco-miR-182-5p has been reported to be over-expressed in bladder cancer (BC) tissues however a detailed functional analysis of miR-182-5p has not been carried out in BC. Therefore the purpose of this study was to: 1. conduct a functional analysis of miR-182-5p in bladder cancer, 2. assess its usefulness as a tumor marker, 3. identify miR-182-5p target genes in BC. Initially we found that miR-182-5p expression was significantly higher in bladder cancer compared to normal tissues and high miR-182-5p expression was associated with shorter overall survival in BC patients. To study the functional significance of miR-182-5p, we over-expressed miR-182-5p with miR-182-5p precursor and observed that cell proliferation, migration and invasion abilities were increased in BC cells. However cell apoptosis was inhibited by miR-182-5p. We also identified Smad4 and RECK as potential target genes of miR-182-5p using several algorithms. 3 UTR luciferase activity of these target genes was significantly decreased and protein expression of these target genes was significantly up-regulated in miR-182-5p inhibitor transfected bladder cancer cells. MiR-182-5p also increased nuclear beta-catenin expression and while Smad4 repressed nuclear beta-catenin expression. In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer.

As an important tumor suppressor, programmed cell death 4 (PDCD4) influences transcription and translation of multiple genes, and modulates different signal transduction pathways. However, the upstream regulation of this gene is largely unknown. In this study, we found that microRNA-182 (miRNA-182, miR-182) was upregulated, whereas PDCD4 was downregulated in ovarian cancer tissues and cell lines. Blocking or increase of miR-182 in ovarian cancer cell lines led to an opposite alteration of endogenous PDCD4 protein level. Using fluorescent reporter assay, we confirmed the direct and negative regulation of PDCD4 by miR-182, which was dependent on the predicted miR-182 binding site within PDCD4 3 untranslated region (3 UTR). MTT and colony formation assays suggested that miR-182 blockage suppressed, whereas miR-182 mimics enhanced viability and colony formation of ovarian cancer cells. These effects may partly be attributed to the cell cycle promotion activity of miR-182. miR-182 also contributed to migration and invasion activities of ovarian cancer cells. Furthermore, miR-182 reduced the chemosensitivity of ovarian cancer cells to CDDP and Taxol, possibly by its anti-apoptosis activity. Importantly, ALL the alterations of the above cellular phenotypes by blocking or enhancing of miR-182 could be alleviated by subsequent suppression or ectopic expression of its target PDCD4, respectively. We conclude that in ovarian cancer cells, miR-182 acts as an oncogenic miRNA by directly and negatively regulating PDCD4.