miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6

Abstract

BackgroundEpithelial ovarian cancer (EOC) is a significant cause of morbidity and mortality. MicroRNAs play important roles in cancer development and progression. The microRNA miR-211 is localized on intron 6 of the Trpm1 gene at 15q13-q14, a locus that is frequently lost in neoplasms. Its function and loss-of-function have been described in normal and cancer cells and tissues. miR-211 is known to be dysregulated in ovarian cancer: however, its function and the downstream effect of its loss-of-function in ovarian cancer have not been described before.MethodsWe analyzed miR-211 expression in clinical samples of primary EOC tissues compared to normal epithelial ovarian tissues and in the EOC cell lines: OVCAR3, Caov3, OVCA429, SKOV3 and A2780 compared to human ovarian surface epithelial cells. We then investigated the effect of miR-211 on EOC cell proliferation and apoptosis by counting cell numbers, MTT, colony formation, cell cycle, and PI/Annexin V staining assays. A luciferase reporter system was developed to assess miR-211 regulation of the predicted targets. Expression level of discovered targets and correlation with miR-211 expression were analyzed in EOC tissues. Finally, OVCAR3 stably expressing miR-211 or control cells were injected subcutaneously into mice to determine in vivo effect of miR-211 on tumorigenesis.ResultsWe found that the expression of miR-211 is downregulated in EOC tissues and cell lines compared to normal epithelial ovarian tissue and human ovarian surface epithelial cells, respectively. miR-211 was found to arrest cells in the G0/G1-phase, inhibit proliferation and induce apoptosis. Cyclin D1 and CDK6 were found to be direct targets of miR-211, and when overexpressed in miR-211-expressing EOC cells, could restore proliferative ability. Finally, in vitro investigation confirmed that miR-211 is a tumor suppressor that controls Cyclin D1 and CDK6 expression.ConclusionsOur results demonstrate that miR-211 is a tumor suppressor that controls expression of Cyclin D1 and CDK6, and that its downregulation results in overexpression of Cyclin D1 and CDK6 which increases proliferation ability of EOC cells to proliferate compared to normal cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0322-4) contains supplementary material, which is available to authorized users.

The Novel Long Noncoding RNA TUSC7 Inhibits Proliferation by Sponging MiR-211 in Colorectal Cancer

“…By bioinformatics analysis, we found there were 2 binding sites of miR-211-3p within sequence of TUSC7. Additionally, it has also been reported that miR-211-3p played as an oncogene in CRC and miR-211-3p could promote cell proliferation by targeting CDK6 in CRC cells [15]. Thus, we hypothesized that TUSC7 might have a ceRNA mechanism in CRC, namely TUSC7 promotes proliferation by sponging miR-211-3p.…”

“…By PCR assay we found miR-211-3p and TUSC7 were negatively correlated. It has been reported that miR-211-3p promoted CRC cell proliferation by targeting CDK6 [15]. And according to an independent dataset [12, 16], TUSC7 and CDK6 are positively correlated.…”

NF-κB-Induced MicroRNA-211 Inhibits Interleukin-10 in Macrophages of Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

“…Like many well-defined miRNAs, the diverse target genes of miR-211 have been identified and characterized, including PP2Cm [18], Cyclin D1, CDK6 [27], SATB2 [28], CDC25B [29], NUAK1 [30], TGFβR II [31], CHD5 [32] and BRN2 [33]. Based on our preliminary finding, we employed the miRanda algorithm [19] to analyze the potential regulatory effect of miR-211-5p on IL-10.…”

miR-211 promotes non-small cell lung cancer proliferation by targeting SRCIN1

“…Cai et al [31] demonstrated that enforced miR-211 expression promotes tumor cell growth in colorectal cancer cells at least partially by downregulating the expression of the tumor suppressor CHD5. However, Xia et al [29] reported that miR-211 expression is downregulated in epithelial ovarian cancer tissues and cell lines compared with normal epithelial ovarian tissue and human ovarian surface epithelial cells and that miR-211 arrests cells in the G0/G1-phase, inhibits proliferation, and induces apoptosis by regulating cyclin D1 and CDK6 expression. However, the role of miR-211 in NSCLC remains uncertain.…”

“…Trpm1 is a target gene of microphthalmia-associated transcription factor (MITF) [31,[36][37][38]. It has also been demonstrated that miR-211 can impact cell invasion, proliferation, and migration in many cancers [28][29][30]. Song et al [30] found that miR-211 directly negatively regulates of CDC25B expression in triple-negative breast cancer cells, alters the expression of the other related target proteins CCNB1 and FOXM1, and inhibits breast cancer cell growth, migration, and invasion leading to G2/ M arrest.…”