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MicroRNA-1 is a candidate tumor suppressor and prognostic marker

ABSTRACT: MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE31620 | GEO | 2011/12/01

SECONDARY ACCESSION(S): PRJNA145531

REPOSITORIES: GEO

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Project description:MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility. In this study we monitored global miRNA expression changes in prostate cancer LNCaP cells treated with the epigenetic compounds 5-Azacytidine (5-AzaC) and/or trichostatin A (TSA). Cells were treated with epigenetic drugs for 36 hours and total RNA was isolated for hybridization to miRNA microarrays. 5 independent experiments were performed (n=4 for combined treatment). The candidate prostate tumor suppressor miRNAs, miR-1, miR-206, and miR-27 were up-regulated in LNCaP cells for Affymetrix microarray analysis. LNCaP cells were transfected with pre-miR oligos and 24 hr post-transfection total RNA was collected for microarray analysis; total of three independent experiments.

Project description:The high rates of mortality associated with epithelial ovarian cancer (EOC) are a direct consequence of its metastatic nature. Metastasis is dependent on many factors, among which activation of angiogenesis is most significant. Angiogenesis is, in turn, contingent upon the cellular response to hypoxia within the tumor microenvironment. Hypoxia-inducible factor 1 (HIF1) is a transcription factor composed of HIF1alpha and HIF1beta subunits and is the master regulator of the hypoxic response. It is therefore a critical mediator of tumor angiogenesis and metastasis. Regulation of HIF1 is primarily at the level of protein. In normoxia, the HIF1alpha subunit is hydroxylated via an oxygen- and iron-dependent mechanism and targeted for destruction. In hypoxia, low oxygen levels preclude hydroxylation and HIF1alpha is stabilized, allowing for its association with constitutively expressed HIF1beta to form bioactive HIF1. We have identified a novel mechanism of HIF1alpha regulation in EOC cells that involves microRNAs (miRs), ~22 nucleotide, non-coding RNA molecules that repress translation of target mRNAs by binding their 3’ untranslated regions (UTRs). Using microarray and qPCR analysis, we found that levels of miR-199a-1, a miR that is predicted in silico to target the HIF1alpha 3’ UTR, were reduced under hypoxia in EOC cells. We further demonstrated that miR-199a-1 directly targets the HIF1alpha 3’ UTR and overexpression of miR-199a-1 suppresses HIF1alpha protein levels and HIF1-driven gene expression. Moreover, cells stably overexpressing miR-199a-1 exhibit marked defects in migratory ability. These data were corroborated by our in vivo findings, which demonstrated that overexpression of miR-199a-1 causes significant reductions in tumor vessel density and tumor burden in nude mice. These findings provide insight into non-canonical, miR- and iron-based mechanisms of HIF1 regulation that may have important implications in the progression of EOC. miRNA expression analysis of A2780 epithelial ovarian cancer cells by microarrays

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MicroRNA-1 is a candidate tumor suppressor and prognostic marker

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