Abstract
BackgroundDysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa).MethodsSerum-based miRNA profiling involved 15 men diagnosed with non-metastatic (stage I, III) and metastatic (stage IV) PCa and five age-matched disease-free men using miRNA arrays with select targets confirmed by quantitative real-time PCR (qRT-PCR). The effect of miR-186-5p inhibition or ectopic expression on cellular behavior of PCa cells (i.e., PC-3, MDA-PCa-2b, and LNCaP) involved the use bromodeoxyuridine (BrdU) incorporation, invasion, and colony formation assays. Assessment of the impact of miR-186-5p inhibition or overexpression on selected targets entailed microarray analysis, qRT-PCR, and/or western blots. Statistical evaluation used the modified t-test and ANOVA analysis.ResultsMiR-186-5p was upregulated in serum from PCa patients and metastatic PCa cell lines (i.e., PC-3, MDA-PCa-2b, LNCaP) compared to serum from disease-free individuals or a normal prostate epithelial cell line (RWPE1), respectively. Inhibition of miR-186-5p reduced cell proliferation, invasion, and anchorage-independent growth of PC-3 and/or MDA-PCa-2b PCa cells. AKAP12, a tumor suppressor target of miR-186-5p, was upregulated in PC-3 and MDA-PCa-2b cells transfected with a miR-186-5p inhibitor. Conversely, ectopic miR-186-5p expression in HEK 293 T cells decreased AKAP12 expression by 30%. Both pAKT and β-catenin levels were down-regulated in miR-186-5p inhibited PCa cells.ConclusionsOur findings suggest miR-186-5p plays an oncogenic role in PCa. Inhibition of miR-186-5p reduced PCa cell proliferation and invasion as well as increased AKAP12 expression. Future studies should explore whether miR-186-5p may serve as a candidate prognostic indicator and a therapeutic target for the treatment of aggressive prostate cancer.
Highlights
Dysregulation of microRNA expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa)
Population description Serum was collected from 15 PCa patients diagnosed with tumor stage I, III, IV and five disease-free patients who selfidentified as men with European ancestry (Additional file 1: Table S1)
Inhibition of miR-186-5p reduces PCa cell proliferation Since miR-186-5p was upregulated in the serum of the metastatic PCa patients, we evaluated the impact of miR-186-5p inhibition on cell proliferation
Summary
Dysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa). The 5-year survival rate drops to 28% for those with metastatic PCa [2]. MicroRNAs (miRs or miRNAs) are 17–25 nucleotide short non-coding RNAs that may serve as ideal biomarkers of metastatic PCa for several reasons. MiRs regulate the expression of genes involved in tumor spread including cell proliferation, invasion, migration, angiogenesis, and anchorage-independent growth (reviewed in [5,6,7]). Dysregulation of miRNA corresponds with aggressive PCa phenotypes including high tumor stage, high Gleason grade, disease recurrence, and biochemical recurrence [8, 9]. Serum miRNA profiles may distinguish between aggressive and non-aggressive PCa [10, 11]
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