MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma

• Published in: Oncogene Vol. 32; no. 3; pp. 277 - 285
• Main Authors: Boll, K, Reiche, K, Kasack, K, Mörbt, N, Kretzschmar, A K, Tomm, J M, Verhaegh, G, Schalken, J, von Bergen, M, Horn, F, Hackermüller, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.01.2013; Nature Publishing Group
• Subjects: 631/337/384/331; 631/80/86; 692/420/755; 692/699/67/589/466; Androgen receptors; Androgens; Apoptosis; Apoptosis - genetics; Argonaute 2 protein; Argonaute Proteins - metabolism; Cancer; Castration; Cell Biology; Cell cycle; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Proliferation; Development and progression; Down-Regulation - genetics; Genes, Reporter - genetics; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Male; MAP kinase; MAP Kinase Signaling System - genetics; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs - genetics; miRNA; Oncogenes; Oncogenes - genetics; Oncology; original-article; Physiological aspects; Prostate cancer; prostate carcinoma; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - surgery; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors, Androgen - metabolism; Sarcoma; Signal transduction; Signal Transduction - genetics; Transfer RNA; Tumor cells; Tumor suppressor genes; Tumors; Western blotting; United States; United States > US; microRNAs; MAPK pathway; androgen receptor signaling; prostate carcinoma; microRNA targets
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.55

With ∼30 000 deaths annually in the United States, prostate cancer (PCa) is a major oncologic disease. Here we show that the microRNAs miR-130a, miR-203 and miR-205 jointly interfere with the two major oncogenic pathways in prostate carcinoma and are downregulated in cancer tissue. Using transcriptomics we show that the microRNAs repress several gene products known to be overexpressed in this cancer. Argonaute 2 (AGO2) co-immunoprecipitation, reporter assays and western blot analysis demonstrate that the microRNAs directly target several components of the mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signaling pathways, among those several AR coregulators and HRAS (Harvey rat sarcoma viral oncogene homolog), and repress signaling activity. Both pathways are central for the development of the primary tumor and in particular the progression to its incurable castration-resistant form. Reconstitution of the microRNAs in LNCaP PCa cells induce morphological changes, which resemble the effect of androgen deprivation, and jointly impair tumor cell growth by induction of apoptosis and cell cycle arrest. We therefore propose that these microRNAs jointly act as tumor suppressors in prostate carcinoma and might interfere with progression to castration resistance.