title: MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma.
abstract: 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.
authors.affiliation: RNomics Group, Fraunhofer IZI, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Boll
authors.forename: K
authors.initials: K
authors.lastname: Reiche
authors.forename: K
authors.initials: K
authors.lastname: Kasack
authors.forename: N
authors.initials: N
authors.lastname: Mörbt
authors.forename: A K
authors.initials: AK
authors.lastname: Kretzschmar
authors.forename: J M
authors.initials: JM
authors.lastname: Tomm
authors.forename: G
authors.initials: G
authors.lastname: Verhaegh
authors.forename: J
authors.initials: J
authors.lastname: Schalken
authors.forename: M
authors.initials: M
authors.lastname: von Bergen
authors.forename: F
authors.initials: F
authors.lastname: Horn
authors.forename: J
authors.initials: J
authors.lastname: Hackermüller
mesh_terms: D017209:Apoptosis / Q000235:genetics; D060565:Argonaute Proteins / Q000378:metabolism; D002369:Castration; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D060565:Argonaute Proteins; D035683:MicroRNAs; D016283:Proto-Oncogene Proteins p21(ras); D011944:Receptors, Androgen; C466422:AGO2 protein, human; C554019:MIRN130 microRNA, human; C546703:MIRN203 microRNA, human; C534425:MIR205, human; C501009:HRAS protein, human