title: The antiapoptotic function of miR-96 in prostate cancer by inhibition of FOXO1.
abstract: microRNAs (miRNAs) are small molecules that regulate gene expression posttranscriptionally. In a previous study, we identified miR-96 to be upregulated in prostate cancer specimens in comparison to normal adjacent tissue and to be an independent marker of biochemical relapse in a multivariate prediction model. Therefore, we investigated the functional role of miR-96 in prostate carcinogenesis. LNCaP and DU145 prostate cancer cells were transiently transfected with miR-96 precursors and phenotypic changes were analyzed. The miR-96 increased proliferation and impaired apoptosis induced by camptothecine in these cells. In silico target prediction analysis identified FOXO1 as potential pro-apoptotic miR-96 target. miR-96 was able to bind to both bindings sites in the FOXO1 3' UTR in a luciferase reporter gene assay. Overexpression of miR-96 in LNCaP cells resulted in a reduced FOXO1 expression. Overexpression of FOXO1 induced a strong apoptotic phenotype that was partially rescued by coexpression of miR-96. RT-qPCR and immunohistochemistry of 69 prostate cancer specimens revealed a downregulation of FOXO1 and an inverse correlation of miR-96 and FOXO1 protein expression. In conclusion, we show that miR-96 can regulate apoptosis in prostate cancer, by inhibiting the FOXO1 transcription factor.
authors.affiliation: Department of Urology, Charité - University Hospital, Berlin, Germany ; Berlin Institute of Urologic Research, Berlin, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Fendler
authors.forename: Monika
authors.initials: M
authors.lastname: Jung
authors.forename: Carsten
authors.initials: C
authors.lastname: Stephan
authors.forename: Andreas
authors.initials: A
authors.lastname: Erbersdobler
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.forename: George M
authors.initials: GM
authors.lastname: Yousef
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D020029:Base Pairing; D001483:Base Sequence; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C541492:MIRN96 microRNA, human; D035683:MicroRNAs