title: Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
abstract: PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol 3-kinase-Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b~25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b~25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a proto-oncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Poliseno
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Luisa
authors.initials: L
authors.lastname: Riccardi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fornari
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Shorheh
authors.initials: S
authors.lastname: Varmeh
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.forename: Lucia
authors.initials: L
authors.lastname: Rameh
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D064168:Minichromosome Maintenance Complex Component 7; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011519:Proto-Oncogenes
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7
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