Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
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.
Poliseno
Laura
L
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
Salmena
Leonardo
L
Riccardi
Luisa
L
Fornari
Alessandro
A
Song
Min Sup
MS
Hobbs
Robin M
RM
Sportoletti
Paolo
P
Varmeh
Shorheh
S
Egia
Ainara
A
Fedele
Giuseppe
G
Rameh
Lucia
L
Loda
Massimo
M
Pandolfi
Pier Paolo
PP
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
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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