Article

Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.

Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
Science Signaling (impact factor: 7.5). 01/2010; 3(117):ra29. DOI:10.1126/scisignal.2000594 pp.ra29
Source: PubMed

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.

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Keywords

cellular transformation
 
concomitant overexpression
 
critical factor
 
genomic loci
 
human prostate cancer
 
initiating prostate tumorigenesis
 
intronic miR-106b~25 cluster cooperates
 
miRNA
 
miRNA cluster triggers prostatic intraepithelial neoplasia
 
miRNA processing enzyme DICER
 
phosphatidylinositol 3-kinase-Akt pathway
 
potentiate cellular transformation
 
proto-oncogenic miRNA-dependent network
 
PTEN abundance
 
PTEN regulation
 
PTEN-targeting microRNA
 
simultaneous oncogenic insults
 
subtle decreases
 
tensin homolog deleted
 
transgenic mice