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Sci. Signal., 13 April 2010
Vol. 3, Issue 117, p. ra29
[DOI: 10.1126/scisignal.2000594]

RESEARCH ARTICLES

Identification of the miR-106b~25 MicroRNA Cluster as a Proto-Oncogenic PTEN-Targeting Intron That Cooperates with Its Host Gene MCM7 in Transformation

Laura Poliseno1, Leonardo Salmena1*, Luisa Riccardi1*, Alessandro Fornari2,3, Min Sup Song1, Robin M. Hobbs1, Paolo Sportoletti1, Shorheh Varmeh1, Ainara Egia1, Giuseppe Fedele2,4, Lucia Rameh5, Massimo Loda2,4, and Pier Paolo Pandolfi1{dagger}

1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Department of Biomedical Sciences and Human Oncology, Molinette Hospital, University of Turin, 10126 Turin, Italy.
4 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
5 Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: ppandolf{at}bidmc.harvard.edu

Citation: L. Poliseno, L. Salmena, L. Riccardi, A. Fornari, M. S. Song, R. M. Hobbs, P. Sportoletti, S. Varmeh, A. Egia, G. Fedele, L. Rameh, M. Loda, P. P. Pandolfi, Identification of the miR-106b~25 MicroRNA Cluster as a Proto-Oncogenic PTEN-Targeting Intron That Cooperates with Its Host Gene MCM7 in Transformation. Sci. Signal. 3, ra29 (2010).

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