title: DGCR8 is essential for tumor progression following PTEN loss in the prostate.
abstract: In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten-knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null-induced expansion of the basal-like, but not luminal, cellular compartment. Furthermore, while late-stage Pten knockout tumors exhibit decreased senescence-associated beta-galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a Pten-Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Center for Reproductive Sciences, University of California - San Francisco, San Francisco, CA, USA Department of Urology, University of California - San Francisco, San Francisco, CA, USA cassandra.belair@ucsf.edu.
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Belair
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Center for Reproductive Sciences, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Paikari
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Department of Urology, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Moltzahn
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Department of Urology, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Shenoy
authors.affiliation: Department of Medicine, University of California - San Francisco, San Francisco, CA, USA Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Department of Urology, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Dall'Era
authors.affiliation: Department of Urology, University of California - San Francisco, San Francisco, CA, USA Department of Anatomic Pathology, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Simko
authors.affiliation: Department of Medicine, University of California - San Francisco, San Francisco, CA, USA Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Benz
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Center for Reproductive Sciences, University of California - San Francisco, San Francisco, CA, USA Department of Urology, University of California - San Francisco, San Francisco, CA, USA Department of Anatomic Pathology, University of California - San Francisco, San Francisco, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
mesh_terms: D000818:Animals; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000503:physiopathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: DGCR8; PTEN; microRNA; microRNA biogenesis; prostate cancer