DGCR 8 is essential for tumor progression following PTEN loss in the prostate
| Autor: | Christopher C. Benz, Christina Yau, Marc A. Dall'Era, Cassandra D. Belair, Robert Blelloch, Alireza Paikari, Archana Shenoy, Jeff Simko, Felix Moltzahn |
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| Rok vydání: | 2015 |
| Předmět: |
Urologic Diseases
Male PTEN Aging Knockout microRNA biogenesis Biochemistry DGCR8 Mice Prostate cancer Prostate microRNA Genetics medicine 2.1 Biological and endogenous factors Animals Humans Aetiology Molecular Biology Protein kinase B Cancer Mice Knockout Prostatic Intraepithelial Neoplasia Neoplastic biology Prostate Cancer PTEN Phosphohydrolase Prostatic Neoplasms RNA-Binding Proteins Articles medicine.disease Gene Expression Regulation Neoplastic MicroRNAs medicine.anatomical_structure Gene Expression Regulation Tumor progression Knockout mouse Disease Progression Cancer research biology.protein Biochemistry and Cell Biology Gene Deletion Biotechnology Developmental Biology |
| Zdroj: | EMBO reports, vol 16, iss 9 |
| ISSN: | 1469-3178 1469-221X |
| DOI: | 10.15252/embr.201439925 |
| Popis: | 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. ![][1] This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia. EMBO Reports (2015) 16: 1219–1232 [1]: /embed/graphic-1.gif |
| Databáze: | OpenAIRE |
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