Downregulation of microRNA-383 is associated with male infertility and promotes testicular embryonal carcinoma cell proliferation by targeting IRF1
Open Access
- 4 November 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 1 (11), e94
- https://doi.org/10.1038/cddis.2010.70
Abstract
Our previous studies have shown that microRNA-383 (miR-383) expression is downregulated in the testes of infertile men with maturation arrest (MA). However, the underlying mechanisms of miR-383 involved in the pathogenesis of MA remain unknown. In this study, we showed that downregulation of miR-383 was associated with hyperactive proliferation of germ cells in patients with mixed patterns of MA. Overexpression of miR-383 in NT2 (testicular embryonal carcinoma) cells resulted in suppression of proliferation, G1-phase arrest and induction of apoptosis, whereas silencing of miR-383 reversed these effects. The effects of miR-383 were mediated through targeting a tumor suppressor, interferon regulatory factor-1 (IRF1), and miR-383 was negatively correlated with IRF1 protein expression in vivo. miR-383 inhibited IRF1 by affecting its mRNA stability, which subsequently reduced the levels of the targets of IRF1, namely cyclin D1, CDK2 and p21. Downregulation of IRF1 or cyclin D1, but not that of CDK2, enhanced miR-383-mediated effects, whereas silencing of p21 partially inhibited the effects of miR-383. Moreover, miR-383 downregulated CDK4 by increasing proteasome-dependent degradation of CDK4, which in turn resulted in an inhibition of phosphorylated retinoblastoma protein (pRb) phosphorylation. These results suggest that miR-383 functions as a negative regulator of proliferation by targeting IRF1, in part, through inactivation of the pRb pathway. Abnormal testicular miR-383 expression may potentiate the connections between male infertility and testicular germ cell tumor.Keywords
This publication has 41 references indexed in Scilit:
- Increased Risk of Testicular Germ Cell Cancer Among Infertile MenArchives of Internal Medicine, 2009
- Altered microRNA expression in patients with non-obstructive azoospermiaReproductive Biology and Endocrinology, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- MicroRNA Biogenesis Is Required for Mouse Primordial Germ Cell Development and SpermatogenesisPLOS ONE, 2008
- Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAsRNA, 2004
- The Tumor Suppressor Interferon Regulatory Factor 1 Interferes with SP1 Activation to Repress the Human CDK2 PromoterOnline Journal of Public Health Informatics, 2003
- Deregulation of the RB pathway in human testicular germ cell tumoursThe Journal of Pathology, 2003
- Genetic dissection of mammalian fertility pathwaysNature, 2002
- D-type cyclins in adult human testis and testicular cancer: relation to cell type, proliferation, differentiation, and malignancyThe Journal of Pathology, 1999
- Suppression of c-myc or fosB-induced cell transformation by the transcription factor IRF-1Cancer Letters, 1994