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PLoS Genet. 2014 Jan 30;10(1):e1004105. doi: 10.1371/journal.pgen.1004105. eCollection 2014 Jan.

Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development.

Author information

1
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
2
Department of Pathology, University of Maryland, Baltimore, Maryland, United States of America.
3
Gene Expression and Genomics Unit, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
4
Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, United States of America.
5
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America ; Veterans Administration Medical Center, Baltimore, Maryland, United States of America.

Abstract

Deregulation of the translational machinery is emerging as a critical contributor to cancer development. The contribution of microRNAs in translational gene control has been established however; the role of microRNAs in disrupting the cap-dependent translation regulation complex has not been previously described. Here, we established that elevated miR-520c-3p represses global translation, cell proliferation and initiates premature senescence in HeLa and DLBCL cells. Moreover, we demonstrate that miR-520c-3p directly targets translation initiation factor, eIF4GII mRNA and negatively regulates eIF4GII protein synthesis. miR-520c-3p overexpression diminishes cells colony formation and reduces tumor growth in a human xenograft mouse model. Consequently, downregulation of eIF4GII by siRNA decreases translation, cell proliferation and ability to form colonies, as well as induces cellular senescence. In vitro and in vivo findings were further validated in patient samples; DLBCL primary cells demonstrated low miR-520c-3p levels with reciprocally up-regulated eIF4GII protein expression. Our results provide evidence that the tumor suppressor effect of miR-520c-3p is mediated through repression of translation while inducing senescence and that eIF4GII is a key effector of this anti-tumor activity.

PMID:
24497838
PMCID:
PMC3907297
DOI:
10.1371/journal.pgen.1004105
[Indexed for MEDLINE]
Free PMC Article

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