Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development.
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.
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Krystyna
K
Mazan-Mamczarz
Department of Pathology, University of Maryland, Baltimore, Maryland, United States of America.
X Frank
XF
Zhao
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Bojie
B
Dai
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
James J
JJ
Steinhardt
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Raymond J
RJ
Peroutka
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Kimberly L
KL
Berk
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Ari L
AL
Landon
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Mariola
M
Sadowska
Gene Expression and Genomics Unit, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Yongqing
Y
Zhang
Gene Expression and Genomics Unit, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Elin
E
Lehrmann
Gene Expression and Genomics Unit, National Institute of Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Kevin G
KG
Becker
Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Rita
R
Shaknovich
Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
Zhenqiu
Z
Liu
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.
Ronald B
RB
Gartenhaus
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation; D039603:Eukaryotic Initiation Factor-4G / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; C575048:MIRN520 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering