Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development

Krystyna Mazan-Mamczarz, X. Frank Zhao, Bojie Dai, James J. Steinhardt, Raymond J. Peroutka, Kimberly L. Berk, Ari L. Landon, Mariola Sadowska, Yongqing Zhang, Elin Lehrmann, Kevin G. Becker, Rita Shaknovich, Zhenqiu Liu, Ronald B. Gartenhaus

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1004105
JournalPLoS genetics
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2014

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Lymphoma, Large B-Cell, Diffuse
senescence
lymphoma
tumor
translation (genetics)
B-lymphocytes
Down-Regulation
MicroRNAs
neoplasms
Neoplasms
protein
microRNA
deregulation
Cell Proliferation
cell proliferation
machinery
Peptide Initiation Factors
protein synthesis
Cell Aging
cancer

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Mazan-Mamczarz, K., Zhao, X. F., Dai, B., Steinhardt, J. J., Peroutka, R. J., Berk, K. L., ... Gartenhaus, R. B. (2014). Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development. PLoS genetics, 10(1), [e1004105]. https://doi.org/10.1371/journal.pgen.1004105
Mazan-Mamczarz, Krystyna ; Zhao, X. Frank ; Dai, Bojie ; Steinhardt, James J. ; Peroutka, Raymond J. ; Berk, Kimberly L. ; Landon, Ari L. ; Sadowska, Mariola ; Zhang, Yongqing ; Lehrmann, Elin ; Becker, Kevin G. ; Shaknovich, Rita ; Liu, Zhenqiu ; Gartenhaus, Ronald B. / Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development. In: PLoS genetics. 2014 ; Vol. 10, No. 1.
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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.",
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Mazan-Mamczarz, K, Zhao, XF, Dai, B, Steinhardt, JJ, Peroutka, RJ, Berk, KL, Landon, AL, Sadowska, M, Zhang, Y, Lehrmann, E, Becker, KG, Shaknovich, R, Liu, Z & Gartenhaus, RB 2014, 'Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development', PLoS genetics, vol. 10, no. 1, e1004105. https://doi.org/10.1371/journal.pgen.1004105

Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development. / Mazan-Mamczarz, Krystyna; Zhao, X. Frank; Dai, Bojie; Steinhardt, James J.; Peroutka, Raymond J.; Berk, Kimberly L.; Landon, Ari L.; Sadowska, Mariola; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.; Shaknovich, Rita; Liu, Zhenqiu; Gartenhaus, Ronald B.

In: PLoS genetics, Vol. 10, No. 1, e1004105, 01.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development

AU - Mazan-Mamczarz, Krystyna

AU - Zhao, X. Frank

AU - Dai, Bojie

AU - Steinhardt, James J.

AU - Peroutka, Raymond J.

AU - Berk, Kimberly L.

AU - Landon, Ari L.

AU - Sadowska, Mariola

AU - Zhang, Yongqing

AU - Lehrmann, Elin

AU - Becker, Kevin G.

AU - Shaknovich, Rita

AU - Liu, Zhenqiu

AU - Gartenhaus, Ronald B.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

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Mazan-Mamczarz K, Zhao XF, Dai B, Steinhardt JJ, Peroutka RJ, Berk KL et al. Down-Regulation of eIF4GII by miR-520c-3p Represses Diffuse Large B Cell Lymphoma Development. PLoS genetics. 2014 Jan 1;10(1). e1004105. https://doi.org/10.1371/journal.pgen.1004105