Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer

E. G. Seviour, V. Sehgal, Y. Lu, Z. Luo, T. Moss, F. Zhang, S. M. Hill, W. Liu, S. N. Maiti, L. Cooper, R. Azencot, G. Lopez-Berestein, C. Rodriguez-Aguayo, R. Roopaimoole, C. Pecot, A. K. Sood, S. Mukherjee, Joe Gray, Gordon Mills, P. T. Ram

Research output: Contribution to journalArticle

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Abstract

The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b∗, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth.

Original languageEnglish (US)
Pages (from-to)691-701
Number of pages11
JournalOncogene
Volume35
Issue number6
DOIs
StatePublished - Feb 11 2016

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MicroRNAs
Proteomics
Ovarian Neoplasms
Breast Neoplasms
Neoplasms
Biological Phenomena
Retinoblastoma Protein
myc Genes
Etoposide
Growth
Heterografts
Genetic Promoter Regions
Protein Binding
Nanoparticles
Cell Cycle
Cell Proliferation
RNA
Cell Line
Survival
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Seviour, E. G., Sehgal, V., Lu, Y., Luo, Z., Moss, T., Zhang, F., ... Ram, P. T. (2016). Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer. Oncogene, 35(6), 691-701. https://doi.org/10.1038/onc.2014.469

Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer. / Seviour, E. G.; Sehgal, V.; Lu, Y.; Luo, Z.; Moss, T.; Zhang, F.; Hill, S. M.; Liu, W.; Maiti, S. N.; Cooper, L.; Azencot, R.; Lopez-Berestein, G.; Rodriguez-Aguayo, C.; Roopaimoole, R.; Pecot, C.; Sood, A. K.; Mukherjee, S.; Gray, Joe; Mills, Gordon; Ram, P. T.

In: Oncogene, Vol. 35, No. 6, 11.02.2016, p. 691-701.

Research output: Contribution to journalArticle

Seviour, EG, Sehgal, V, Lu, Y, Luo, Z, Moss, T, Zhang, F, Hill, SM, Liu, W, Maiti, SN, Cooper, L, Azencot, R, Lopez-Berestein, G, Rodriguez-Aguayo, C, Roopaimoole, R, Pecot, C, Sood, AK, Mukherjee, S, Gray, J, Mills, G & Ram, PT 2016, 'Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer', Oncogene, vol. 35, no. 6, pp. 691-701. https://doi.org/10.1038/onc.2014.469
Seviour, E. G. ; Sehgal, V. ; Lu, Y. ; Luo, Z. ; Moss, T. ; Zhang, F. ; Hill, S. M. ; Liu, W. ; Maiti, S. N. ; Cooper, L. ; Azencot, R. ; Lopez-Berestein, G. ; Rodriguez-Aguayo, C. ; Roopaimoole, R. ; Pecot, C. ; Sood, A. K. ; Mukherjee, S. ; Gray, Joe ; Mills, Gordon ; Ram, P. T. / Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer. In: Oncogene. 2016 ; Vol. 35, No. 6. pp. 691-701.
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