Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant MIR-193a-3p

E. G. Seviour, V. Sehgal, D. Mishra, R. Rupaimoole, C. Rodriguez-Aguayo, G. Lopez-Berestein, J. S. Lee, A. K. Sood, M. P. Kim, Gordon Mills, P. T. Ram

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3′UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3'UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.

Original languageEnglish (US)
Pages (from-to)1339-1350
Number of pages12
JournalOncogene
Volume36
Issue number10
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Seviour, E. G., Sehgal, V., Mishra, D., Rupaimoole, R., Rodriguez-Aguayo, C., Lopez-Berestein, G., Lee, J. S., Sood, A. K., Kim, M. P., Mills, G., & Ram, P. T. (2017). Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant MIR-193a-3p. Oncogene, 36(10), 1339-1350. https://doi.org/10.1038/onc.2016.308