Oncotarget

Research Papers:

Selective targeting of KRAS-Mutant cells by miR-126 through repression of multiple genes essential for the survival of KRAS-Mutant cells

Toshifumi Hara, Matthew F. Jones, Murugan Subramanian, Xiao Ling Li, Oliver Ou, Yuelin Zhu, Yuan Yang, Lalage M. Wakefield, Perwez S. Hussain, Jochen Gaedcke, Thomas Ried, Ji Luo, Natasha J. Caplen & Ashish Lal _

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Oncotarget. 2014; 5:7635-7650. https://doi.org/10.18632/oncotarget.2284

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Abstract

Toshifumi Hara1, Matthew F. Jones1, Murugan Subramanian1, Xiao Ling Li1, Oliver Ou2, Yuelin Zhu3, Yuan Yang4, Lalage M. Wakefield4, S. Perwez Hussain5, Jochen Gaedcke6, Thomas Ried7, Ji Luo8, Natasha J. Caplen2 and Ashish Lal1

1 Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2 Gene Silencing Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

3 Molecular Genetics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

4 Cancer Biology of TGF-beta Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

5 Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

6 Department of General and Visceral Surgery, University Medicine Göttingen, Germany

7 Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

8 Cancer Systems Biology Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence:

Ashish Lal, email:

Keywords: Colorectal Cancer, miRNA, miR-126, KRAS, KRAS mutant

Received: May 30, 2014 Accepted: July 31, 2014 Published: July 31, 2014

Abstract

MicroRNAs (miRNAs) regulate the expression of hundreds of genes. However, identifying the critical targets within a miRNA-regulated gene network is challenging. One approach is to identify miRNAs that exert a context-dependent effect, followed by expression profiling to determine how specific targets contribute to this selective effect. In this study, we performed miRNA mimic screens in isogenic KRAS-Wild-type (WT) and KRAS-Mutant colorectal cancer (CRC) cell lines to identify miRNAs selectively targeting KRAS-Mutant cells. One of the miRNAs we identified as a selective inhibitor of the survival of multiple KRAS-Mutant CRC lines was miR-126. In KRAS-Mutant cells, miR-126 over-expression increased the G1 compartment, inhibited clonogenicity and tumorigenicity, while exerting no effect on KRAS-WT cells. Unexpectedly, the miR-126-regulated transcriptome of KRAS-WT and KRAS-Mutant cells showed no significant differences. However, by analyzing the overlap between miR-126 targets with the synthetic lethal genes identified by RNAi in KRAS-Mutant cells, we identified and validated a subset of miR-126-regulated genes selectively required for the survival and clonogenicity of KRAS-Mutant cells. Our strategy therefore identified critical target genes within the miR-126-regulated gene network. We propose that the selective effect of miR-126 on KRAS-Mutant cells could be utilized for the development of targeted therapy for KRAS mutant tumors.


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