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

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.

MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma

“…Similarly, MIR126 was found to suppress tumours by directly targeting the insulin receptor substrate-1 (IRS1) [12–14] and the disintegrin- and metalloproteinase domain-containing protein-9 (ADAM9) [15]. Using luciferase assay, it was found that MIR126 targets other factors, such as SOX2, SLC7A5, EGFL7 and VEGF [16–20]. …”

Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies

“…The expression of miR-126 and its host gene was reduced in most cancers with a high frequency of KRAS mutations including lung cancer (36). A subset of miR-126-regulated genes selectively required for the survival and clonogenicity of KRAS-Mutant cells have been identified, supporting the role of miR-126 in tumor formation and progression (37).…”

MicroRNA-126 and epidermal growth factor-like domain 7 predict recurrence in patients with colon cancer treated with neoadjuvant chemotherapy

“…This is also true for miRNA-126 and the regulation of several of these mRNA targets may all impact on the risk of disease recurrence from local colon cancer. Some of the more well described targets are SPRED1, p85β, and PI3KR2 governing vascular integrity [10,27] , VEGF-A regulating AKT-pathway signaling [28] , CXCR4 and IRS-1 involved in CRC cell proliferation and migration [29,30] , and KRAS impacting on the viability of the mutated tumor cells [31] . Recent reviews have also highlighted the clinical potential of miRNA-126 [32][33][34] .…”