miRNA Alterations Modify Kinase Activation In The IGF-1 Pathway And Correlate With Colorectal Cancer Stage And Progression In Patients

Investigation of therapy naive human tumor and adjacent normal tissue biopsies demonstrated that expression levels of miRNAs are altered at and between stages of CRC. Targets of these altered miRNAs are members of the Insulin signaling pathways. Phosphorylation states of several molecules in the Insulin signaling pathways were altered between stages of CRC, and significantly the change in molecular phosphorylation state correlated with decreases in specific miRNAs that target them. This data establishes a direct relationship between decreased expression of specific miRNAs and increased phosphorylation events in the IGF-1 pathway and identifies the IGF-1 pathway as a critical driver of colorectal cancer. The expression levels of 319 miRNAs and phosphorylation levels of major signaling proteins were determined. Interestingly, we observed that miRNAs were altered in expression and several signaling molecules were altered in phosphorylation levels at and between each stage of CRC. Furthermore, many of the miRNAs that are differentially expressed at each CRC stage were targeting these same signaling proteins identified to be altered in phosphorylation level. Thus, our studies define a subset of important miRNAs to classify CRC stage and a relationship between miRNA depression and elevated phosphorylation of IGF-1R pathway signaling molecules.