IGF‐1R Regulation of Colon Cancer Stem Cells

Abstract

Despite recent advances in therapeutics, recurrence of colon cancer occurs in 50% of the cases, which could partly be due to the presence of self renewing cancer stem‐like cells (CSCs) which are resistant to chemotherapy. We have observed that chemosurviving colon cancer cells are enriched in CSCs as evidenced by increased number of CD44+ cells, associated with activated growth factor receptors especially IGF‐1R (4.5‐fold). Depletion of IGF‐1R by si‐RNA results in growth inhibition of chemosurviving cells accompanied by a reduction in CD44 suggesting that IGF‐1R might target CSCs. Indeed, we observed a significant inhibition of colonosphere formation, a CSC property, in IGF‐1R si‐RNA transfected cells in p53 wt HCT‐116 cells accompanied by decrease in CD44 and CD166 expression and induction in miRNA which post transcriptional regulate gene expression. We identified miRNA‐363, a non‐p53 regulated miRNA, to be highly overexpressed (18.9‐fold) following IGF‐1R inhibition. In addition, miR‐215, a p53 regulated miRNA, which is normally downregulated in colon cancer, was upregulated by 2‐fold following IGF‐1R inhibition resulting in induction of its downstream effector p21waf1/cip1 only in p53 wild type colon cancer cells. We conclude that Inhibition of IGF‐1R results in reduction of CSC phenotype in colorectal cancer cells which could partly be due to induction of miRNAs ‐363 and ‐215.