Authors:
Adhip PN Majumdar, Yingie Yu, Jianhua Du, and Bhaumik B Patel
Summary:
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.
Source:
The Journal of the Federation of American Societies for Experimental Biology; (2010)