Effect of genomic instability and mutations on the signaling pathways in colon cancer cells.

Microsatellite instability (MSI) is present in about 15% of colorectal cancers and plays critical roles in the development and progression of these cancers. The goal of this study is to determine the global effect of microsatellite instability on the signaling pathways and network in colon cancer cells. We profiled the expression and phosphorylation of 110 proteins in six colon cancer cell lines by using Protein Pathway Array. The pathways and network constituted by these proteins were identified by using Ingenuity Pathway Analysis. Our results showed that 25 proteins and phosphoproteins change more than 1.5-fold between MSI and microsatellite stable (MSS) cells. Sixteen major pathways were affected in MSI cells, including p53 and 14-3-3ß pathways, with p53 and HGF being the most important pathways. Finally, although the EGFR/K-RAS/MEK pathway was not affected in MSI cells, collateral pathways such as the p70S6K and p90RSK pathways were activated in MSI cells. Thus, suppression of the p53 pathway and activation of the HGF pathway in MSI cells may be critical in the tumorigenesis of MSI colorectal cancer.