Proteomic and Functional Investigation of the Colon Cancer Relapse-Associated Genes NOX4 and ITGA3

Colon cancer is a major cause of cancer-related deaths worldwide. Adjuvant chemotherapy significantly reduces mortality in stage III colon cancer; however, it is only marginally effective in stage II patients. There is also increasing evidence that right-side colon cancer is different from left-side colon cancer. We have observed that the genes altered in expression between the poor and good prognosis tumors vary significantly depending on whether the malignancy originates on the right or left side of the colon. We have identified NADPH oxidase 4 (NOX4) to be highly predictive of relapse in stage II left-side colon cancer, whereas integrin alpha 3 beta 1 (ITGA3) is predictive of relapse in stage II right-side colon cancer. To investigate the underlying molecular mechanisms, we are analyzing the effect of ITGA3 and NOX4 silencing via RNA interference and pharmacological inhibition on global protein expression patterns via iTRAQ labeling and mass spectrometry in colon cancer cells. On the basis of bioinformatic analysis, the functions of these genes were assessed through phenotypic assays, revealing roles in cell migration and reactive oxygen species generation. These biomarkers for relapse risk are of clinical interest and lead to insight into how a tumor progresses to metastasis.