The actin-cytoskeleton pathway and its potential role in inflammatory bowel disease-associated human colorectal cancer.

introductionTo improve our understanding of the various clinical phenotypes in inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) and provide potential targets for early diagnosis and future therapy, we sought to identify new candidate genes and molecular pathways involved in the pathogenesis and progression of this disorder. Recent evidence has implicated the actin-cytoskeleton pathway in the development of metastatic sporadic CRC through cytoskeletal proteins such as fascin-1. We hereby propose that similar genetic polymorphisms and mutations among regulatory genes of the actin-cytoskeleton pathway may also be associated with increased dysplasia, carcinogenesis, and susceptibility for invasion and metastasis in IBD-associated CRC, as compared with sporadic CRC. MATERIALS AND

methodsTo test this hypothesis, we identified three patients with IBD-associated CRC. We subsequently retrieved normal, dysplastic, and cancerous tissue from within the same surgical colonic specimen. Messenger RNA was subsequently isolated from fresh frozen tissue, and oligonucleotide arrays were carried out to identify genes that were differentially expressed between the three various tissue types (normal, dysplasia, and cancer). By utilizing the same specimen to obtain each of the three various tissue types, we excluded intersubject variability during the analysis. Finally, we performed bioinformatic interaction pathway analysis using the "Ingenuity Pathway Analysis" software.

resultsComputerized pathway analysis revealed that the actin-cytoskeleton pathway was significantly dysregulated in the progression of normal cells, via dysplasia, to IBD-associated CRC (p < 0.05). Significantly up-regulated genes identified in the analysis included the fibroblast growth factor, Abelson interactor gene-2, profilin-2, and radixin genes. Conversely, the diaphanous homolog gene appeared to be significantly down-regulated.

conclusionVia the dysregulation of these five genes within the actin-cytoskeleton pathway, we propose that this molecular pathway provides a potential mechanism for the malignant transformation and progression of normal tissue, via dysplasia, to IBD-associated CRC.