Colitis-accelerated colorectal cancer and metabolic dysregulation in a mouse model

The connection between inflammation and colorectal cancer (CRC) has been well recognized, and numerous related molecular mechanisms have been uncovered. To gain further insight, we used BALB/c mice treated with azoxymethane (AOM) and dextran sulfate sodium salt (DSS) to establish a colitis-associated CRC model recapitulating tubulovillous adenoma with high-grade dysplasia at week 14. We evaluated the mice in four groups: a control group fed a standard diet; a group given DSS, in which we observed no tumor or dysplasia; a group given AOM, in which we observed few dysplastic foci despite repeated administrations of the carcinogen and a group given both AOM and DSS, in which our observations agreed with those of other studies that found accelerated colorectal carcinogenesis following DSS-induced colitis. We examined the messenger RNA and micro RNA (miRNA) expression profiles of the four groups. In colitis-associated CRC, we observed the dysregulation of many pathways, including the upregulation of Wnt signaling and CRC pathways and the downregulation of apoptosis. Also, most differentially expressed genes were significantly enriched in metabolic rather than immune/inflammation pathways/processes. Additionally, we demonstrated that the expression of several important miRNAs involved in both the inflammatory response and metabolism was dramatically altered during colitis-associated CRC. Gene network analysis and gene profile analysis confirmed a close relationship between metabolic and inflammatory genes in colitis-associated CRC. Thus, our study may provide a framework for identifying metabolic genes as targets of novel molecular-based therapies against CRC.