Western-type diet affects the expression of genes known to be involved in human colorectal carcinogenesis in histologically normal mucosa of ApcMin/+ mice

Marjaana Pussila1, Sarantaus Laura1, Päivärinta Essi2, Ollila Saara1, Dermadi Bebek Denis1, Niku Mikael2, Nyström Minna1
1 University of Helsinki, Department of Biological and Environmental Sciences, Genetics, Helsinki, Finland; 2 University of Helsinki, Department of Food and Environmental Sciences, Nutrition, Helsinki, Finland

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and its incidence is increasing in all industrialized countries. The development of CRC is a multistep process. Over the past recent years, evidence has accumulated indicating that apart from genetic alterations, epigenetic alterations play a major role in the initiation and progression of CRC, also in the hereditary colon cancer syndromes. Epigenetics refers to heritable changes in phenotype or gene expression without a change in the genetic code itself, as opposed to genetics, which refers to information transmitted in gene sequences. The best-known epigenetic marker is DNA methylation, and diet is a major aspect of the environment that may influence DNA methylation thus providing an important link between cancer and nutrition. Based on human and experimental evidence it has been concluded that Western-type diet (WD) may predispose gut mucosa to colon cancer. Here, we evaluated the effects of WD on the early phases of intestinal carcinogenesis by using the ApcMin/+ (multiple intestinal neoplasia) mouse model, which is analogous to human familial adenomatous polyposis (FAP) (syndrome). ApcMin/+ mice were assigned randomly into two dietary groups [WD (n=12) or AIN-93G diet (n=14)] at the age of 5 weeks. WD is a modified AIN-93G that contains more fat, especially saturated fat, and less calcium, fiber, vitamin D and folic acid. Mice were sacrificed at the age of 15 weeks, and the small and large intestines were removed and opened. Samples from histologically normal mucosa were collected both from distal small and large intestine. Using custom StellARray qPCR arrays (Lonza), the expression of 94 genes previously demonstrated to play a role in human colorectal carcinogenesis, and many of which have been reported to be aberrantly methylated during the carcinogenic process, was analyzed and compared between the two diet groups (WD vs. AIN-93G). The expression of 5 genes out of the 94 studied was found to be significantly different between the two diet groups in both parts of the intestine (fold change 1.3 – 2.9; p<0.033). The expression of one gene linked to fatty acid metabolism was increased in the WD group as compared to control diet group both in the small and the large intestine. Otherwise, the two parts of intestine showed different spectra of altered gene expression. In summary, based on observed mRNA expression differences, 9 candidate genes for CRC initation were detected by using StellARray qPCR arrays. Further studies, e.g. methylation analyses, will be performed to survey the biological significance of the findings.

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