Abstract 5699: Obesity-induced colon tumorigenesis is associated with increased cytokine production and alterations in microRNA expression

Abstract

Abstract Obesity has been associated with increased colon cancer risk. Although the molecular pathways underlying the obesity-colon cancer link are unknown, one hypothesis is obesity induces a chronic inflammatory state which increases cancer risk. MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression. There is little known about whether differential expression of miRs affects the ability of obesity to promote cancer. To test the hypothesis that obesity promotes colon tumorigenesis through alteration of cytokine and miR expression, we utilized an azoxymethane (AOM)-induced model of colon cancer in FVB mice. Colon tumorigenesis was initiated in FVB mice with AOM and mice were subsequently administered a high fat (45% kcal from fat) or control diet (10% kcal from fat). Tumorigenesis and cytokine expression was determined 5, 10, and 20 weeks after AOM. Expression of miRs was determined at 5 and 10 weeks after AOM. Obesity promoted tumor progression 20 weeks after AOM compared to the control group. The obese mice had an average of 12.0 ± 1.3 tumors per mouse, while the control mice had an average of 9.2 ± 1.8 tumors per mouse (p<0.0001). Cytokine levels were measured 5, 10, and 20 weeks after the last injection of AOM to investigate the role of inflammation in obesity-promoted colon tumorigenesis. Ten different cytokines were measured from the serum of mice in each group. Six cytokines were significantly altered 5 weeks after the last injection of AOM among the mice fed a high fat diet. Levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly higher in obese mice compared to control mice. In addition, all of these cytokines remained significantly altered in the obese mice at 10 and 20 weeks after AOM. Expression of miRs was determined 5 and 10 weeks after AOM to determine if miRs were differentially expressed among treatment groups. Microarray data demonstrated in a comparison of the high fat group versus the control group, fourteen miRs were differentially expressed with a false discovery rate less than 0.05. Real time PCR was used to validate ten of these miRs. At both 5 and 10 weeks post AOM, five miRs were validated to be significantly downregulated in mice on a high fat diet compared to those on a control diet. These miRs included miR-138, miR-150, miR-34c, let-7f, and miR-16. In addition, two miRs, miR-155 and miR-196, were validated to be significantly upregulated in the mice on a high fat diet at both 5 and 10 weeks post AOM. This study supports the hypothesis that obesity contributes to an increased inflammatory environment which may lead to increased colon tumor growth. Furthermore, differential expression of miRs may be involved in promoting colon tumor growth induced by obesity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5699.