Abstract 823: Genetic reduction of circulating insulin-like growth factor (IGF)-1 inhibits obesity-promoted colon tumorigenesis in mice and alters microRNA expression
Authors: Olivo-Marston Susan E. , Hursting Stephen , Schetter Aaron , Khan Mohammed , Harris Curtis , Lavigne Jackie 
Published: June 2012

Obesity has been associated with increased colon cancer risk. Although the molecular pathways underlying the obesity-colon cancer link are unknown, obesity is associated with several metabolic alterations including the IGF-1 pathway. Also, high circulating levels of IGF-1 are associated with increased colon cancer risk. MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression. There is little known about differential expression of miRs affecting the ability of obesity to promote cancer and IGF-1's potential role. We tested the hypothesis that obesity enhances colon tumorigenesis and inhibition of IGF-1 would attenuate this effect and alter miR expression. We utilized genetically altered mice with a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice display a ∼70% reduction in circulating IGF-1 levels. Colon tumorigenesis was initiated in LID and wildtype mice with AOM, and mice were subsequently administered a high fat (45% kcal from fat) or control diet (10% kcal from fat).

Obesity promoted tumorigenesis at 20 weeks among both LID (n=82) and wildtype mice (n=71). The obese LID mice had an average of 5.7 + 1.9 tumors per mouse, while the LID control mice had an average of 3.9 + 2.3 tumors per mouse (p=0.195). However, the obese wildtype mice had an average of 9.3 + 3.0 tumors per mouse, while the control wildtype mice had an average of 6.7 + 2.9 tumors per mouse (p=0.02).

IGF-1 signaling activates several growth-related pathways, resulting in an increase in proliferation and a decrease in apoptosis. Therefore, we examined markers of proliferation and apoptosis in the tumors and normal epithelium of the LID and wildtype mice. We observed an increase in proliferation in tumors from both the LID and wildtype mice as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, there was a significant decrease in proliferation in the normal epithelium of the LID mice LID mice had a proliferative index of 21.3% + 4.2% while the wildtype mice had a proliferative index of 37.1% + 3.9 (p&lt;0.0001). Additionally, inhibition of IGF-1 resulted in a significant increase in apoptosis (as measured by TUNEL assay) in the crypts of the normal epithelium of the LID mice (p&lt;0.0001).

Based on a previous study of obesity-promoted colon carcinogenesis, expression levels of ten miRs were investigated through real time PCR. LID mice had increased expression of miR-138, miR-34c, let-7f, and miR-16. In addition, LID mice had a significant decrease in expression of miR-155 and miR-196, regardless of diet.

This study supports the hypothesis that the IGF-1 pathway and specific microRNAs are involved in obesity-promoted colon tumorigenesis. Targeting the IGF-1 pathway and the associated microRNAs may be an effective strategy to prevent colon tumors associated with obesity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 823. doi:10.1158/1538-7445.AM2011-823