Abstract
Abstract Obesity-associated cancers, including colon cancer, are increasing in Western countries. It has been demonstrated that increased amounts of visceral fat and decreased levels of plasma adiponectin (APN) are associated with development of human colorectal cancer. Thus, we here investigated the function of APN in intestinal carcinogenesis. Male APN+/+, APN+/- or APN-/- C57BL/6J mice were injected with azoxymethane (AOM) once a week for 6 weeks, which led to the development of intestinal tumors. C57BL/6J mice with each genotype were sacrificed at the age of 55 weeks, and the number and size of colorectal tumors were examined by pathological study. Furthermore, these strains of mice were also crossed with Min mice (C57BL/6J background) to assess the effects of APN on intestinal polyp formation. At the age of 9 and 12 weeks, Min mice each with the APN genotype were sacrificed, and the number and size of intestinal polyps were examined by pathological study. Levels of adipocytokine and phosphorylation of AMPK were also evaluated to clarify the effect of APN on intestinal tumor development. The incidence of AOM-induced tumors was 40% of APN+/+, 50% of APN+/- and 71% (p<0.05) of male APN-/- C57BL/6J mice, respectively. Multiplicities of AOM-induced tumors in each genotype were 0.5±0.7, 0.6±0.7 and 1.1±1.0 (p<0.05), respectively. The total number of intestinal polyps developed in 9-week-old male APN+/- Min and APN-/-Min mice increased 2.4- and 3.2-fold compared with those in APN+/+Min mice, respectively, and was further enhanced at 12 weeks of age, being 3.2- and 3.4-fold, respectively. Studies with female mice gave similar results. Phosphorylation levels of AMPK in intestinal epithelial cells were decreased in APN-/- mice compared with APN+/+ mice. Among serum adipocytokines, levels of serum Pai-1 increased in APN-/- C57BL/6J mice and APN-/-Min mice with AOM injection. Activation of AMPK by metformin treatment suppressed Pai-1 expression in Min mice. AOM-induced colorectal aberrant crypt foci in APN-/- C57BL/6J mice were decreased by a Pai-1 blocker. In conclusion, APN-deficient mice developed more intestinal tumors. Decreased phosphorylation of AMPK and increased levels of Pai-1 were observed in APN-deficient mice compared with wild-type mice. APN and its receptors might be good targets for developing colorectal cancer chemopreventive agents. 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 2837. doi:10.1158/1538-7445.AM2011-2837
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