Fenton Jenifer I, Lavigne Jackie A, Perkins Susan N, Liu Huaitian, Chandramouli Gadisetti V R, Shih Joanna H, Hord Norman G, Hursting Stephen D
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, USA.
Mol Carcinog. 2008 Jan;47(1):9-21. doi: 10.1002/mc.20357.
The imbalance in systemic mediators of inflammation, such as leptin, is thought to be involved in obesity-associated cancers. In addition, systemic endocrine signals can influence the local autocrine/paracrine factors produced within this microenvironment to influence epithelial cell fate. We previously demonstrated that leptin preferentially promotes the survival and proliferation of colon epithelial cells possessing an Apc mutation (IMCE) but not model normal cells (YAMC). Therefore, the purpose of this study was to identify leptin-induced functional gene family changes which characterize the response of colon epithelial cells possessing an Apc mutation but not normal cells. Consistent with our knowledge of colon carcinogenesis, genes regulating the Wnt/beta-catenin-mediated pathway including Mdm2, Pik3r1, and Rb1 were upregulated by leptin. Importantly, leptin induced IGF-mediated pathway gene expression changes and their protein products in IMCE cells. In the IMCE cells IGFBP-6, IGF-1, and Crim1 expression was upregulated, while IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and Nov expression was downregulated by leptin treatment. These data establish a biologically plausible mechanistic link between the elevated levels of growth factors and the increased risk of colon cancer associated with obesity.
瘦素等全身炎症介质的失衡被认为与肥胖相关癌症有关。此外，全身内分泌信号可影响该微环境中产生的局部自分泌/旁分泌因子，从而影响上皮细胞命运。我们之前证明，瘦素优先促进具有Apc突变的结肠上皮细胞（IMCE）的存活和增殖，但对正常模型细胞（YAMC）无此作用。因此，本研究的目的是确定瘦素诱导的功能基因家族变化，这些变化可表征具有Apc突变的结肠上皮细胞而非正常细胞的反应。与我们对结肠癌发生的认识一致，瘦素上调了包括Mdm2、Pik3r1和Rb1在内的调节Wnt/β-连环蛋白介导途径的基因。重要的是，瘦素在IMCE细胞中诱导了IGF介导的途径基因表达变化及其蛋白产物。在IMCE细胞中，瘦素处理使IGFBP-6、IGF-1和Crim1表达上调，而IGFBP-2、IGFBP-3、IGFBP-4、IGFBP-5和Nov表达下调。这些数据在生长因子水平升高与肥胖相关结肠癌风险增加之间建立了生物学上合理的机制联系。
