GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1

描述(由申请人提供)：本申请的目标是确定肥胖、肿瘤抑制基因GUCY2C的激素沉默和结直肠癌风险之间的机制联系；这种联系的可逆性；以及口服GUCY2C激素替代以降低该风险的效用。GUCY2C是结肠直肠中旁分泌激素鸟苷的肠道受体，鸟苷是小鼠和人类散发性结直肠癌中最常见的缺失基因产物。GUCY2C调节肠道内环境的稳定，旁分泌激素的缺失使其沉默，导致上皮功能障碍，表现为细胞过度增殖，DNA损伤增加，细胞代谢重编程，增加肠道肿瘤的发生。出乎意料的是，初步研究表明，在小鼠和人类中，肥胖会消除结肠中鸟苷素的表达。鸟苷素的表达似乎受摄入卡路里的可逆调节，而不是受与肥胖相关的内分泌、脂肪因子或炎症环境的调节。这些观察表明了一种癌症风险模型，在该模型中，摄入的卡路里导致肥胖，通过抑制鸟巢蛋白的表达，沉默GUCY2C肿瘤抑制因子，扰乱上皮细胞的动态平衡，增加肿瘤的发生，概括了散发性结直肠癌的既定机制。在目前的应用中，第一个目的将检验肥胖通过抑制鸟苷表达和沉默GUCY2C而导致上皮功能障碍和肿瘤发生的假说。这些研究将确定抑制鸟苷素的表达是饮食、肥胖和癌症风险之间的关键机制联系。第二个目标将确定可逆的卡路里依赖的鸟苷素表达调节在肥胖症上皮功能障碍中的作用。这些研究将扩大目前癌症风险的范例，超越肥胖及其相关的内分泌环境，包括摄入卡路里作为连接肥胖和癌症的可逆风险因素的作用。最后，第三个目标将探索口服GUCY2C配体补充在预防肥胖诱导的上皮功能障碍和结直肠癌方面的应用。这些研究将确定口服GUCY2C配体替代作为一种化学预防策略的效用，以降低肥胖相关的癌症风险。总之，这些研究将确定一种将肥胖与癌症联系起来的具体机制，作为识别风险因素(肥胖、饮食、摄入的卡路里)和通过沉默GUCY2C肿瘤抑制基因来研究癌症发展的分子生物学之间的桥梁。了解肥胖带来的癌症风险背后的这些机制，将为应对这些风险提供新的策略，包括限制卡路里和口服激素替代。在监管部门即将批准口服GUCY2C配体治疗便秘的背景下，立即转换这些结果以降低肥胖患者患结直肠癌风险的潜力可以得到理解。

DESCRIPTION (provided by applicant): The goal of this application is to define the mechanistic link between obesity, hormone silencing of the tumor suppressor GUCY2C, and colorectal cancer risk; the reversibility of this link; and the utility of oral GUCY2C hormone replacement to mitigate that risk. GUCY2C is the intestinal receptor for the paracrine hormone guanylin in the colorectum, the most commonly lost gene product in sporadic colorectal cancer in mice and humans. GUCY2C regulates intestinal homeostasis, and its silencing by paracrine hormone loss produces epithelial dysfunction characterized by hyperproliferation, increased DNA damage, and reprogramming of cell metabolism, increasing intestinal tumorigenesis. Unexpectedly, preliminary studies revealed that guanylin expression in colon is eliminated by obesity in mice and humans. Guanylin expression appears to be reversibly modulated by ingested calories, rather than by the endocrine, adipokine or inflammatory milieu associated with obesity. These observations suggest a model of cancer risk in which ingested calories contributing to obesity recapitulate established mechanisms underlying sporadic colorectal cancer, by suppressing guanylin expression, silencing the GUCY2C tumor suppressor and disrupting epithelial homeostasis, increasing tumorigenesis. In the present application, the first aim will test the hypothesis that obesity induces epithelial dysfunction and tumorigenesis by suppressing guanylin expression and silencing GUCY2C. These studies will establish suppression of guanylin expression as a critical mechanistic link between diet, obesity, and cancer risk. The second aim will define the contribution of reversible calorie- dependent modulation of guanylin expression to epithelial dysfunction in obesity. These studies will expand the current paradigm of cancer risk beyond obesity and its associated endocrine milieu, to include the role of ingested calories as a reversible risk factor linking obesity and cancer. Finally, the third aim will explore the utility of oral GUCY2C ligand supplementation to prevent obesity-induced epithelial dysfunction and colorectal cancer. These studies will establish the utility of oral GUCY2C ligand replacement as a chemopreventive strategy to mitigate obesity-related cancer risk. Together, these studies will define one concrete mechanism linking obesity to cancer, serving as a bridge between identification of risk factors (obesity, diet, ingested calories) and the molecular biology of cancer development through silencing of the GUCY2C tumor suppressor. Understanding these mechanisms underlying cancer risk posed by obesity will provide new strategies for countering these risks, including calorie restriction and oral hormone replacement. The potential for immediate translation of these results to mitigate colorectal cancer risk in obese patients can be appreciated in the context of the imminent regulatory approval of oral GUCY2C ligands to treat constipation.