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

描述（由申请人提供）：本申请的目的是确定肥胖、肿瘤抑制因子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激素替代品来降低这种风险。GUCY2C是结肠中旁分泌激素观音碱的肠道受体，是小鼠和人类散发性结直肠癌中最常见的基因产物。GUCY2C调节肠道内稳态，由于旁分泌激素缺失导致其沉默，导致上皮功能障碍，其特征是增殖过度，DNA损伤增加，细胞代谢重编程，增加肠道肿瘤发生。出乎意料的是，初步研究表明，在小鼠和人类中，结肠中的观音表达被肥胖所消除。观音林的表达似乎是由摄入的卡路里可逆调节的，而不是由与肥胖相关的内分泌、脂肪因子或炎症环境调节的。这些观察结果表明，通过抑制观音表达、沉默GUCY2C肿瘤抑制因子、破坏上皮稳态、增加肿瘤发生，摄入的卡路里导致肥胖的癌症风险模型概括了散发性结直肠癌的既定机制。在本应用中，第一个目的是验证肥胖通过抑制观音林表达和沉默GUCY2C诱导上皮功能障碍和肿瘤发生的假设。这些研究将证实观音表达的抑制是饮食、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性的热量依赖性观音表达调节对肥胖上皮功能障碍的贡献。这些研究将扩大目前的癌症风险范式，超越肥胖及其相关的内分泌环境，将摄入的卡路里作为一种可逆的风险因素，将肥胖和癌症联系起来。最后，第三个目标将探讨口服GUCY2C配体补充剂在预防肥胖诱导的上皮功能障碍和结直肠癌中的作用。这些研究将确立口服GUCY2C配体替代作为一种化学预防策略的效用，以减轻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肿瘤抑制因子的癌症发展的分子生物学之间的桥梁。了解由肥胖引起的癌症风险的潜在机制将为应对这些风险提供新的策略，包括卡路里限制和口服激素替代。在口服GUCY2C配体治疗便秘即将获得监管机构批准的背景下，这些结果立即转化为降低肥胖患者结直肠癌风险的潜力可以得到重视。

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.