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

肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导（PQ1

• 批准号: 8517056
• 负责人: SCOTT A WALDMAN
• 金额: $ 30.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517056
• 关键词: Address; Caloric Restriction; Calories; Cancer Etiology; Carcinogens; Cell Cycle; Cells; Cessation of life; Chemicals; Chemopreventive Agent; Colon; Colorectal; Colorectal Cancer; Constipation; DNA Damage; Development; Diet; Endocrine; Epidemiology; Epithelial; Epithelial Cells; Failure; Functional disorder; Gastrointestinal tract structure; Genetic; Goals; Homeostasis; Hormone replacement therapy; Hormones; Human; Incidence; Individual; Inflammatory; Intestinal Mass; Intestinal Neoplasms; Intestines; Lead; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Neoplasms; Obesity; Obesity associated cancer; Oral; Outcome Study; Pathogenesis; Patients; Predisposition; Process; Proteins; Reducing diet; Risk; Risk Factors; Role; Signal Transduction; Supplementation; Testing; Therapeutic; Translating; Translations; Tumor Suppressor Proteins; cancer prevention; cancer risk; carcinogenesis; chemical carcinogenesis; cytokine; defined contribution; genotoxicity; guanylin; hormone therapy; intestinal homeostasis; mortality; mouse model; novel; paracrine; prevent; receptor; tumor initiation; tumor progression; tumorigenesis

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.

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；该链接的可逆性；以及口服 GUCY2C 激素替代疗法可降低该风险的效用。 GUCY2C 是结直肠中旁分泌激素鸟苷酸的肠道受体，鸟苷酸是小鼠和人类散发性结直肠癌中最常见丢失的基因产物。 GUCY2C 调节肠道稳态，旁分泌激素丢失导致的沉默会导致上皮功能障碍，其特征是过度增殖、DNA 损伤增加和细胞代谢重新编程，从而增加肠道肿瘤的发生。出乎意料的是，初步研究表明，小鼠和人类的肥胖会消除结肠中鸟苷蛋白的表达。鸟苷蛋白的表达似乎是通过摄入的卡路里进行可逆调节的，而不是通过与肥胖相关的内分泌、脂肪因子或炎症环境来调节。这些观察结果提出了一种癌症风险模型，其中摄入的热量导致肥胖，通过抑制鸟苷蛋白表达、沉默 GUCY2C 肿瘤抑制因子并破坏上皮稳态，从而增加肿瘤发生，从而概括了散发性结直肠癌的既定机制。在本申请中，第一个目标将检验肥胖通过抑制鸟苷蛋白表达和沉默GUCY2C诱导上皮功能障碍和肿瘤发生的假设。这些研究将确定鸟苷蛋白表达的抑制是饮食、肥胖和癌症风险之间的关键机制联系。第二个目标将确定鸟苷蛋白表达的可逆热量依赖性调节对肥胖症上皮功能障碍的影响。这些研究将扩大目前癌症风险的范式，超越肥胖及其相关的内分泌环境，将摄入的卡路里作为连接肥胖和癌症的可逆风险因素包括在内。最后，第三个目标将探索口服 GUCY2C 配体补充剂在预防肥胖引起的上皮功能障碍和结直肠癌方面的效用。这些研究将确定口服 GUCY2C 配体替代作为化学预防策略的效用，以减轻与肥胖相关的癌症风险。这些研究将共同​​确定一种将肥胖与癌症联系起来的具体机制，通过沉默 GUCY2C 肿瘤抑制因子，作为识别危险因素（肥胖、饮食、摄入热量）和癌症发展分子生物学之间的桥梁。了解肥胖引起的癌症风险的这些机制将为应对这些风险提供新的策略，包括热量限制和口服激素替代。在监管机构即将批准口服 GUCY2C 配体治疗便秘的背景下，可以认识到这些结果立即转化为减轻肥胖患者结直肠癌风险的潜力。