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: 8680189
• 负责人: SCOTT A WALDMAN
• 金额: $ 31.2万
• 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/8680189
• 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GUCY 2C的激素沉默和结直肠癌风险之间的机制联系;该联系的可逆性;以及口服GUCY 2C激素替代物减轻该风险的效用。GUCY 2C是结肠直肠中旁分泌激素鸟苷素的肠道受体，鸟苷素是小鼠和人类散发性结肠直肠癌中最常见的基因产物。GUCY 2C调节肠内稳态，并且其通过旁分泌激素损失的沉默产生上皮功能障碍，其特征在于过度增殖、增加的DNA损伤和细胞代谢的重编程，增加肠肿瘤发生。出乎意料的是，初步研究表明，鸟苷素在结肠中的表达被小鼠和人类的肥胖所消除。鸟苷素的表达似乎是由摄入的卡路里可逆地调节，而不是由内分泌，脂肪因子或炎症环境与肥胖相关。这些观察结果表明了一种癌症风险模型，其中摄入的热量导致肥胖，通过抑制鸟苷素表达、沉默GUCY 2C肿瘤抑制因子和破坏上皮稳态、增加肿瘤发生，重现了散发性结直肠癌的既定机制。在本申请中，第一个目的将检验肥胖通过抑制鸟苷素表达和沉默GUCY 2C诱导上皮功能障碍和肿瘤发生的假设。这些研究将确立鸟苷素表达的抑制作为饮食、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素表达的可逆性卡路里依赖性调节对肥胖症中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，包括摄入的卡路里作为联系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GUCY 2C配体补充剂预防肥胖诱导的上皮功能障碍和结直肠癌的效用。这些研究将确立口服GUCY 2C配体替代作为减轻肥胖相关癌症风险的化学预防策略的效用。总之，这些研究将定义一个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GUCY 2C肿瘤抑制因子来发展癌症的分子生物学之间的桥梁。了解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，包括热量限制和口服激素替代。在口服GUCY 2C配体治疗便秘即将获得监管批准的背景下，可以理解这些结果立即转化为减轻肥胖患者结直肠癌风险的潜力。