2022-Sustainable Industrial Processing Summit
SIPS2022 Volume 19 Intl. Symp on Technological Innovations in Medicine and Covid19 and Infectious Diseases
| Editors: | F. Kongoli, F. Murad, T. Yoshikawa, S. Waldman, J. Ribas, S. Hirano, D. Joseph, R. Guerrant, W. Petri, H. Inufusa, H. Yedoyan, S. Heysell. |
| Publisher: | Flogen Star OUTREACH |
| Publication Year: | 2022 |
| Pages: | 130 pages |
| ISBN: | 978-1-989820-70-4(CD) |
| ISSN: | 2291-1227 (Metals and Materials Processing in a Clean Environment Series) |
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Hormone loss silencing GUCY2C at the nexus of obesity and colorectal cancer
Scott Waldman1;1THOMAS JEFFERSON UNIVERSITY, Philadelphia, United States;
Type of Paper: Regular
Id Paper: 84
Topic: 65
Abstract:
Obesity is a worldwide health crisis, with >1 billion adults who are overweight (BMI >25 kg/m2), and 500 million who are obese (BMI >30 kg/m2). Annual US medical costs in the U.S. reflecting obesity are in excess of $150 billion, and by 2030 will increase 120%. Obesity reflects excess nutrition, in which calories consumed exceed those expended metabolically, in part due to abnormal satiety responses regulating appetite. Beyond cardiovascular and metabolic consequences producing morbidity and mortality in obesity, there is a linkage between body weight and cancer risk, including colorectal cancer. Obese patients have up to a 60% greater risk of, and ~200% greater death rate from, colorectal cancer. While the epidemiology of this relationship is known, mechanisms linking obesity and colorectal cancer have not been defined. GUCY2C is the receptor for the hormones uroguanylin in small intestine and guanylin in the colorectum. A novel mechanistic paradigm suggests that guanylin loss silencing GUCY2C signaling, and epithelial cell homeostasis, is an essential step initiating colorectal cancer.[1] Further, small intestine secretion of uroguanylin into the circulation forms an intestine-brain axis controlling hypothalamic GUCY2C regulating satiety, body weight, and metabolic balance.[2-4] In the present studies, we reveal that hyperphagia, and the consumption of excess calories, suppresses the expression guanylin and uroguanylin by the colorectum and small intestine, respectively, disrupting GUCY2C paracrine and endocrine signaling axes at the intersection of colorectal cancer and obesity.5 Expression of those hormones, but not GUCY2C, is reduced in across the rostral-caudal axis of the intestine, by diet-induced obesity in mice and humans. Expression of hormones are reversibly suppressed by consumed calories by a mechanism involving endoplasmic reticulum stress. Indeed, transgenic supplementation of guanylin in intestine eliminates tumorigenesis induced by obesity. Additionally, transgenic uroguanylin in brain improves satiety responses in diet-induced obesity. Together, these data suggest a pathophysiological model in which caloric suppression of hormone expression silencing GUCY2C is at the nexus of mechanisms underlying obesity and the risk of colorectal cancer.[5] Beyond this mechanism, these studies offer a therapeutic paradigm which exploits the preservation of GUCY2C expression in hyper-nutrition, in which hormone supplementation restores endocrine and paracrine axes to reconstitute appetite control opposing obesity and intestinal homeostasis preventing transformation.[5]
Keywords:
Medicine;References:
1. Blomain ES, Rappaport JA, Pattison AM, Bashir B, Caparosa E, Stem J, Snook AE, Waldman SA. (2020) APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. Cancer Biol. Ther. 21:441-451. 2. Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA. (2011) A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J. Clin. Invest. 121:3578-3588. 3. Kim GW, Lin JE, Snook AE, Aing A, Merlino DJ, Li P, Waldman, SA. (2016) Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity. Nutr Diabetes 23;6:e211. doi: 10.1038/nutd.2016.18. 4. Merlino DJ, Barton JR, Charsar BA, Byrne MD, Rappaport JA, Smeyne RJ, Lepore AC, Snook, AE, Waldman SA. (2019). Two distinct GUCY2C circuits with PMV (hypothalamic) and SN/VTA (midbrain) origin. Brain Structure and Function, 224:2983-2999. 5. Lin JE, Colon-Gonzalez F, Blomain E, Kim GW, Aing A, Stoecker B, Rock J, Snook AE, Zhan T, Hyslop T, Tomczak M, Blumberg RS, Waldman SA. (2016) Calories suppress guanylin silencing the GUCY2C tumor suppressor in colorectal cancer in obesity. Can. Res. 76:339-346.