Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis

Cancer Research
Jieru E LinScott A Waldman

Abstract

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colore...Continue Reading

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Citations

Mar 5, 2016·Expert Review of Anticancer Therapy·Erik S Blomain, Scott A Waldman
Apr 23, 2016·Cancer Biology & Therapy·Erik S BlomainScott A Waldman
Jun 3, 2016·Molecular Pharmacology·Erik S BlomainScott A Waldman
Feb 7, 2017·Expert Review of Clinical Pharmacology·Allison A AkaScott A Waldman
Nov 8, 2017·Journal of Pediatric Gastroenterology and Nutrition·Matthew D Di GuglielmoKenneth L van Golen
Jun 21, 2017·International Journal of Molecular Sciences·Cécily LucasHang Thi Thu Nguyen
Dec 27, 2017·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·S FukudoH Miwa
Aug 30, 2017·Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society·Matthew D Di GuglielmoDiana U Corao
Aug 8, 2018·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Shin FukudoToshifumi Ohkusa
Aug 24, 2018·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Shin FukudoYoshikazu Kinoshita
Dec 6, 2017·Journal of Molecular Endocrinology·C FolgueiraL M Seoane
Aug 3, 2016·Infection and Immunity·Amanda M PattisonScott A Waldman
Mar 23, 2018·Gut·Scott A Waldman, Michael Camilleri
Oct 26, 2018·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Shin FukudoToshifumi Ohkusa
Jul 19, 2019·Clinical and Translational Gastroenterology·Scott A WaldmanPatrick Griffin
Feb 11, 2020·Cancer Biology & Therapy·Erik S BlomainScott A Waldman
Dec 22, 2017·Oncotarget·Crystal L KraftScott A Waldman
Oct 1, 2016·World Journal of Gastroenterology : WJG·Amanda M PattisonScott A Waldman
Aug 23, 2018·Frontiers in Oncology·Jeffrey A Rappaport, Scott A Waldman
Jul 1, 2020·Cancer Biology & Therapy·Amanda M PattisonScott A Waldman
Jun 9, 2020·Cancer Biomarkers : Section a of Disease Markers·Yongjian ZhangKoujun Zhu
Sep 19, 2020·Expert Review of Clinical Pharmacology·Jeffrey A Rappaport, Scott A Waldman
Apr 12, 2017·Cancer Prevention Research·David S WeinbergScott A Waldman
Sep 17, 2017·Cancer Research·Peng LiScott A Waldman
Jan 21, 2021·Biomarkers in Medicine·John C FlickingerScott A Waldman
May 25, 2021·Expert Review of Precision Medicine and Drug Development·Amanda N LisbyScott A Waldman
Jun 1, 2021·Expert Opinion on Therapeutic Targets·Ariana A EntezariScott A Waldman

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