Skip to Content
Merck
  • Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.

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

Cancer research (2016-01-17)
Jieru E Lin, Francheska Colon-Gonzalez, Erik Blomain, Gilbert W Kim, Amanda Aing, Brian Stoecker, Justin Rock, Adam E Snook, Tingting Zhan, Terry M Hyslop, Michal Tomczak, Richard S Blumberg, Scott 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 colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.

MATERIALS
Product Number
Brand
Product Description

Custom DNA Oligos, Design and Order Custom Oligos
Sigma-Aldrich
Formaldehyde solution, for molecular biology, 36.5-38% in H2O
Sigma-Aldrich
Tris Buffered Saline, with Tween™ 20, pH 8.0, powder
Sigma-Aldrich
Tunicamycin from Streptomyces sp.
Sigma-Aldrich
Transferrin from human blood plasma, ≥95% (GE)
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - high glucose, With 4500 mg/L glucose, L-glutamine, sodium pyruvate, and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Tris buffered saline with Tween® 20, BioUltra, tablet (for 500 mL), pH 7.6
Sigma-Aldrich
Escort IV Transfection Reagent, Lipid reagent for transient and stable transfection of mammalian and insect cells.
Sigma-Aldrich
Donkey serum
Sigma-Aldrich
Fetal Bovine Serum, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma
Sigma-Aldrich
Thapsigargin, ≥98% (HPLC), solid film
MISSION® siRNA Product Offerings, Custom and Predesigned siRNA