Editors' ChoiceCancer

Silence of the GUCY2C tumor suppressor

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Science Translational Medicine  10 Feb 2016:
Vol. 8, Issue 325, pp. 325ec22
DOI: 10.1126/scitranslmed.aaf2009

Population-based data linking obesity to colorectal cancer are strong, with reports of over 50% increased risk of colorectal cancer in obese persons. However, much less is known about how obesity promotes the development of colorectal cancer, especially at the molecular level. The complex dietary and metabolic factors associated with obesity make it difficult to pinpoint an exact mechanism. Many hypotheses have been suggested, including the idea that an enhanced proinflammatory and oxidative environment promotes tumorigenesis. Here, Lin et al. investigate the effects of obesity on the guanylin and guanylyl cyclase C (GUCY2C) tumor-suppressing pathway. GUCY2C is an intestinal cell surface receptor that regulates epithelial repair. Loss of its ligand, the paracrine hormone guanylin, shuts off GUCY2C and contributes to tumor progression.

To link obesity with this tumor-suppressing pathway, investigators showed that guanylin mRNA expression in human colonic tissue samples was 80% lower in patients with morbid obesity compared with lean patients. In mice, both high-fat and high-carbohydrate diets suppressed guanylin mRNA expression and GUCY2C signaling. The investigators then used a combination of obesity-prone and obesity-resistant mouse models with varying diets to show that it is excess calorie intake, and not obesity per se, that silences the guanylin-GUCY2C signaling axis. More specifically, it was endoplasmic reticulum stress induced by excess calorie intake that resulted in the silencing of this pathway. Last, tumorigenesis induced by overfeeding mice was offset by the transgenic expression of guanylin. Together, these studies offer insight to a potential therapeutic target—guanylin or its associated receptor, GUCY2C—for reducing colorectal cancer risk in obese individuals, whether it be through caloric restriction or by pharmacological treatment.

J. E. Lin et al., Obesity-induced colorectal cancer is driven by caloric silencing of the guanylin–GUCY2C paracrine signaling axis. Cancer Res. 10.1158/0008-5472.CAN-15-1467-T (2016). [Abstract]

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