Guanylyl Cyclase C Suppresses Intestinal Tumorigenesis by Restricting Proliferation and Maintaining Genomic Integrity

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

“…21,29 Knockout mice that are deficient in cGMP signaling exhibit aberrant AKT activity in the colon mucosa that coincides with elevated epithelial proliferation within crypts. 21,22 Because AKT is an established promoter of proliferation and survival, this pathway may directly contribute to crypt hyperplasia in these knockout mice. However, it is not clear how aberrant AKT activity would increase the epithelial apoptosis and barrier dysfunction that are also observed in these animals.…”

“…18e21 These observations suggest that GC-C/cGMP signaling is tumor suppressive in the gut, which has been supported by studies using mouse models of intestinal tumorigenesis. 22,23 The mechanisms and signaling responsible for the reduced resilience of the epithelial barrier in cGMP-deficient mice are poorly understood. Type 2 cGMP-dependent protein kinase (PKG2) is the central cGMP effector in the gut epithelium that mediates fluid secretion by controlling ion channels.…”

Emergent Concepts from the Intestinal Guanylyl Cyclase C Pathway

“…In addition, reactivation of GCC signalling through cGMP opposes the Wnt/ -catenin/Tcf4 signalling axis, the regulator of the proliferative crypt phenotype and tumor promoter in intestine (Pinto & Clevers 2005;Reya & Clevers 2005;van Es et al, 2005), by directly inhibiting -catenin stability (Liu et al, 2001;Thompson et al, 2000). Underscoring the significance of the dormant GCC pathway in colon cancer, elimination of GCC in mice significantly enhances intestinal tumor initiation and progression (Li et al, 2007b). Mice deficient of GCC signalling exhibit enhanced sensitivity to tumorigenesis induced by Apc Min/+ and the carcinogen azoxymethane, reflected by increased tumor incidence, multiplicity, and burden (Li et al, 2007b).…”

“…Underscoring the significance of the dormant GCC pathway in colon cancer, elimination of GCC in mice significantly enhances intestinal tumor initiation and progression (Li et al, 2007b). Mice deficient of GCC signalling exhibit enhanced sensitivity to tumorigenesis induced by Apc Min/+ and the carcinogen azoxymethane, reflected by increased tumor incidence, multiplicity, and burden (Li et al, 2007b). A principal mechanism by which GCC promotes colorectal tumorigenesis is the perturbation of regulators of G 1 /S cell cycle transition, including increased expression of oncogenes cyclin D 1 and pRb, and decreased activity of tumor suppressor p27 (Li et al, 2007b).…”

“…Mice deficient of GCC signalling exhibit enhanced sensitivity to tumorigenesis induced by Apc Min/+ and the carcinogen azoxymethane, reflected by increased tumor incidence, multiplicity, and burden (Li et al, 2007b). A principal mechanism by which GCC promotes colorectal tumorigenesis is the perturbation of regulators of G 1 /S cell cycle transition, including increased expression of oncogenes cyclin D 1 and pRb, and decreased activity of tumor suppressor p27 (Li et al, 2007b). Beyond hyperproliferation, GCC-deficient mice also exhibit increased genomic instability in their intestinal mucosa cells.…”