Colorectal cancer(CRC) is a major cause of cancerrelated mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, a...Colorectal cancer(CRC) is a major cause of cancerrelated mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C(GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin(GUCA2A) and uroguanylin(GUCA2B), which bind and activate GUCY2 C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2 C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2 C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2 C ligand linaclotide(Linzess^(TM)). Here we review the known contributions of the GUCY2 C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.展开更多
Guanylin family, described in recent 10 years, is a series of small peptides （including guanylin, uroguanylin and lymphoguanylin） with structural and functional similarities to heat-stable enterotoxins （STs） elabo...Guanylin family, described in recent 10 years, is a series of small peptides （including guanylin, uroguanylin and lymphoguanylin） with structural and functional similarities to heat-stable enterotoxins （STs） elaborated by various pathogenic bacteria. They are abundance of cysteines and are endogenous activators of guanylyl cyclase-C （GC-C） receptors. Immunoreactive guanylin family peptides are localized in many human organs and tissues, especially in gastrointestinal tract and kidney, and play an important role in regulation of water and salt homeostasis. Recent studies showed that the mRNA levels of guanylin family peptides were down-regulated in colorectal cancers; oral intake of uroguanylin might suppress polyp formation in Apc（Min/+） mouse, and 111In-labeled-ST peptide analog might specifically target human colon cancers. These evidences highlight that guanylin family may have a potential application in diagnosis and therapy effects of colorectal cancers.展开更多
基金Supported by NIH,No.R01CA170533,No.R01CA206026 and No.P30CA56036Targeted Diagnostic and Therapeutics,Inc.+2 种基金a Ruth L.Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows from the NIH,No.CA180500(To Blomain ES)a Ruth L.Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows from the NIH,No.F30 DK103492(To Merlino DJ)a Predoctoral Fellowship in Pharmacology/Toxicology from the PhR MA Foundation
文摘Colorectal cancer(CRC) is a major cause of cancerrelated mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C(GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin(GUCA2A) and uroguanylin(GUCA2B), which bind and activate GUCY2 C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2 C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2 C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2 C ligand linaclotide(Linzess^(TM)). Here we review the known contributions of the GUCY2 C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.
文摘Guanylin family, described in recent 10 years, is a series of small peptides （including guanylin, uroguanylin and lymphoguanylin） with structural and functional similarities to heat-stable enterotoxins （STs） elaborated by various pathogenic bacteria. They are abundance of cysteines and are endogenous activators of guanylyl cyclase-C （GC-C） receptors. Immunoreactive guanylin family peptides are localized in many human organs and tissues, especially in gastrointestinal tract and kidney, and play an important role in regulation of water and salt homeostasis. Recent studies showed that the mRNA levels of guanylin family peptides were down-regulated in colorectal cancers; oral intake of uroguanylin might suppress polyp formation in Apc（Min/+） mouse, and 111In-labeled-ST peptide analog might specifically target human colon cancers. These evidences highlight that guanylin family may have a potential application in diagnosis and therapy effects of colorectal cancers.
