A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer

Rappaport, Jeff; Entezari, Ariana A; Caspi, Adi; Caksa, Signe; Jhaveri, Aakash; Stanek, Timothy J.; Ertel, Adam; Kupper, Joan; Fortina, Paolo; McMahon, Steven B.; Jaynes, James B.; Snook, Adam E.

doi:10.1016/j.jcmgh.2021.12.014

Cited by 9 publications

(11 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most colorectal tumors are caused by adenomatous polyposis coli (APC) loss-of-function mutations or β-catenin gain-of-function mutations, both of which result in abnormal Wnt signaling activation ( 78 ). This is consistent with a substantial reduction in guanylin and uroguanylin expression during the early stages of tumorigenesis in colorectal cancer compared to normal tissue ( 15 ) ( Figure 1 ). The loss of GC-C ligands early in the transformation process suggests that oncogenic pathways disrupt the normal cellular homeostasis maintained by GC-C. Can these ligands be used as colorectal cancer diagnostic or prognostic markers?…”

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...supporting

confidence: 81%

“…PKGII-mediated signaling opposes pro-proliferative and pro-migratory phenotypes mediated by β-catenin/TCF ( 67 , 68 ). In turn, β-catenin/TCF signaling dampens the GC-C axis by silencing the transcription of its ligands, guanylin and uroguanylin ( 15 ). GC-C/cGMP has also been shown to inhibit protumorigenic Akt signaling via a PTEN-mediated mechanism ( 69 ).…”

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...mentioning

confidence: 99%

“…In contrast, uroguanylin is predominantly expressed in the small intestine ( 33 , 77 ). Because uroguanylin and guanylin expression is negatively regulated by Wnt signaling, they are mostly found on the surface epithelium facing the lumen, which has tapering Wnt expression, as opposed to GC-C, which is expressed along the crypt-to-surface axis ( 15 ). Most colorectal tumors are caused by adenomatous polyposis coli (APC) loss-of-function mutations or β-catenin gain-of-function mutations, both of which result in abnormal Wnt signaling activation ( 78 ).…”

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...mentioning

confidence: 99%

“…Notably, while genetic deletion of uroguanylin resulted in a significant decrease in guanylin expression, deletion of guanylin did not affect uroguanylin expression ( 52 , 53 ). Recent studies attempting to decipher the mechanism of silencing guanylins in the context of colorectal cancer may provide important clues into their regulation in physiological conditions ( 15 ). Intriguingly, in some studies, uroguanylin levels in the circulation increased significantly with high dietary salt intake, but the hormone levels in the gut remained unchanged ( 204 , 205 ).…”

Section: Learning Opportunities and Prospectsmentioning

confidence: 99%

“…These studies, along with the discovery of disease-causing mutations, helped elucidate how GC-C activation and deficiency contribute to human disease (6,(10)(11)(12). In the last five years, new and unexplored interactions between GC-C, mucosal homeostasis, the gut microbiome, and host immunity have emerged, along with a better mechanistic understanding of its role in colorectal cancer (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

2022

View full text Add to dashboard Cite

Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.

show abstract

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...supporting

confidence: 81%

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...mentioning

confidence: 99%

Section: Gc-c and Colorectal Cancer: Roles In Tumorigenesis And Clini...mentioning

confidence: 99%

Section: Learning Opportunities and Prospectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

2022

View full text Add to dashboard Cite

show abstract

cDNA Display Selection of Interacting Peptide Ligands of the Guanylate Cyclase C Receptor

Ochiai,

Takahashi,

Inokuchi

et al. 2024

Journal of Peptide Science

View full text Add to dashboard Cite

Guanylate cyclase C (GC‐C), a receptor expressed on the apical membrane of intestinal mucosal cells, is activated by heat‐stable enterotoxin (STa) produced by enterotoxigenic Escherichia coli, as well as the endogenous ligands guanylin and uroguanylin. In this study, novel peptides that interact with GC‐C were generated using the cDNA display method, and their binding affinity and biological activity were evaluated. While the linear peptide library did not yield peptides with sufficient affinity for GC‐C, three cyclic peptides (GCC‐P1, GCC‐P2, and GCC‐P3), each containing two cysteine residues within a 15‐residue sequence, were obtained from a cyclic peptide library containing nine‐residue random sequences. GC‐P2 exhibited significant binding affinity in Biacore assays, although the affinity was lower than those reported for known ligands. Notably, GCC‐P2 and GCC‐P3 demonstrated enhanced cGMP activity when used in combination with linaclotide. However, the agonist activity of these peptides was minimal, indicating that further modifications may be necessary to develop them for clinical applications. This study successfully extracted consensus sequences of peptide motifs that bind to GC‐C from a highly diverse nine‐residue random sequence library, which provides fundamental insights for the discovery and optimization of novel GC‐C ligands.

show abstract

Recent advances in CRISPR-Cas systems for colorectal cancer research and therapeutics

Khorshid Sokhangouy,

Alizadeh,

Lotfi

et al. 2024

Expert Review of Molecular Diagnostics

View full text Add to dashboard Cite

A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer

Cited by 9 publications

References 76 publications

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

cDNA Display Selection of Interacting Peptide Ligands of the Guanylate Cyclase C Receptor

Recent advances in CRISPR-Cas systems for colorectal cancer research and therapeutics

Contact Info

Product

Resources

About