Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia.

Authors

Babar Bashir, Thomas Jefferson UniversityFollow
Dante J. Merlino, Thomas Jefferson UniversityFollow
Jeff A. Rappaport, Thomas Jefferson UniversityFollow
Esteban Gnass, Thomas Jefferson UniversityFollow
Juan P. Palazzo, Thomas Jefferson UniversityFollow
Ying Feng, The University Of Michigan
Eric R R. Fearon, The University Of Michigan
Adam E. Snook, Thomas Jefferson UniversityFollow
Scott A. Waldman, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-1-2019

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Human Pathology, Volume 87, May 2019, Pages 103-114.

The published version is available at https://doi.org/10.1016/j.humpath.2018.11.032. Copyright © Elsevier

Abstract

Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor-suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined the potential role of the GUCA2A-GUCY2C axis and its suitability as a target in tumors arising through the SA and MSI pathways. GUCA2A hormone expression was eliminated in TAs, SAs, and MSI tumors compared to their corresponding normal adjacent tissues. In contrast to the hormone, the tumor-suppressing receptor GUCY2C was retained in TA and MSI tumors. Surprisingly, GUCY2C expression was nearly eliminated in SAs, reflecting loss of the transcription factor CDX2. Changes in the GUCA2A-GUCY2C axis in human SAs and MSI tumors were precisely recapitulated in genetic mouse models. These data reveal the possibility of GUCA2A loss silencing GUCY2C in the pathophysiology of, and oral hormone replacement to restore GUCY2C signaling to prevent, MSI tumors. Also, they highlight the potential for targeting GUCY2C to prevent and treat metastases arising from TA and MSI tumors. In contrast, loss of GUCY2C excludes patients with SAs as candidates for GUCY2C-based prevention and therapy.

Recommended Citation

Bashir, Babar; Merlino, Dante J.; Rappaport, Jeff A.; Gnass, Esteban; Palazzo, Juan P.; Feng, Ying; Fearon, Eric R R.; Snook, Adam E.; and Waldman, Scott A., "Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia." (2019). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 106.
https://jdc.jefferson.edu/petfp/106

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

30716341

Language

English