Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis

Ketan K. Thanki; Paul Johnson; Edward J. Higgins; Manjit Maskey; Ches’Nique Phillips; Swetaleena Dash; Francisco Arroyo Almenas; Armita Abdollahi Govar; Bing Tian; Romain Villéger; Ellen Beswick; Rui Wang; Csaba Szabo; Celia Chao; Irina V. Pinchuk; Mark R. Hellmich; Katalin Módis

Redox Biology (Sep 2022)

Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis

Ketan K. Thanki,
Paul Johnson,
Edward J. Higgins,
Manjit Maskey,
Ches’Nique Phillips,
Swetaleena Dash,
Francisco Arroyo Almenas,
Armita Abdollahi Govar,
Bing Tian,
Romain Villéger,
Ellen Beswick,
Rui Wang,
Csaba Szabo,
Celia Chao,
Irina V. Pinchuk,
Mark R. Hellmich,
Katalin Módis

Affiliations

Ketan K. Thanki: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Paul Johnson: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Edward J. Higgins: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Manjit Maskey: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Ches’Nique Phillips: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Swetaleena Dash: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Francisco Arroyo Almenas: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Armita Abdollahi Govar: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Bing Tian: Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA
Romain Villéger: Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA
Ellen Beswick: Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
Rui Wang: Department of Biology, York University, Toronto, ON, Canada
Csaba Szabo: Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland
Celia Chao: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
Irina V. Pinchuk: Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA
Mark R. Hellmich: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA; Corresponding author. The University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX, 77555, USA.
Katalin Módis: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA; Corresponding author. The University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX, 77555, USA.

Journal volume & issue: Vol. 55
p. 102417

Abstract

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Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development.In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice.These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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