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

doi:10.1016/j.redox.2022.102417

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

Redox Biol. 2022 Sep:55:102417. doi: 10.1016/j.redox.2022.102417. Epub 2022 Jul 21.

Authors

Ketan K Thanki¹, Paul Johnson², Edward J Higgins³, Manjit Maskey⁴, Ches'Nique Phillips⁵, Swetaleena Dash⁶, Francisco Arroyo Almenas⁷, Armita Abdollahi Govar⁸, Bing Tian⁹, Romain Villéger¹⁰, Ellen Beswick¹¹, Rui Wang¹², Csaba Szabo¹³, Celia Chao¹⁴, Irina V Pinchuk¹⁵, Mark R Hellmich¹⁶, Katalin Módis¹⁷

Affiliations

¹ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: kkthanki@gmail.com.
² Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: pjohnson08.2012@gmail.com.
³ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: Edward.higgins1@gmail.com.
⁴ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: mamaskey@utmb.edu.
⁵ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: cphi11@lsuhsc.edu.
⁶ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: swetaleena.dash@outlook.com.
⁷ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: farroyo10@yahoo.com.
⁸ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: armita.lsu@gmail.com.
⁹ Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA. Electronic address: bitian@utmb.edu.
¹⁰ Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA. Electronic address: romain.villeger@univ-poitiers.fr.
¹¹ Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address: ellen.beswick@hsc.utah.edu.
¹² Department of Biology, York University, Toronto, ON, Canada. Electronic address: ruiwang@yorku.ca.
¹³ Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland. Electronic address: csaba.szabo@unifr.ch.
¹⁴ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: cchao986@gmail.com.
¹⁵ Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA. Electronic address: ipinchuk@pennstatehealth.psu.edu.
¹⁶ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: mhellmic@utmb.edu.
¹⁷ Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: kamodis@utmb.edu.

Abstract

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.

Keywords: Bone marrow; Colorectal cancer; Hydrogen sulfide; Inflammatory bowel disease; Transsulfuration pathway; Ulcerative colitis.

Published by Elsevier B.V.

Abstract

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