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.
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.
