Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis
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 ho...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722001896 |
| _version_ | 1818084628905328640 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ketan K. Thanki |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T19:56:55Z |
| format | Article |
| id | doaj.art-cddf13ab321245b493b61123dbfb744c |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T19:56:55Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-cddf13ab321245b493b61123dbfb744c2022-12-22T01:35:37ZengElsevierRedox Biology2213-23172022-09-0155102417Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesisKetan K. Thanki0Paul Johnson1Edward J. Higgins2Manjit Maskey3Ches’Nique Phillips4Swetaleena Dash5Francisco Arroyo Almenas6Armita Abdollahi Govar7Bing Tian8Romain Villéger9Ellen Beswick10Rui Wang11Csaba Szabo12Celia Chao13Irina V. Pinchuk14Mark R. Hellmich15Katalin Módis16Department of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Internal Medicine, University of Texas Medical, Galveston, TX, USADepartment of Internal Medicine, University of Texas Medical, Galveston, TX, USADepartment of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USADepartment of Biology, York University, Toronto, ON, CanadaChair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandDepartment of Surgery, University of Texas Medical Branch, Galveston, TX, USADepartment of Internal Medicine, University of Texas Medical, Galveston, TX, USADepartment 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.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.http://www.sciencedirect.com/science/article/pii/S2213231722001896Inflammatory bowel diseaseColorectal cancerHydrogen sulfideTranssulfuration pathwayUlcerative colitisBone marrow |
| spellingShingle | 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 Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis Redox Biology Inflammatory bowel disease Colorectal cancer Hydrogen sulfide Transsulfuration pathway Ulcerative colitis Bone marrow |
| title | Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis |
| title_full | Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis |
| title_fullStr | Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis |
| title_full_unstemmed | Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis |
| title_short | Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis |
| title_sort | deletion of cystathionine γ lyase in bone marrow derived cells promotes colitis associated carcinogenesis |
| topic | Inflammatory bowel disease Colorectal cancer Hydrogen sulfide Transsulfuration pathway Ulcerative colitis Bone marrow |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722001896 |
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