Elsevier

Redox Biology

Volume 55, September 2022, 102417
Redox Biology

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

https://doi.org/10.1016/j.redox.2022.102417Get rights and content
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Highlights

  • CSE is reduced in colonic biopsies from patients with ulcerative colitis.

  • CSE regulates mucosal inflammation.

  • CSE stimulates colon epithelial cell migration, proliferation, and transepithelial permeability.

  • CSE modulates mucosal cytokine expression.

  • Loss of CSE in bone marrow-derived cells accelerates the development of colitis-associated cancer.

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.

Graphical abstract

Downregulation of CSE expression and/or activity promotes excessive inflammation in the gut resulting in the development of CAC. A schematic model of colon epithelial cell function under conditions of (a) increased and (b) decreased CSE activity. (a) In physiological conditions, intact CSE function is critical in limiting mucosal inflammation and stimulating the permeability, cellular mobility, and proliferation of the colon epithelial layer in response to injury. (b) Loss or inhibition of CSE impairs transepithelial permeability, cell migration, and proliferation, accelerating both the development and progression of CAC. An altered cytokine profile of the pro-and anti-inflammatory mediators in colon mucosa has been suggested to play a critical role in the development of CAC. Several of these alterations, including reduced IL-10 and increased IL-6 expression levels may be initiated by the lack of CSE activity in BM-derived cells.

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Keywords

Inflammatory bowel disease
Colorectal cancer
Hydrogen sulfide
Transsulfuration pathway
Ulcerative colitis
Bone marrow

Cited by (0)

1

These authors contributed equally to this work.

2

Laboratoire Ecologie & Biologie des Interactions, UMR CNRS 7267 Université de Poitiers, 86,000 Poitiers, France.

3

Mechanisms of Carcinogenesis Program, Division of Gastroenterology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.