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 N. 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

Ketan K. Thanki, Paul Johnson, Edward J. Higgins, Manjit Maskey, Ches'Nique N. 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

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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.

Original language	English (US)
Article number	102417
Journal	Redox Biology
Volume	55
DOIs	https://doi.org/10.1016/j.redox.2022.102417
State	Published - Sep 2022

Keywords

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

ASJC Scopus subject areas

Organic Chemistry

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10.1016/j.redox.2022.102417

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Thanki, K. K., Johnson, P., Higgins, E. J., Maskey, M., Phillips, CN. N., Dash, S., Almenas, F. A., Govar, A. A., Tian, B., Villéger, R., Beswick, E., Wang, R., Szabo, C., Chao, C., Pinchuk, I. V., Hellmich, M. R., & Módis, K. (2022). Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis. Redox Biology, 55, Article 102417. https://doi.org/10.1016/j.redox.2022.102417

Thanki, KK, Johnson, P, Higgins, EJ, Maskey, M, Phillips, CNN, Dash, S, Almenas, FA, Govar, AA, Tian, B, Villéger, R, Beswick, E, Wang, R, Szabo, C, Chao, C, Pinchuk, IV, Hellmich, MR & Módis, K 2022, 'Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis', Redox Biology, vol. 55, 102417. https://doi.org/10.1016/j.redox.2022.102417

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title = "Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis",

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",

author = "Thanki, {Ketan K.} and Paul Johnson and Higgins, {Edward J.} and Manjit Maskey and Phillips, {Ches'Nique N.} and Swetaleena Dash and Almenas, {Francisco Arroyo} and Govar, {Armita Abdollahi} and Bing Tian and Romain Vill{\'e}ger and Ellen Beswick and Rui Wang and Csaba Szabo and Celia Chao and Pinchuk, {Irina V.} and Hellmich, {Mark R.} and Katalin M{\'o}dis",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = sep,

doi = "10.1016/j.redox.2022.102417",

language = "English (US)",

volume = "55",

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T1 - Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis

AU - Thanki, Ketan K.

AU - Johnson, Paul

AU - Higgins, Edward J.

AU - Maskey, Manjit

AU - Phillips, Ches'Nique N.

AU - Dash, Swetaleena

AU - Almenas, Francisco Arroyo

AU - Govar, Armita Abdollahi

AU - Tian, Bing

AU - Villéger, Romain

AU - Beswick, Ellen

AU - Wang, Rui

AU - Szabo, Csaba

AU - Chao, Celia

AU - Pinchuk, Irina V.

AU - Hellmich, Mark R.

AU - Módis, Katalin

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Bone marrow

KW - Colorectal cancer

KW - Hydrogen sulfide

KW - Inflammatory bowel disease

KW - Transsulfuration pathway

KW - Ulcerative colitis

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

Abstract

Keywords

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