Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation.

Acute Disease Animals Azoxymethane Carcinogenesis / genetics Chronic Disease Colon / pathology Colorectal Neoplasms / enzymology Cyclooxygenase 2 / metabolism Cytokines / metabolism Dextran Sulfate Disease Progression Extracellular Space / enzymology Granzymes / antagonists & inhibitors Humans Inflammasomes / metabolism Inflammation / pathology Inflammation Mediators / metabolism Interleukin-6 / biosynthesis Mice, Knockout NF-kappa B / metabolism RNA, Messenger / genetics

IL6 STAT3 colorectal cancer extracellular granzyme gut inflammation macrophage

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
07 07 2020

Historique:

received: 14 10 2019

revised: 11 02 2020

accepted: 11 06 2020

entrez: 9 7 2020

pubmed: 9 7 2020

medline: 29 4 2021

Statut: ppublish

Résumé

If not properly regulated, the inflammatory immune response can promote carcinogenesis, as evident in colorectal cancer (CRC). Aiming to gain mechanistic insight into the link between inflammation and CRC, we perform transcriptomics analysis of human CRC, identifying a strong correlation between expression of the serine protease granzyme A (GzmA) and inflammation. In a dextran sodium sulfate and azoxymethane (DSS/AOM) mouse model, deficiency and pharmacological inhibition of extracellular GzmA both attenuate gut inflammation and prevent CRC development, including the initial steps of cell transformation and epithelial-to-mesenchymal transition. Mechanistically, extracellular GzmA induces NF-κB-dependent IL-6 production in macrophages, which in turn promotes STAT3 activation in cultured CRC cells. Accordingly, colon tissues from DSS/AOM-treated, GzmA-deficient animals present reduced levels of pSTAT3. By identifying GzmA as a proinflammatory protease that promotes CRC development, these findings provide information on mechanisms that link immune cell infiltration to cancer progression and present GzmA as a therapeutic target for CRC.

Identifiants

DOI: 10.1016/j.celrep.2020.107847 PMID: 32640217

pubmed: 32640217

pii: S2211-1247(20)30828-7

doi: 10.1016/j.celrep.2020.107847

pii:

doi:

Substances chimiques

Cytokines 0

Inflammasomes 0

Inflammation Mediators 0

Interleukin-6 0

NF-kappa B 0

RNA, Messenger 0

Dextran Sulfate 9042-14-2

Cyclooxygenase 2 EC 1.14.99.1

GZMB protein, human EC 3.4.21.-

Granzymes EC 3.4.21.-

granzyme A, mouse EC 3.4.21.-

GZMA protein, human EC 3.4.21.78

Azoxymethane MO0N1J0SEN

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

107847

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.