Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Llipsy Santiago; Marta Castro; Rebeca Sanz-Pamplona; Marcela Garzón; Ariel Ramirez-Labrada; Elena Tapia; Víctor Moreno; Elena Layunta; Gabriel Gil-Gómez; Marta Garrido; Raúl Peña; Pilar M Lanuza; Laura Comas; Paula Jaime-Sanchez; Iratxe Uranga-Murillo; Rosa Del Campo; Pablo Pelegrín; Eric Camerer; Luis Martínez-Lostao; Guillermo Muñoz; José A Uranga; Anabel Alcalde; Eva M Galvez; Angel Ferrandez; Phillip I Bird; Sunil Metkar; Maykel A Arias; Julian Pardo

doi:10.1016/j.celrep.2020.107847

Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Cell Rep. 2020 Jul 7;32(1):107847. doi: 10.1016/j.celrep.2020.107847.

Authors

Llipsy Santiago¹, Marta Castro², Rebeca Sanz-Pamplona³, Marcela Garzón¹, Ariel Ramirez-Labrada¹, Elena Tapia⁴, Víctor Moreno⁵, Elena Layunta⁶, Gabriel Gil-Gómez⁷, Marta Garrido⁷, Raúl Peña⁷, Pilar M Lanuza¹, Laura Comas⁸, Paula Jaime-Sanchez¹, Iratxe Uranga-Murillo¹, Rosa Del Campo⁹, Pablo Pelegrín¹⁰, Eric Camerer¹¹, Luis Martínez-Lostao¹², Guillermo Muñoz¹³, José A Uranga¹⁴, Anabel Alcalde⁶, Eva M Galvez⁸, Angel Ferrandez¹⁵, Phillip I Bird¹⁶, Sunil Metkar¹⁷, Maykel A Arias¹⁸, Julian Pardo¹⁹

Affiliations

¹ Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragon (CIBA), 50009 Zaragoza, Spain.
² Department of Pharmacology and Physiology, Faculty of Health and Sports Sciences, University of Zaragoza, 22002 Huesca, Spain.
³ Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
⁴ Animal Unit, University of Zaragoza, 50009 Zaragoza, Spain.
⁵ Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
⁶ Department of Pharmacology and Physiology, Faculty of Veterinary, University of Zaragoza, 50013 Zaragoza, Spain.
⁷ Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona.
⁸ Instituto de Carboquímica ICB-CSIC, 50018 Zaragoza, Spain.
⁹ Department of Microbiology, University Hospital Ramón y Cajal & Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
¹⁰ Unidad de Inflamación Molecular y Cirugía Experimental, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
¹¹ Université de Paris, Paris Cardiovascular Research Center, INSERM U970, 75015 Paris, France.
¹² Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragon (CIBA), 50009 Zaragoza, Spain; Department of Immunology, University Clinic Hospital Lozano Blesa, 50009, Zaragoza, Spain and Department of Pathology, University Clinic Hospital Lozano Blesa, University of Zaragoza, IIS Aragón, CIBEREHD, 50009 Zaragoza, Spain; Nanoscience Institute of Aragon (INA), University of Zaragoza, 50018 Zaragoza, Spain; Department Biochemistry and Molecular and Cell Biology and Department Microbiology, Preventive Medicine and Public Health, University of Zaragoza, 50009 Zaragoza, Spain.
¹³ Department of Immunology, University Clinic Hospital Lozano Blesa, 50009, Zaragoza, Spain and Department of Pathology, University Clinic Hospital Lozano Blesa, University of Zaragoza, IIS Aragón, CIBEREHD, 50009 Zaragoza, Spain.
¹⁴ Department of Basis Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain.
¹⁵ Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, University of Zaragoza, IIS Aragón, CIBEREHD, Zaragoza, Spain.
¹⁶ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University 3800 Melbourne, Australia.
¹⁷ XEME Biopharma Inc., Lombard, IL, USA.
¹⁸ Instituto de Carboquímica ICB-CSIC, 50018 Zaragoza, Spain. Electronic address: [email protected].
¹⁹ Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragon (CIBA), 50009 Zaragoza, Spain; Aragon I+D Foundation (ARAID), Zaragoza, Spain; Nanoscience Institute of Aragon (INA), University of Zaragoza, 50018 Zaragoza, Spain; Department Biochemistry and Molecular and Cell Biology and Department Microbiology, Preventive Medicine and Public Health, University of Zaragoza, 50009 Zaragoza, Spain; CIBER-BBN, Madrid, Spain. Electronic address: [email protected].

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

Abstract

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.

Keywords: IL6; STAT3; colorectal cancer; extracellular; granzyme; gut; inflammation; macrophage.

Publication types

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

MeSH terms

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

Substances

Cytokines
Inflammasomes
Inflammation Mediators
Interleukin-6
NF-kappa B
RNA, Messenger
Dextran Sulfate
Cyclooxygenase 2
GZMB protein, human
Granzymes
granzyme A, mouse
GZMA protein, human
Azoxymethane