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Título

Extracellular granzyme A promotes colorectal cancer development by enhancing gut inflammation

AutorSantiago, Llipsy CSIC ORCID; Castro, Marta; Sanz-Pamplona, Rebeca; Garzón, Marcela; Ramírez-Labrada, Ariel; Tapia, Elena; Moreno, Víctor; Layunta, Elena; Gil-Gómez, Gabriel; Garrido, Marta; Peña, Raúl; Lanuza, Pilar M. CSIC ORCID; Comas, Laura CSIC ORCID; Jaime Sánchez, Paula; Uranga Murillo, Iratxe; Campo, Rosa del; Pelegrín, Pablo; Camerer, Eric; Martínez-Lostao, Luis CSIC ORCID CVN; Muñoz, Guillermo; Uranga, José A.; Alcalde, Anabel; Gálvez Buerba, Eva Mª CSIC ORCID ; Ferrández, Ángel; Bird, Phillip I.; Metkar, Sunil; Arias, Maykel CSIC ORCID; Pardo, Julián
Palabras claveGranzyme
Extracellular
Gut
Colorectal cancer
Inflammation
STAT3
IL6
Macrophage
Fecha de publicación7-jul-2020
EditorCell Press
Elsevier BV
CitaciónCell Reports 32(1): 107847 (2020)
ResumenIf 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.
Descripción8 figures, 1 table.-- Electronic supplementary information available
Versión del editorhttp://dx.doi.org/10.1016/j.celrep.2020.107847
URIhttp://hdl.handle.net/10261/217477
DOI10.1016/j.celrep.2020.107847
ISSN2211-1247
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