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Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation Santiago, Llipsy Castro, Marta Sanz Pamplona, Rebeca Garzón, Marcela Ramirez-Labrada, Ariel Tapia, Elena Moreno Aguado, Víctor Layunta, Elena Gil Gómez, Gabriel Garrido, Marta Peña, Raúl Lanuza, Pilar M. Comas, Laura Jaime Sánchez, Paula Uranga Murillo, Iratxe Campo, Rosa del Pelegrin, Pablo Camerer, Eric Martínez Lostao, Luis Muñoz, Guillermo Uranga, José A. Alcalde, Anabel Galvez, Eva M. Ferrandez, Angel Bird, Phillip I. Metkar, Sunil Arias, Maykel A. Pardo, Julián Càncer colorectal Carcinogènesi Colorectal cancer Carcinogenesis 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-kappa B-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. 2021-01-28T12:57:16Z 2021-01-28T12:57:16Z 2020-07-07 2021-01-25T08:11:03Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1016/j.celrep.2020.107847 Cell Reports, 2020, vol. 32, num.1 https://doi.org/10.1016/j.celrep.2020.107847 cc by (c) Santiago et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Cell Press Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))