95923 20231108202259.0 doi 10.1016/j.celrep.2020.107847 sideral 118092 ART-2020-118092 eng Santiago, L. Universidad de Zaragoza (orcid)0000-0002-1861-5981 Extracellular granzyme A promotes colorectal cancer development by enhancing gut inflammation 2020 Access copy available to the general public Unrestricted 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. info:eu-repo/grantAgreement/ES/DGA/B29 info:eu-repo/grantAgreement/ES/MINECO/SAF2014-54763-C2-1 info:eu-repo/grantAgreement/ES/MINECO/SAF2017-83120-C2-1-R info:eu-repo/grantAgreement/ES/ISCIII/PI13-00864 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 9.423 2020 CELL BIOLOGY 33 / 195 = 0.169 2020 Q1 T1 6.264 2020 Biochemistry, Genetics and Molecular Biology (miscellaneous) 2020 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Castro, Marta Universidad de Zaragoza (orcid)0000-0001-8584-3979 Sanz-Pamplona, Rebeca Garzón, Marcela Universidad de Zaragoza (orcid)0000-0001-6778-0636 Ramírez-Labrada A. (orcid)0000-0002-3888-7036 Tapia E. Universidad de Zaragoza Moreno V. Layunta, E. Universidad de Zaragoza (orcid)0000-0001-5573-6144 Gil-Gómez, G. Garrido, M. Peña R. Lanuza, P.M. (orcid)0000-0001-7328-2094 Comas L. Universidad de Zaragoza Jaime-Sánchez, P. (orcid)0000-0002-8731-4269 Uranga-Murillo, I. del Campo, R. Pelegrín, P. Camerer, E. Martínez-Lostao, L. Universidad de Zaragoza (orcid)0000-0003-3043-147X Muñoz, G. Universidad de Zaragoza (orcid)0000-0001-8567-4327 Uranga, J.A. Alcalde, A. Galvez, E.M. (orcid)0000-0001-6928-5516 Ferrández, A. Universidad de Zaragoza (orcid)0000-0003-2280-9372 Bird, P.I. Metkar, S. Arias, M.A. (orcid)0000-0002-9730-2210 Pardo, J. Universidad de Zaragoza (orcid)0000-0003-0154-0730 1012 410 Universidad de Zaragoza Dpto. Farmac.Fisiol.y Med.L.F. Área Fisiología 1011 566 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Inmunología 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina 0 X Universidad de Zaragoza Serv.Gral. Apoyo Investigación Servicios. División Biomédica 1013 020 Universidad de Zaragoza Dpto. Cirugía Área Anatomía Patológica 32, 1 (2020), 107847 [23 pp.] Cell Reports Cell Reports 2211-1247 5247116 http://zaguan.unizar.es/record/95923/files/texto_completo.pdf Versión publicada 159974 http://zaguan.unizar.es/record/95923/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:95923 articulos driver 2023-11-08-20:13:55 ARTICLE