TY - JOUR
T1 - Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation
AU - Santiago, Llipsy
AU - Castro, Marta
AU - Sanz-Pamplona, Rebeca
AU - Garzón, Marcela
AU - Ramirez-Labrada, Ariel
AU - Tapia, Elena
AU - Moreno, Víctor
AU - Layunta, Elena
AU - Gil-Gómez, Gabriel
AU - Garrido, Marta
AU - Peña, Raúl
AU - Lanuza, Pilar M.
AU - Comas, Laura
AU - Jaime-Sanchez, Paula
AU - Uranga-Murillo, Iratxe
AU - del Campo, Rosa
AU - Pelegrín, Pablo
AU - Camerer, Eric
AU - Martínez-Lostao, Luis
AU - Muñoz, Guillermo
AU - Uranga, José A.
AU - Alcalde, Anabel
AU - Galvez, Eva M.
AU - Ferrandez, Angel
AU - Bird, Phillip I.
AU - Metkar, Sunil
AU - Arias, Maykel A.
AU - Pardo, Julian
PY - 2020/7/7
Y1 - 2020/7/7
N2 - 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. Santiago et al. show that extracellular granzyme A (GzmA) contributes to gut inflammation and colorectal cancer (CRC) development by promoting IL-6 production in macrophages. Therapeutic inhibition of GzmA attenuates inflammation and CRC development, suggesting that GzmA could be useful to treat gut inflammation and prevent CRC.
AB - 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. Santiago et al. show that extracellular granzyme A (GzmA) contributes to gut inflammation and colorectal cancer (CRC) development by promoting IL-6 production in macrophages. Therapeutic inhibition of GzmA attenuates inflammation and CRC development, suggesting that GzmA could be useful to treat gut inflammation and prevent CRC.
KW - colorectal cancer
KW - extracellular
KW - granzyme
KW - gut
KW - IL6
KW - inflammation
KW - macrophage
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85087384727&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.107847
DO - 10.1016/j.celrep.2020.107847
M3 - Article
C2 - 32640217
AN - SCOPUS:85087384727
SN - 2211-1247
VL - 32
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 107847
ER -