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Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation. 2020
Llipsy Santiago, and
Marta Castro, and
Rebeca Sanz-Pamplona, and
Marcela Garzón, and
Ariel Ramirez-Labrada, and
Elena Tapia, and
Víctor Moreno, and
Elena Layunta, and
Gabriel Gil-Gómez, and
Marta Garrido, and
Raúl Peña, and
Pilar M Lanuza, and
Laura Comas, and
Paula Jaime-Sanchez, and
Iratxe Uranga-Murillo, and
Rosa Del Campo, and
Pablo Pelegrín, and
Eric Camerer, and
Luis Martínez-Lostao, and
Guillermo Muñoz, and
José A Uranga, and
Anabel Alcalde, and
Eva M Galvez, and
Angel Ferrandez, and
Phillip I Bird, and
Sunil Metkar, and
Maykel A Arias, and
Julian Pardo
Fundación Instituto de Investigación Sanitaria Aragón (IIS Aragón), Biomedical Research Centre of Aragon (CIBA), 50009 Zaragoza, Spain.
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.
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