Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation - Université Paris Cité Access content directly
Journal Articles Cell Reports Year : 2020

Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Llipsy Santiago
  • Function : Author
Marta Castro
  • Function : Author
Rebeca Sanz-Pamplona
  • Function : Author
Marcela Garzón
  • Function : Author
Ariel Ramirez-Labrada
  • Function : Author
Elena Tapia
  • Function : Author
Víctor Moreno
  • Function : Author
Elena Layunta
  • Function : Author
Gabriel Gil-Gómez
  • Function : Author
Marta Garrido
  • Function : Author
Raúl Peña
  • Function : Author
Pilar Lanuza
  • Function : Author
Laura Comas
  • Function : Author
Paula Jaime-Sanchez
  • Function : Author
Iratxe Uranga-Murillo
  • Function : Author
Rosa del Campo
  • Function : Author
Pablo Pelegrín
  • Function : Author
Eric Camerer
Luis Martínez-Lostao
  • Function : Author
Guillermo Muñoz
  • Function : Author
José Uranga
  • Function : Author
Anabel Alcalde
  • Function : Author
Eva Galvez
  • Function : Author
Angel Ferrandez
  • Function : Author
Phillip Bird
  • Function : Author
Sunil Metkar
  • Function : Author
Maykel Arias
  • Function : Author
Julian Pardo
  • Function : Author

Abstract

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.

Domains

Cancer

Dates and versions

hal-03906241 , version 1 (19-12-2022)

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Cite

Llipsy Santiago, Marta Castro, Rebeca Sanz-Pamplona, Marcela Garzón, Ariel Ramirez-Labrada, et al.. Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation. Cell Reports, 2020, 32 (1), pp.107847. ⟨10.1016/j.celrep.2020.107847⟩. ⟨hal-03906241⟩

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