Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Llipsy Santiago,Elena Layunta,Iratxe Uranga-Murillo,Marta Castro,Marcela Garzón,Marta Garrido,Raúl Peña,Pilar M Lanuza,Elena Tapia,Eric Camerer,Anabel Alcalde,Luis Martínez-Lostao,Rosa Del Campo,Guillermo Muñoz,Laura Comas,Phillip I Bird,Eva M Gálvez ,José Antonio Uranga ,Gabriel Gil‐Gómez ,Ángel Ferrández ,Paula Jaime-Sánchez ,Rebeca Sanz‐Pamplona ,Sunil S Metkar ,Maykel Arias ,Ariel Ramírez-Labrada ,Vı́ctor Moreno ,Pablo Pelegrı́n ,Julián Pardo

doi:10.1016/j.celrep.2020.107847

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.

Highlights

Colorectal cancer (CRC) is the second-leading cause of cancer cell death in developed countries and the third-most common cancer
Inflammation and gut permeability in steady-state conditions were unaffected by granzyme A (GzmA) deficiency, confirming that reduction of inflammatory response and CRC is not related to intestinal phenotypic changes in the absence of GzmA. It correlated with the ability of extracellular GzmA to induce macrophage interleukin (IL) 6 production. These results show that GzmA, acting in the extracellular environment, regulates the inflammatory response in the gut and is a key mediator in the development of inflammatory CRC, identifying a new molecular mechanism involved in inflammation-induced CRC and validating it as a potential new therapeutic target
A Positive Correlation between GZMA, but Not GZMB, and Inflammation in Human CRC Samples An analysis of mRNA expression was performed in 98 CRC tumor samples from stage 2 patients undergoing surgery (Sanz-Pamplona et al, 2014)

Summary

Introduction

Colorectal cancer (CRC) is the second-leading cause of cancer cell death in developed countries and the third-most common cancer. Reactive oxygen species (ROS); lipid mediators produced by cyclooxygenase activity, such as prostaglandin E2 (PGE2); and several proinflammatory cytokines are involved in CRC development (Lasry et al, 2016; Shalapour and Karin, 2015) All these molecules contribute to epithelial cell transformation and tumor progression through the activation of genetic and signaling pathways, including nuclear factor kB (NF-kB), pSTAT3 (phospho-Signal transducer and activator of transcription 3), Wnt, b-catenin, or K-ras (Kaler et al, 2009; Karin, 1998; Li and Laterra, 2012; Shalapour and Karin, 2015; Shenoy et al, 2012; Yu et al, 2009). Pharmacological regulation of inflammation to prevent and/or improve CRC treatment is nonspecific and associated with serious side effects related to infection and (paradoxically) tumor progression (Yang et al, 2017)

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