Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism
| Autor: | Liang Yu, Adele Preaudet, Hazel Tye, Virginie Deswaerte, Masanobu Oshima, Hiroko Oshima, Jesse J. Balic, Alison C. West, Alison F. Browning, Matthias Ernst, Brendan J. Jenkins, Thaleia Livis, Saleela Ruwanpura, Paul M Nguyen, Meri Najdovska, Ka Yee Fung, Charlotte Girard, Tracy L Putoczki, Cem Gabay |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Inflammasomes medicine.medical_treatment Inflammation Apoptosis medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Immune system Stomach Neoplasms Biomarkers Tumor Cytokine Receptor gp130 Tumor Cells Cultured Medicine Animals Humans Cell Proliferation ddc:616 Mice Knockout business.industry Interleukin-18 Cancer Inflammasome medicine.disease Prognosis Immunity Innate CARD Signaling Adaptor Proteins Mice Inbred C57BL 030104 developmental biology Cytokine Cell Transformation Neoplastic Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research medicine.symptom Signal transduction Inflammation Mediators business Carcinogenesis medicine.drug Follow-Up Studies Signal Transduction |
| Zdroj: | Cancer Research, Vol. 78, No 5 (2018) pp. 1293-1307 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1β, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer. Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293–307. ©2017 AACR. |
| Databáze: | OpenAIRE |
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