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Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism

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Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism Published OnlineFirst December 27, 2017; DOI: 10.1158/0008-5472.CAN-17-1887 Cancer Tumor Biology and Immunology Research Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18- Mediated Inflammation-Independent Mechanism Virginie Deswaerte1,2, Paul Nguyen3,4, Alison West1,2, Alison F. Browning1,2, Liang Yu1,2, Saleela M. Ruwanpura1,2, Jesse Balic1,2, Thaleia Livis1,2, Charlotte Girard5,6, Adele Preaudet3,4, Hiroko Oshima7, Ka Yee Fung3,4, Hazel Tye1,2, Meri Najdovska1,2, Matthias Ernst8, Masanobu Oshima7, Cem Gabay5,6, Tracy Putoczki3,4,and Brendan J. Jenkins1,2 Abstract Inflammasomes are key regulators of innate immunity in for IL18 was associated with high IL18 gene expression in the chronic inflammatory disorders and autoimmune diseases, but gastric tumor epithelium compared with IL1b, which was pref- their role in inflammation-associated tumorigenesis remains ill- erentially expressed in immune cells. Supporting an epithelial- defined. Here we reveal a protumorigenic role in gastric cancer for specific role for IL18, we found it to be highly secreted from the key inflammasome adaptor apoptosis-related speck-like pro- human gastric cancer cell lines. Moreover, IL18 blockade either tein containing a CARD (ASC) and its effector cytokine IL18. by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven Genetic ablation of ASC in the gp130F/F spontaneous mouse deletion of ASC augmented apoptosis in human gastric cancer model of intestinal-type gastric cancer suppressed tumorigenesis cells. In clinical specimens of human gastric cancer tumors, we by augmenting caspase-8-like apoptosis in the gastric epithelium, observed a significant positive correlation between elevated independently from effects on myeloid cells and mucosal inflam- mature IL18 protein and ASC mRNA levels. Collectively, our mation. This phenotype was characterized by reduced activation findings reveal the ASC/IL18 signaling axis as a candidate ther- of caspase-1 and NF-kB activation and reduced expression of apeutic target in gastric cancer. mature IL18, but not IL1b, in gastric tumors. Genetic ablation of Significance: Inflammasome activation that elevates IL18 IL18 in the same model also suppressed gastric tumorigenesis, helps drive gastric cancer by protecting cancer cells against apo- whereas blockade of IL1b and IL1a activity upon genetic ablation ptosis, with potential implications for new therapeutic strategies of the IL1 receptor had no effect. The specific protumorigenic role in this setting. Cancer Res; 78(5); 1293–307. Ó2017 AACR. Introduction logic subtype of gastric cancer is intestinal-type, and despite the causal correlation between chronic gastric inflammation triggered Gastric cancer is the third most lethal cancer worldwide, and is by pathogenic microbes (i.e., Helicobacter pylori) and intestinal- among a growing number of cancers associated with precursory type gastric cancer (2, 4), the identity of innate immune regulators chronic inflammatory responses (1–3). The predominant histo- within the host gastric mucosa that promote gastric cancer remains unclear. Consistent with an altered host immune response predisposing to gastric cancer, gene polymorphisms for 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical the proinflammatory cytokine IL1b, which are associated with Research, Clayton, Victoria, Australia. 2Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, augmented gene expression, increase the risk of human gastric b Australia. 3Inflammation Division, Walter and Eliza Hall Institute of Medical cancer (5, 6), and transgenic overexpression of IL1 in mice Research, Parkville, Victoria, Australia. 4Department of Medical Biology, Uni- triggers gastric inflammation and tumors (7). In addition, clinical versity of Melbourne, Parkville, Victoria, Australia. 5Division of Rheumatology, studies on the related IL1 cytokine family member IL18, which 6 University Hospital of Geneva, Geneva, Switzerland. Department of Pathology can display opposing anti- or protumorigenic effects dependent and Immunology, University of Geneva School of Medicine, Geneva, Switzerland. upon the tissue and cellular context in various cancers (8), 7Division of Genetics, Cancer Research Institute, Kanazawa University, Kana- zawa, Japan. 8Olivia Newton-John Cancer Research Institute, La Trobe Univer- demonstrate that IL18 levels are increased in gastric cancer – sity School of Cancer Medicine, Heidelberg, Victoria, Australia. patients and serve as a poor prognostic marker (9 11). Although experimental data from human gastric cancer cell lines also Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). suggest that IL18 may contribute to the malignant progression of tumors (9, 12, 13), a definitive role for IL18 in gastric cancer V. Deswaerte and P. Nguyen contributed equally to this article. remains unproven. Corresponding Author: Brendan J. Jenkins, Hudson Institute of Medical Inflammasomes have recently been identified as multi- Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia. Phone: 613- protein complexes that are essential for the production of 8572-2740; E-mail: [email protected] mature and bioactive IL1b and IL18 proteins. Accordingly, they doi: 10.1158/0008-5472.CAN-17-1887 have attracted much attention as key factors of the immune Ó2017 American Association for Cancer Research. system with the potential to influence susceptibility to many www.aacrjournals.org 1293 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 27, 2017; DOI: 10.1158/0008-5472.CAN-17-1887 Deswaerte et al. autoimmune and inflammatory diseases, as well as cancers, Human biopsies where IL1b and IL18 are implicated (14–17). These cytokines Gastric biopsies were collected at the Xin Hua Hospital (Shang- are initially produced as inactive proIL1b and proIL18 forms, hai, China) from patients, upon formal written informed consent, with proIL1b expression upregulated following ligand-mediat- undergoing upper gastrointestinal endoscopy or surgical resec- ed activation of pattern recognition receptors (PRR) such as tion. Clinicopathologic features and demographics of gastric Toll-like receptor (TLR) or nucleotide-binding oligomerization cancer patient cohorts are described in Supplementary Table domain-containing (NOD) family members, whereas proIL18 S1. Biopsies were snap-frozen in liquid nitrogen. Studies were is constitutively expressed. Subsequently, their inflammasome- approved by the Xin Hua Hospital Human Research Ethics mediated secretion as bioactive cytokines is controlled by Committee and undertaken in accordance with the appropriate members of the nucleotide-binding domain and leucine-rich ethics guidelines. Patient studies were conducted in accordance repeat containing protein (NLR) family, namely NLR pyrin with the World Medical Association Declaration of Helsinki domaincontaining1(NLRP1),NLRP3,NLRP6,NLRP12,NLR statement on the ethical principles for medical research involving CARD domain containing 4 (NLRC4) and NLR apoptosis human subjects. inhibitory protein (NAIP), as well as the cytosolic DNA sensor absent in melanoma 2 (AIM2; refs. 15, 18). Specifically, each of Laser microdissection F/F these NLRs and AIM2 form the core of distinct inflammasome Tumor epithelial and stroma samples from gp130 mice were complexes, whereby upon sensing host- and/or microbial- collected from OCT-embedded frozen sections stained with tolu- derived ligands, they associate with the key adaptor protein idine blue using laser microdissection (Leica). Total RNA was apoptosis-related speck-like protein containing a CARD (ASC) extracted from microdissected samples using the miRNeasy to facilitate activation of caspase-1, which catalyzes the matu- microkit (Qiagen), and then reverse transcribed with the Prime- ration of proIL1b and proIL18 precursors into bioactive secret- Script RT Reagent Kit (Takara). Quantitative RT-PCR (qPCR) was ed cytokines (15). performed as described later. Although ASC is critical for inflammasome-mediated patho- logies involving IL1b and/or IL18, investigations into the RNA isolation and gene expression analyses definitive role of ASC in tumorigenesis are still in their infancy Total RNA was isolated from snap-frozen mouse and human and have been largely restricted to intestinal and skin carcino- stomach tissues using TRI Reagent Solution (Sigma) followed by genesis, with contrasting findings (19). Here, we reveal that on-column RNeasy Mini Kit RNA clean-up and DNase treatment elevated PYCARD (hereafter referred to as ASC)mRNAand (Qiagen). qPCR was performed on cDNA with Taqman Gene mature IL18, but not IL1b, protein levels are a coincident Expression Assays (mouse Il1b, Il1r, Il18, Il18r1, Pycard; Thermo- feature of gastric tumors from both gastric cancer patients and Fisher Scientific) or SYBR Green chemistry (Life Technologies) the gp130F/F intestinal-type gastric cancer mouse model (20). using the Applied Biosystems 7300, 7900HT Fast, and Viia7 Real- Furthermore, genetic ablation of either Asc or Il18 in gp130F/F Time PCR Systems (ThermoFisher Scientific). Data acquisition mice suppressed gastric tumor growth, independent of inflam- and analyses were undertaken using the Sequence Detection mation, which was associated with augmented neoplastic System Version 2.4 software (Applied Biosystems). Forward and
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