Abstract
Inflammasomes are important multiprotein regulatory complexes of innate immunity and have recently emerged as playing divergent roles in numerous inflammation-associated cancers. Among these include gastric cancer (GC), the third leading cause of cancer-associated death worldwide, and we have previously discovered a pro-tumorigenic role for the key inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) in the spontaneous genetic gp130 F/F mouse model for GC. However, the identity of the specific pattern recognition receptors (PRRs) that activate tumor-promoting inflammasomes during GC is unknown. Here, we investigated the role of the best-characterized inflammasome-associated PRR, nucleotide-binding domain, and leucine-rich repeat containing receptor, pyrin domain-containing (NLRP) 3, in GC. In gastric tumors of gp130 F/F mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in gp130 F/F:Nlrp3 -/- mice did not alleviate the development of gastric tumors. Similarly, cellular processes associated with tumorigenesis in the gastric mucosa, namely, proliferation, apoptosis, and inflammation, were comparable between gp130 F/F and gp130 F/F:Nlrp3 -/- mice. Furthermore, inflammasome activation levels, determined by immunoblotting and immunohistochemistry for cleaved Caspase-1, which along with ASC is another integral component of inflammasome complexes, were unchanged in gp130 F/F and gp130 F/F:Nlrp3 -/- gastric tumors. We also observed variable NLRP3 expression levels (mRNA and protein) among independent GC patient cohorts, and NLRP3 was not prognostic for survival outcomes. Taken together, these data suggest that NLRP3 does not play a major role in promoting inflammasome-driven gastric tumorigenesis, and thus pave the way for further investigations to uncover the key inflammasome-associated PRR implicated in GC.
Highlights
Gastric cancer (GC) has the fifth highest incidence of cancer and is the third leading cause of cancer-associated death worldwide [1]
Analysis of intestinal-type GC patient data within The Cancer Genome Atlas (TCGA) revealed that NLRP3 mRNA levels were comparable between total gastric tumor tissues of patients (n = 375) compared to non-tumor gastric tissues (n = 32) (Figure 1A)
The altered tumoral expression of NLRP3 did not align with a specific disease stage, since NLRP3 mRNA expression levels were comparable in early and advanced GC patients (Figure 1E)
Summary
Gastric cancer (GC) has the fifth highest incidence of cancer and is the third leading cause of cancer-associated death worldwide [1]. GC is among a growing number of cancers for which there is a link with chronic inflammation (at least 20%) triggered by dysregulated innate immune responses to microbial infection, in particular the Helicobacter pylori (H. pylori) bacterium that causes ~75% of all GC cases [4–9]. A role for innate immunity in GC was first suggested by the observation that polymorphisms in host genes that encode innate immune cytokines and/or their receptors, in particular IL1B encoding the pro-inflammatory cytokine interleukin-1 beta (IL-1b), conferred a marked increase in risk of H. pylori-infected individuals developing GC [10]. We and others have reported that polymorphisms and/or elevated expression of key regulators of the innate immune system belonging to the pattern recognition receptor (PRR) superfamily are associated with the onset and/or progression of GC, as well as poor survival outcomes [13–17]
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