AUTHOR=West Alice J. , Deswaerte Virginie , West Alison C. , Gearing Linden J. , Tan Patrick , Jenkins Brendan J. 

TITLE=Inflammasome-Associated Gastric Tumorigenesis Is Independent of the NLRP3 Pattern Recognition Receptor

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.830350

DOI=10.3389/fonc.2022.830350

ISSN=2234-943X

ABSTRACT=<p>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 <italic>gp130</italic><sup>F/F</sup> 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 <italic>gp130</italic><sup>F/F</sup> mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in <italic>gp130</italic><sup>F/F</sup>:<italic>Nlrp3</italic><sup>-/-</sup> 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 <italic>gp130</italic><sup>F/F</sup> and <italic>gp130</italic><sup>F/F</sup>:<italic>Nlrp3</italic><sup>-/-</sup> 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 <italic>gp130</italic><sup>F/F</sup> and <italic>gp130</italic><sup>F/F</sup>:<italic>Nlrp3</italic><sup>-/-</sup> 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.</p>