TY - JOUR
T1 - Inflammasome-Associated Gastric Tumorigenesis Is Independent of the NLRP3 Pattern Recognition Receptor
AU - West, Alice J.
AU - Deswaerte, Virginie
AU - West, Alison C.
AU - Gearing, Linden J.
AU - Tan, Patrick
AU - Jenkins, Brendan J.
N1 - Funding Information:
The authors would like to thank K. Fitzgerald (University of Massachusetts Chan Medical School, USA) for kindly providing Nlrp3 -/- mice, and A. Vais (Monash Histology Platform, Melbourne, Australia) for immunohistochemistry expertise.
Funding Information:
This work was funded (ID 1139371) by the National Health and Medical Research Council (NHMRC) of Australia (BJJ) and the Operational Infrastructure Support Program by the Victorian Government of Australia. AlicW was supported by an Australian Postgraduate Award from the Australian Government, as well as the Daniel Wilson-Metafit Australia Postgraduate Research Scholarship. BJ was supported by an NHMRC Senior Medical Research Fellowship.
Publisher Copyright:
Copyright © 2022 West, Deswaerte, West, Gearing, Tan and Jenkins.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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 gp130F/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 gp130F/F mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in gp130F/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 gp130F/F and gp130F/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 gp130F/F and gp130F/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.
AB - 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 gp130F/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 gp130F/F mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in gp130F/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 gp130F/F and gp130F/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 gp130F/F and gp130F/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.
KW - gastric cancer
KW - inflammasomes
KW - innate immunity
KW - NLRP3
KW - pattern recognition receptors
UR - http://www.scopus.com/inward/record.url?scp=85127205428&partnerID=8YFLogxK
U2 - 10.3389/fonc.2022.830350
DO - 10.3389/fonc.2022.830350
M3 - Article
C2 - 35299732
AN - SCOPUS:85127205428
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 830350
ER -
