West Alice J, Deswaerte Virginie, West Alison C, Gearing Linden J, Tan Patrick, Jenkins Brendan J
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
Front Oncol. 2022 Mar 1;12:830350. doi: 10.3389/fonc.2022.830350. eCollection 2022.
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 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 mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in : 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 and : 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 and : 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.
炎性小体是天然免疫中重要的多蛋白调节复合物，最近发现其在众多炎症相关癌症中发挥着不同作用。其中包括胃癌（GC），它是全球癌症相关死亡的第三大主要原因，我们之前在GC的自发遗传小鼠模型中发现关键炎性小体接头蛋白含半胱天冬酶激活和招募结构域的凋亡相关斑点样蛋白（ASC）具有促肿瘤作用。然而，在GC过程中激活促肿瘤炎性小体的特定模式识别受体（PRR）的身份尚不清楚。在这里，我们研究了特征最明确的炎性小体相关PRR、含核苷酸结合结构域和富含亮氨酸重复序列的吡啉结构域受体（NLRP）3在GC中的作用。在小鼠胃肿瘤中，尽管NLRP3在mRNA（定量聚合酶链反应）和蛋白质（免疫组织化学）水平上表达升高，但在 小鼠中对NLRP3进行基因敲除并不能减轻胃肿瘤的发展。同样，胃黏膜中与肿瘤发生相关的细胞过程，即增殖、凋亡和炎症，在 和 小鼠之间是可比的。此外，通过免疫印迹和针对裂解的半胱天冬酶 -1的免疫组织化学测定的炎性小体激活水平在 和 胃肿瘤中没有变化，裂解的半胱天冬酶 -1与ASC一起是炎性小体复合物的另一个组成部分。我们还在独立的GC患者队列中观察到NLRP3表达水平（mRNA和蛋白质）存在差异，并且NLRP3对生存结果没有预后价值。综上所述，这些数据表明NLRP3在促进炎性小体驱动的胃肿瘤发生中不发挥主要作用，从而为进一步研究揭示GC中涉及的关键炎性小体相关PRR铺平了道路。
