Upregulation of the NLRC4 inflammasome contributes to poor prognosis in glioma patients

Lim, Jaejoon; Kim, Min Jun; Park, Young Joon; Ahn, Ju Won; Hwang, So Jung; Moon, Jong‐Seok; Cho, Kyung Gi; Kwack, KyuBum

doi:10.1038/s41598-019-44261-9

Cited by 34 publications

(21 citation statements)

References 51 publications

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“…These survival plots extend to glioma patients, demonstrating a similar relationship between higher NLRC4 expression and poor prognosis 130 . The study also confirmed increased IL‐1β expression in glioma patients with a poorer outcome, 130 implicating a role of IL‐1β secretion in driving glioma progression. Further studies are therefore required to investigate the tentative link between NLRC4‐mediated IL‐1β secretion and tumor progression, potentially positioning the NLRC4‐IL‐1β pathway as a potential therapeutic target for inhibition in glioma and other cancers.…”

Section: Nlrc4 In Cancermentioning

confidence: 52%

“…Indeed, these mouse studies are supported by data from a cohort of human patients with breast cancer, showing that patients with higher levels of NLRC4 mRNA transcripts have a poorer survival rate 128 . These survival plots extend to glioma patients, demonstrating a similar relationship between higher NLRC4 expression and poor prognosis 130 . The study also confirmed increased IL‐1β expression in glioma patients with a poorer outcome, 130 implicating a role of IL‐1β secretion in driving glioma progression.…”

Section: Nlrc4 In Cancermentioning

confidence: 62%

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Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Kay

Wang

Kirkby

et al. 2020

Immunological Reviews

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Cytosolic innate immune sensing is a cornerstone of innate immunity in mammalian cells and provides a surveillance system for invading pathogens and endogenous danger signals. The NAIP‐NLRC4 inflammasome responds to cytosolic flagellin, and the inner rod and needle proteins of the type 3 secretion system of bacteria. This complex induces caspase‐1‐dependent proteolytic cleavage of the proinflammatory cytokines IL‐1β and IL‐18, and the pore‐forming protein gasdermin D, leading to inflammation and pyroptosis, respectively. Localized responses triggered by the NAIP‐NLRC4 inflammasome are largely protective against bacterial pathogens, owing to several mechanisms, including the release of inflammatory mediators, liberation of concealed intracellular pathogens for killing by other immune mechanisms, activation of apoptotic caspases, caspase‐7, and caspase‐8, and expulsion of an entire infected cell from the mammalian host. In contrast, aberrant activation of the NAIP‐NLRC4 inflammasome caused by de novo gain‐of‐function mutations in the gene encoding NLRC4 can lead to macrophage activation syndrome, neonatal enterocolitis, fetal thrombotic vasculopathy, familial cold autoinflammatory syndrome, and even death. Some of these clinical manifestations could be treated by therapeutics targeting inflammasome‐associated cytokines. In addition, the NAIP‐NLRC4 inflammasome has been implicated in the pathogenesis of colorectal cancer, melanoma, glioma, and breast cancer. However, no consensus has been reached on its function in the development of any cancer types. In this review, we highlight the latest advances in the activation mechanisms and structural assembly of the NAIP‐NLRC4 inflammasome, and the functions of this inflammasome in different cell types. We also describe progress toward understanding the role of the NAIP‐NLRC4 inflammasome in infectious diseases, autoinflammatory diseases, and cancer.

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Section: Nlrc4 In Cancermentioning

confidence: 52%

Section: Nlrc4 In Cancermentioning

confidence: 62%

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Kay

Wang

Kirkby

et al. 2020

Immunological Reviews

View full text Add to dashboard Cite

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“…Several evidences indicate that, in glioma, the inflammatory component increases in parallel with tumor aggressiveness and grade ( 48 ). Furthermore, glioma cells are able to recruit glioma associated peripheral monocyte/macrophage and activated microglia (GAMMs) favoring a tumorigenic phenotype ( 49 , 50 ) which plays a central role in drug resistance and treatment failures.…”

Section: Discussionmentioning

confidence: 99%

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

et al. 2021

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Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro, MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo, MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals’ survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.

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“…CAPN14 gene is highly expressed in the esophagus and is associated with epithelial barrier impairment observed in esosinophilic esophagitis ( Davis et al, 2016 ). In the NLRC4 inflammasome, upregulation is a marker of poor prognosis in gliomas although the role of inflammasomes in tumors continues to evolve ( Lim et al, 2019 ). The RASGRP3, a RAS activator is known to play a role in several cancers, including breast ( Nagy et al, 2014 ), papillary thyroid ( Qiu et al, 2017 ), and prostate cancers ( Yang et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Recurring Translocations in Barrett’s Esophageal Adenocarcinoma

et al. 2021

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Barrett’s esophagus (BE) is a premalignant metaplasia in patients with chronic gastroesophageal reflux disease (GERD). BE can progress to esophageal adenocarcinoma (EA) with less than 15% 5-year survival. Chromosomal aneuploidy, deletions, and duplication are early events in BE progression to EA, but reliable diagnostic assays to detect chromosomal markers in premalignant stages of EA arising from BE are lacking. Previously, we investigated chromosomal changes in an in vitro model of acid and bile exposure-induced Barrett’s epithelial carcinogenesis (BEC). In addition to detecting changes already known to occur in BE and EA, we also reported a novel recurring chromosomal translocation t(10:16) in the BE cells at an earlier time point before they undergo malignant transformation. In this study, we refine the chromosomal event with the help of fluorescence microscopy techniques as a three-way translocation between chromosomes 2, 10, and 16, t(2:10;16) (p22;q22;q22). We also designed an exclusive fluorescent in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay that detects these chromosomal breakpoints and fusions. We validate the feasibility of the FISH-EA assay to objectively detect these chromosome events in primary tissues by confirming the presence of one of the fusions in paraffin-embedded formalin-fixed human EA tumors. Clinical validation in a larger cohort of BE progressors and non-progressors will confirm the specificity and sensitivity of the FISH-EA assay in identifying malignant potential in the early stages of EA.

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Upregulation of the NLRC4 inflammasome contributes to poor prognosis in glioma patients

Cited by 34 publications

References 51 publications

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

Recurring Translocations in Barrett’s Esophageal Adenocarcinoma

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