The Ala134Thr variant in TMEM176B exerts a beneficial role in colorectal cancer prognosis by increasing NLRP3 inflammasome activation

Purpose TMEM176B was recently described as a negative modulator of Nlrp3 inflammasome activation in mice. In the mouse model, the inhibition of TMEM176B leads to an increased anti-tumoral activity which is dependent on Nlrp3. Since we have recently shown that single nucleotide variants (SNPs) in inf...

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Bibliographic Details
Published in:Journal of cancer research and clinical oncology 2023-07, Vol.149 (7), p.3729-3738
Main Authors: Cambui, Raylane Adrielle Gonçalves, Fernandes, Fernanda Pereira, Leal, Vinicius Nunes Cordeiro, Reis, Edione Cristina, de Lima, Dhemerson Souza, do Espírito Santo, Gilmar Ferreira, Elias, Rosa Maria, Pontillo, Alessandra
Format: Article
Language:English
Subjects:
Animals
Cancer
Cancer Research
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Dendritic cells
Gene expression
Genetic diversity
Genomes
Genotype
Genotypes
Hematology
Humans
Inflammasomes
Inflammasomes - genetics
Internal Medicine
Medical prognosis
Medicine
Medicine & Public Health
Membrane Proteins - genetics
Mice
Monocytes
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
Oncology
Prognosis
Single-nucleotide polymorphism
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Summary:Purpose TMEM176B was recently described as a negative modulator of Nlrp3 inflammasome activation in mice. In the mouse model, the inhibition of TMEM176B leads to an increased anti-tumoral activity which is dependent on Nlrp3. Since we have recently shown that single nucleotide variants (SNPs) in inflammasome genes, including NLRP3 , significantly affect colorectal cancer (CRC) prognosis, we proposed to investigate here the association between genetic variants in TMEM176B and CRC prognosis. Methods Considering that, up to now, no genetic study analyzing this gene in humans exists, we selected possible functional SNPs and genotyped them in a cohort of CRC patients submitted to surgery and followed up for more than 10 years. Genotype-guided assays were realized to evaluate the effect of the variant on NLRP3 inflammasome activation. Gene expression from The Cancer Genome Atlas (TCGA) cohort was analyzed to valid possible prognostic and predictive features. Results We identified the Ala134Thr variant (rs2072443) in TMEM176B as a protective factor for CRC prognosis. This SNP is associated with decreased gene expression and with an increased activation of NLRP3 inflammasome, at least in monocytes and dendritic cells. Furthermore, low TMEM176B expression is associated with higher overall survival. Conclusion Altogether, these findings supported the role of TMEM176B in NLRP3 inflammasome biology and for the first time demonstrated the genetic association between rs2072443 and CRC in humans.
ISSN:0171-5216
1432-1335
DOI:10.1007/s00432-022-04284-8