Abstract
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.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to acknowledge to all the volunteers and the professional team from “Instituto de Tumores e Cuidados Paliativos'' of the “Hospital Geral”, “Clínica de Tratamento Multidisciplinar do Câncer” (ONCOMED) and “Oswaldo Cruz” Hospital for the samples and clinical data. Authors also would like to thank Prof. Marcelo Hill from the “Universidad de la Republica” and Institute Pasteur, Montevideo, Uruguay for helpful discussion, and the Laboratory of Genetics and Molecular Biology, Institute of Medicine, Federal University of Mato Grosso (Cuiaba, Brazil) headed by Dr. Bianca Borsatto Galera for the assistance with the samples handling and storage.
Funding
This study was supported by “Fundação de Suporte a Pesquisa do Estado de Sao Paulo” (FAPESP; grant number 19/06363-4). A.P. is a recipient of a Fellowship from “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq; grant number 302206/2019-1). R.A.G.C. is a recipient of a PhD Fellowship from “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES; grant number 88887.469122/2019-00). The other authors have no competing interests to declare that are relevant to the content of this article.
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RAGC and AP designed the study, analyzed the data, wrote the manuscript and did the association study and genotype-guided assays. RAGC, VNCL and FPF performed the genotyping assay. VNCL, ECR and DSL realized the cell culture assays. GFES and RME recruited the CRC patients and collected the clinical data.
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Cambui, R.A.G., Fernandes, F.P., Leal, V.N.C. et al. The Ala134Thr variant in TMEM176B exerts a beneficial role in colorectal cancer prognosis by increasing NLRP3 inflammasome activation. J Cancer Res Clin Oncol 149, 3729–3738 (2023). https://doi.org/10.1007/s00432-022-04284-8
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DOI: https://doi.org/10.1007/s00432-022-04284-8