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

Abstract

TMEM176B was recently described as a negative modulator of Nlrp3 in ammasome 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 in ammasome genes, including NLRP3, signi cantly affect colorectal cancer (CRC) prognosis, we proposed to investigate here the association between genetic variants in TMEM176B and CRC prognosis. MethodsConsidering 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 in ammasome activation. Gene expression from The Cancer Genome Atlas (TCGA) cohort were analyzed to valid possible prognostic and predictive features. ResultsWe identi ed 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 in ammasome, at least in monocytes and dendritic cells. Furthermore, low TMEM176B expression is associated with higher overall survival. ConclusionAltogether these ndings supported the role of TMEM176B in NLRP3 in ammasome biology and for the rst time demonstrated the genetic association between rs2072443 and CRC in humans.

The Multifaceted Role and Regulation of Nlrp3 Inflammasome in Colitis-Associated Colo-Rectal Cancer: A Systematic Review

“…Since TMEM176B inhibits NLRP3 activation, this stands in seeming contrast to the results of the studies presented above. However, TMEM176B appears to primarily affect immune infiltrating cells and not the primary tumor [ 33 ]. Segovia et al highlighted the key role of the TMEM176B channel in anti-tumoral therapy; thus, an upregulation of the molecule leads to inhibition of the NLRP3/caspase-1/IL-1 pathway, which is relevant for dendritic cell activation and cytotoxic response [ 34 ].…”

Monocyte programming by cancer therapy

“…Thus, in monocytes, the Ala134Thr variant (rs2072443) in TMEM176B is associated with poor gene expression and with an increased activation of NLRP3 inflammasome. This SNP correlates with longer overall survival in colorectal cancer cohort ( Table 3 ) ( 248 ). Patients with nasopharyngeal carcinoma with AA and AG gene variants showed a significant correlation with the development of distant metastasis after the initial RT ( 251 ).…”

The intracellular cation channel TMEM176B as a dual immunoregulator

“…( Nickles et al, 2013 ). Moreover, this genetic variant has been linked to beneficial prognosis in colorectal cancer ( Cambui et al, 2022 ). In the last years we started to get some insight on the potential role of this molecule in immunoregulatory mechanisms.…”