Double-edged sword of inflammasome genetics in colorectal cancer prognosis

Cambui, Raylane Adrielle Gonçalves; Santo, Gilmar Ferreira do Espírito; Fernandes, Fernanda Pereira; Leal, Vinícius Nunes Cordeiro; Galera, Bianca Borsatto; Fávaro, Emerson Giuliano Palacio; Rizzo, Leonardo; Elias, Rosa Maria; Pontillo, Alessandra

doi:10.1016/j.clim.2020.108373

Cited by 14 publications

(8 citation statements)

References 32 publications

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“…On the other side, it is well known that the constitutive in ammasome-mediated release of IL-18 by intestinal epithelial cells is important for the maintenance of intestinal homeostasis (Rathinam, 2018) [6]. Accordingly, we also reported that loss-of-function variants in IL18 gene were associated with increased risk for CRC (Cambui, 2020) [2]. These ndings lead us to hypothesize that the hyperactivation of in ammasome in immune cells, but not in epithelial cells, could play a detrimental role for CRC prognosis.…”

Section: Introductionmentioning

confidence: 51%

“…As far as we know, there are only three independent association studies demonstrating a role for in ammasome in CRC prognosis, including one recently published by our group. Two of these studies show a gain-of-function variant in NLRP3 as a risk factor for a poor CRC prognosis (Ungerbäck, 2012, Cambui, 2020 [28,2], and one study show that a higher NLRP3 expression is associated with poor overall survival (Wang, 2020) [29].…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported the signi cant association between two common single nucleotide polymorphisms (SNPs) in NLRP1 and NLRP3 genes, and a worse prognosis of CRC in patients who underwent surgery (Cambui, 2020) [1]. These genes codify for ubiquitous innate immune receptors NLRP1 and NLRP3, which activate the production of the two pro-in ammatory cytokines IL-1ß and IL-18 through the activation of in ammasome complex and caspase-1.…”

Section: Introductionmentioning

confidence: 99%

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

Cambui

Fernandes

Leal

et al. 2022

J Cancer Res Clin Oncol

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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.

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Section: Introductionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cambui

Fernandes

Leal

et al. 2022

J Cancer Res Clin Oncol

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“…Investigating the link between epithelial-to-mesenchymal transition (EMT) markers and NLRP3 inflammasome in CRC in vitro, Wang et al revealed enhanced NLRP3 expression during EMT in HT29 and HCT116 cells, while active caspase-1 and PYCARD were not detected, indicating inflammasome-independent NLRP3 is involved in EMT in CRC [ 45 ]. Cambui et al suggested that genetic variants leading to increased NLRP1 or NLRP3 activation along with decreased IL-18 levels have detrimental effects on CRC prognosis [ 46 ]. The protective role of IL-18 in CRC is an interesting finding since IL-18 expression has been studied in various cancers and is generally linked with poor prognosis [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

The role of curcumin on apoptosis and NLRP3 inflammasome-dependent pyroptosis on colorectal cancer in vitro

DAL,

ARU

2023

Turkish Journal of Medical Sciences

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Background/aim Colorectal cancer (CRC) is one of the most common cancers worldwide. Many factors such as stress, lifestyle, and dietary habits are known to play a role in the initiation and progression of the disease. Herbal therapeutic agents including curcumin can hold a great potential against cancer treatment; however, their efficacy on CRC is still under investigation. Herein, we evaluated the anticancer mechanism of curcumin on four different CRC cell lines. Materials and methods Cells were treated with curcumin for 24, 48 and 72 h, and IC 50 doses for each cell line were calculated. Mechanistic studies were conducted with the lowest IC 50 dose determined for each cell line by evaluating apoptosis and necrosis, cell division, and NLRP3-mediated pyroptosis. Results Curcumin treatment significantly decreased viability while increasing the SubG1 phase in all cell lines tested, indicating apoptosis is the main programmed cell death pathway activated upon curcumin treatment in CRC. In terms of pyroptosis, components of NLRP3 inflammasome were found to be elevated in SW480 and HCT116 cell lines, although to a lesser extent in the latter, and NLRP3 inflammasome activation was not observed in LoVo and HT29 cells. Conclusion Our results reveal that while curcumin effectively induces apoptosis, its effects on NLRP3-inflammasome mediated pyroptosis vary. Our results underline the need for further research focusing on the other inflammasome complexes to confirm the differential effects of curcumin on CRC.

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“…It has been found that in the intestinal mucosa with high expression of antigen, inflammation with low levels is indispensable for the harmony between the immune system and the microbiota and helps to maintain homeostasis ( 157 ). To sum up, controversy remains and some people believe that the NLRP3 inflammasome is a double-edged sword in the development of CRC ( 158 , 159 ). While long-term effects of the NLRP3 inflammasome activation, and inflammatory reaction are associated with poor outcomes, mild inflammation may be beneficial.…”

Section: The Role Of Nlrp3 Inflammasome In the Pathomechanism Of Dige...mentioning

confidence: 99%

NLRP3 inflammasome in digestive diseases: From mechanism to therapy

Qiang

Dai

et al. 2022

Front. Immunol.

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Digestive system diseases remain a formidable challenge to human health. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex and is involved in a wide range of digestive diseases as intracellular innate immune sensors. It has emerged as a research hotspot in recent years. In this context, we provide a comprehensive review of NLRP3 inflammasome priming and activation in the pathogenesis of digestive diseases, including clinical and preclinical studies. Moreover, the scientific evidence of small‐molecule chemical drugs, biologics, and phytochemicals, which acts on different steps of the NLRP3 inflammasome, is reviewed. Above all, deep interrogation of the NLRP3 inflammasome is a better insight of the pathomechanism of digestive diseases. We believe that the NLRP3 inflammasome will hold promise as a novel valuable target and research direction for treating digestive disorders.

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Double-edged sword of inflammasome genetics in colorectal cancer prognosis

Cited by 14 publications

References 32 publications

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

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

The role of curcumin on apoptosis and NLRP3 inflammasome-dependent pyroptosis on colorectal cancer in vitro

NLRP3 inflammasome in digestive diseases: From mechanism to therapy

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