Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

Catalano, Calogerina; Filho, Miguel Inácio da Silva; Christoph, Frank; Lü, Shun; Jirásková, Kateřina; Vymetalková, Veronika; Levý, Miroslav; Liška, Václav; Vyčítal, Ondřej; Naccarati, Alessio; Vodičková, Ľudmila; Hemminki, Kari; Vodička, Pavel; Weber, Alexander N.R.; Försti, Asta

doi:10.1002/cam4.2804

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…Although the data also showed that HFD increased TLR3 by 20-fold as indicated by the total count, it had a discrepancy with the FPKM read count that showed HFD increased TLR3 by 38-fold. Furthermore, the null expression of TLR3 in CRC was not in agreement with other published studies [ 21 , 22 ]. Therefore, we shortlisted TLR4 for the study and further validated its expressions in the tumor tissues by qPCR.…”

Section: Resultscontrasting

confidence: 63%

Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism

Fatima

Chen

et al. 2021

Cell Death Dis

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Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.

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Section: Resultscontrasting

confidence: 63%

Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism

Fatima

Chen

et al. 2021

Cell Death Dis

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“…Recently, several studies demonstrated that the STING pathway had tremendous potential for immunotherapy (Chon et al, 2019;Su et al, 2019;Catalano et al, 2020). Its conformational changes and phosphorylation result in its translocation from the ER to distinct perinuclear endosomes near the Golgi (Bai and Liu, 2019;Chon et al, 2019;Yang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy

Liu

Kuai

Ding

et al. 2022

Front. Synaptic Neurosci.

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Our previous work indicated that ER-phagy level had altered in spinal nerve ligation (SNL) rats. In this study, we investigated whether dexmedetomidine or ketamine exhibits anti-anxiety or anti-nociceptive effects via modulation of the spinal STING/TBK pathway to alter ER-phagy in SNL rats. We evaluated the analgesic and anti-anxiety effects of ketamine and dexmedetomidine in SNL rats. 2’3’-cGAMP (a STING pathway agonist) was administrated to investigate whether enhanced spinal STING pathway activation could inhibit dexmedetomidine or ketamine treatment effects in SNL rats. Analgesic effects were assessed with the mechanical withdrawal threshold (MWT) and anti-anxiety effects were measured via an open field test (OFT). Protein expression levels were evaluated by immunoblotting. Distribution and cellular localization of Grp78 (ER stress marker) were evaluated by confocal immunofluorescence. SNL induced mechanical hypersensitivity and anxiety in rats; dexmedetomidine and ketamine both provided analgesia and anti-anxiety effects in SNL rats. Furthermore, the STING pathway was involved in the modulation of ER stress and ER-phagy in SNL rats and dexmedetomidine and ketamine alleviated ER stress by inhibiting STING pathway to enhance ER-phagy. Thus, both ketamine and dexmedetomidine provided anti-anxiety and anti-nociceptive effects by alleviating ER stress through the inhibition of the STING/TBK pathway to modulate spinal ER-phagy in SNL rats.

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“…[94][95][96] The expression of genes in cGAS-STING signaling pathway could be affected by single nucleotide polymorphisms (SNPs) and the SNPs may lead to colorectal cancer susceptibility (Table 2). 97 In addition, hypermethylation within the cGAS promoter region may partly account for the suppressed expression of cGAS in CA cells. 94 Notably, high STING expression, particularly in endothelial, was regarded as an independent prognostic factor for better overall survival in colorectal cancer patients.…”

Section: Colorectal Cancermentioning

confidence: 99%

“… 94–96 The expression of genes in cGAS–STING signaling pathway could be affected by single nucleotide polymorphisms (SNPs) and the SNPs may lead to colorectal cancer susceptibility (Table 2). 97 In addition, hypermethylation within the cGAS promoter region may partly account for the suppressed expression of cGAS in CA cells 94 98–100 …”

Section: The Cgas–sting Signaling Pathway In Gi Cancersmentioning

confidence: 99%

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

Jiang

2021

The FASEB Journal

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Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a key DNA-sensing machinery in innate immunity. Activation of cGAS-STING signaling pathway mediates the production of interferons and proinflammatory cytokines. Although cGAS-STING signaling pathway shows critical function in the maintenance of gut homeostasis, overactive cGAS-STING signaling pathway leads to gastrointestinal (GI) inflammation.Harnessing the effect and mechanism of the cGAS-STING signaling pathway could be beneficial for the development of novel strategies for the treatment of GI diseases. This review presents recent advances regarding the role of cGAS-STING signaling pathway in GI inflammatory disease and cancers and describes perspective therapeutic strategies targeting the signaling pathway.

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Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

Cited by 10 publications

References 43 publications

Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism

Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism

Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

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