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Aop: 298
AOP Title
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Chronic reactive oxygen species leading to human gastric cancer resistance
Short name:
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Chronic ROS leading to human gastric cancer
Graphical Representation
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Click to download graphical representation template
Authors
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Shihori Tanabe, Akihiko Hirose, Takashi Yamada
Point of Contact ?
Shihori Tanabe
(email point of contact)
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Status
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Author status
OECD status
OECD project
SAAOP status
Open for citation & comment
This AOP was last modified on March 23, 2020 04:45
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Revision dates for related pages
Page
Revision Date/Time
Epithelial-mesenchymal transition
March 23, 2020 04:18
Cancer resistance
March 23, 2020 04:21
Chronic reactive oxygen species
March 23, 2020 03:57
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion
March 23, 2020 04:12
Proliferation/ beta-catenin activation
March 23, 2020 04:15
Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion
March 23, 2020 04:28
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion leads to Proliferation/ beta-catenin activation
March 23, 2020 04:39
Proliferation/ beta-catenin activation leads to Epithelial-mesenchymal transition
March 23, 2020 04:44
Epithelial-mesenchymal transition leads to Cancer resistance
October 08, 2019 02:06
Wnt
May 29, 2019 03:59
WNT2
May 29, 2019 03:59
Porcupine
January 19, 2020 21:19
Wntless
January 19, 2020 21:20
Abstract
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The injury or sustained reactive oxygen species (ROS) causes resistance in human gastric cancer. This AOP entitled “Chronic reactive oxygen species leading to human gastric cancer resistance” consists of MIE as sustained ROS, followed by KE1 as sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion, KE2 as proliferation / beta-catenin activation, KE3 as epithelial-mesenchymal transition (EMT), and AO as gastric cancer resistance. ROS has multiple roles such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of chronic ROS with sustained level to induce the therapy-resistance in human gastric cancer. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like feature, demonstrates cancer stem cell-like characteristics in human gastric cancer. EMT is induced by Wnt/beta-catenin signaling, which confers rationale to have Wnt secretion and beta-catenin activation as KE1 and KE2 on the AOP, respectively.
Background (optional)
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Summary of the AOP
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Events: Molecular Initiating Events (MIE)
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Key Events (KE)
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Adverse Outcomes (AO)
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Sequence
Type
Event ID
Title
Short name
Relationships Between Two Key Events
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Title
Adjacency
Evidence
Quantitative Understanding
Network View
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Show names
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Stressors
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Life Stage Applicability
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Life stage
Evidence
All life stages
High
Taxonomic Applicability
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Term
Scientific Term
Evidence
Link
Homo sapiens
Homo sapiens
High
NCBI
Sex Applicability
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Sex
Evidence
Unspecific
High
Overall Assessment of the AOP
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Attached file:
1. Support for Biological Plausibility of KERs
MIE => KE1:
Biological Plausibility of the MIE => KE1 is moderate.Vallée & Lecarpentier, 2018 )..
KE1 => KE2:
Biological Plausibility of the KE1 => KE2 is high.
KE2 => KE3:
Biological Plausibility of the KE2 => KE3 is moderate.
EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 2014). The transcription factors such as Snail, ZEB and Twist bind to E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).
KE3 => AO:
Biological Plausibility of the KE3 => AO is high.
EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). Increase expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT is associated with therapy resistance (Smith & Bhowmick, 2016).
2. Support for essentiality of KEs
KE1: Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion
Essentiality of the KE1 is moderate.
KE2: Proliferation / beta-catenin activation
Essentiality of the KE2 is moderate.
KE3: Epithelial-mesenchymal transition (EMT)
Essentiality of the KE3 is moderate.
3. Empirical support for KERs
MIE => KE1:
Empirical Support of the MIE => KE1 is moderate.Gao et al., 2019 ).
ROS signaling induces Wnt/beta-catenin signaling (Pérez et al., 2017).
KE1 => KE2:
Empirical Support of the KE1 => KE2 is high.
Wnt binds to FZD and activate the Wnt signaling (Clevers & Nusse, 2012; Janda, Waghray, Levin, Thomas, & Garcia, 2012; Nile et al., 2017). Wnt binding towards FZD induce the formation of the protein complex with LRP5/6 and DVL, leading to the down-stream signaling activation including beta-catenin (Clevers & Nusse, 2012).
KE2 => KE3:
Empirical Support of the KE2 => KE3 is moderate.
The garcinol, that has anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibit EMT (Ahmad et al., 2012).
The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in decrease in beta-catenin and Twist expression in human glioblastoma cells (W. Yang et al., 2019).
Histone deacetylase inhibitors affect on EMT-related transcription factors including ZEB, Twist and Snail (Wawruszak et al., 2019).
Snail and Zeb induces EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado, Olmeda, & Cano, 2007).
KE3 => AO:
Empirical Support of the KE3 => AO is moderate.
TGFbeta-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties (Pirozzi et al., 2011; Shibue & Weinberg, 2017).
Snail-induced EMT induces the cancer metastasis and resistance to dendritic cell-mediated immunotherapy (Kudo-Saito et al., 2009).
Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in the relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8+ T cell immunosuppression and metastasis (Chen et al., 2014).
Domain of Applicability
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Homo sapiens
Essentiality of the Key Events
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Sustained ROS contributes into the initiation and development of human gastric cancer (Gu H. 2018).
Wnt signaling is involved in cancer malignancy (Tanabe, 2018 ).
Upon stimulation with Wnt ligand to Frizzled receptor, Wnt/beta-catenin signaling is activated. Wnt/beta-catenin consists of GSK3 beta inactivation, beta-catenin activation and up-regulation of transcription factors such as Zeb, Twist and Snail. The transcription factors Zeb, Twist and Snail relate to the activation of EMT-related genes. EMT is regulated with various gene networks (S. Tanabe, 2015 ).
Evidence Assessment
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The Wnt signaling promotes EMT and cancer malignancy in colorectal cancer (Lazarova & Bordonaro, 2017). Although the potential pathways other than Wnt signaling exist in EMT induction and the mechanism underlaid cancer malignancy, Wnt signaling is one of the main pathways to induce EMT and cancer malignancy (Polakis, 2012).
Quantitative Understanding
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Wnt signaling activates the CSCs to promote cancer malignancy ( Reya & Clevers, 2005 ) . The responses in KEs related to Wnt signaling, Frizzled activation, GSK3beta inactivation, beta-catenin activation, Snail, Zeb, Twist activation are dose-dependently related. The quantification of EMT and cancer malignancy would require the further investigation.
Considerations for Potential Applications of the AOP (optional)
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AOP entitled “Chronic reactive oxygen species leading to human gastric cancer resistance” might be utilized for the development and risk assessment of anti-cancer drugs. EMT is involved in the acquisition of drug resistance, which is one of the critical features of cancer malignancy. The assessment of EMT would be the potential prediction of the adverse effects of anti-cancer drugs.
References
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