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Relationship: 2071

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

beta-catenin activation leads to Epithelial-mesenchymal transition

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

beta-catenin activation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Epithelial-mesenchymal transition

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Increases in cellular reactive oxygen species and chronic reactive oxygen species leading to human treatment-resistant gastric cancer	adjacent	Moderate	Moderate	Agnes Aggy (send email)	Open for comment. Do not cite	EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induce the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; Yang et al., 2019).

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).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

It is possible that the inhibition of ZEB1 and ZEB2 by garcinol treatment is caused by down-regulation of NFkappaB and Wnt/beta-catenin signaling (Ahmad et al., 2012).

The EMT is induced different transcription factors other than Zeb, Twist, and Snail, which includes E47 and KLF8 (Diaz et al., 2014).

Zeb, Twist, and Snail may activate or inactivate different genes or molecules to induce phenomena related to EMT and other phenomena other than EMT (Li & Balazsi, 2018).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

The proto-oncogene MET regulates beta-catenin and Snail expression (Sohn et al., 2019).

The inhibition of GSK3beta by SB216763 induced expression of beta-catenin and Twist, as well as mesenchymal markers such as N-cadherin, vimentin, and MMP9 (Yang et al., 2019).

The decrease in E-cadherin (CDH1), a cell adhesion molecule, is related to EMT (Diaz et al., 2014).

Methyltransferase-like 3 (METTL3) modulates methylation of Snail (SNAI1) mRNA and EMT (Lin et al., 2019).

The binding of beta-catenin to members of the TCF/LEF family transcription factors increase gene expression related to EMT such as Twist and decrease E-cadherin protein expression (Qualtrough, Rees, Speight, Williams, & Paraskeva, 2015).

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The treatment with AF38469, a sortilin inhibitor, in 0, 100, 200, 400, 800, and 1600 nM concentration inhibited beta-catenin and Twist (EMT regulator) expression dose-dependently in human glioblastoma cells (Yang et al., 2019).

Snail (SNAI1, a key transcription factor of EMT induced by beta-catenin) mRNA is methylated, and N⁶-methyladenosine (m⁶A) in its coding region (CDS) and 3’ untranslated region (3’UTR) are significantly enriched during EMT progression (Lin et al., 2019). The m⁶A enrichment fold of SNAI1 mRNA in EMT cells is about 2.3-fold greater than in control cells (Lin et al., 2019).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Nuclear accumulation of beta-catenin induces endogenous ZEB1 in 15 and 30 min (Sanchez-Tillo E et al., 2011).

The treatment with 25 uM of garcinol for 48 hours induced an increase in phosphorylated beta-catenin and decreased nuclear beta-catenin protein and ZEB1/ZEB2 mRNA in human breast cancer cells (Ahmad et al., 2012).

The treatment with AF38469, a sortilin inhibitor, for 0, 2, 4, 8, 16, or 24 hours shows that the expression of beta-catenin and Twist decrease in 8 hours followed by the subsequent decrease in 16 and 24 hours in human glioblastoma cells (Yang et al., 2019).

Snail (SNAI1) transfection for 48 hours induces the repression of E-cadherin (CDH1) protein expression (Lin et al., 2019).

SNAI1 mRNA in polysome is up-regulated in EMT-undergoing HeLa cells treated with 10 ng/ml of TGF-beta for 3 days compared with control cells (Lin et al., 2019).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

The inhibited expression of phosphorylated GSK3beta, beta-catenin, and Twist by sortilin inhibition is reversed by GSK3beta inhibition. Furthermore, twist overexpression by lentivirus increased the inhibited expression of N-cadherin, MMP9, and vimentin and reverses the inhibitory effect of AF38469 on sortilin, which suggests that sortilin induces glioblastoma invasion mainly via GSK3beta/beta-catenin/Twist induced mesenchymal transition (Yang et al., 2019).

The inhibition of Hedgehog signaling pathway with cyclopamine reduces beta-catenin-TCF transcriptional activity, decreases the Twist expression, induces E-cadherin expression, and inhibits EMT (Qualtrough et al., 2015).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The inhibition of c-MET decreases the expression of beta-catenin and Snail in human diffuse-type gastric cancer (Homo sapiens) (Sohn et al., 2019).
The treatment with garcinol decreases the expression of beta-catenin and ZEB1/ZEB2 in human breast cancer cells (Homo sapiens) (Ahmad et al., 2012).
Zeb1 activation leads to EMT via Prex1 activation in NCH421k, NCH441, and NCH644 human glioblastoma model cells (Homo sapiens) (Rosmaninho et al., 2018).
Zeb1 siRNA induced the suppression of EMT in SGC-7901 human gastric cancer cell line (Homo sapiens) (Xue et al., 2019). Snail induces EMT in SAS and HSC-4 human head and neck squamous cancer cells (Homo sapiens) (Ota et al., 2016).
Snail induces EMT in B16-F10 murine melanoma cells (Mus musculus) (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009; Wang, Shi, Chai, Ying, & Zhou, 2013).
Twist1 is related to EMT in MCF-7 and MDA-MB-231 human breast cancer cell lines (Homo sapiens) (Menendez-Menendez et al., 2019).
Twist induces EMT in Huh7 human hepatocellular carcinoma cell lines (Homo sapiens) (Hu et al., 2019).