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Relationship: 1928

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

Snail, Zeb, Twist activation leads to Epithelial-mesenchymal transition

Upstream event

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

Snail, Zeb, Twist 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

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

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 Supporting this KER

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

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The transcription factors such as Snail, Zeb and Twist inhibit the CDH1 expression through their binding towards the promoter of CDH1, which leads to inhibition of cell adhesion and EMT (Diaz et al., 2014).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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).

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

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 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).

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

Snail (SNAI1) 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

Snail (SNAI1) transfection for 48 hours induce 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 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

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; Y. 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).Hu et al., 2019).

References

List of the literature that was cited for this KER description. More help

Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., & García de Herreros, A. (2000). The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84-89. doi:10.1038/35000034

Diaz, V. M., Vinas-Castells, R., & Garcia de Herreros, A. (2014). Regulation of the protein stability of EMT transcription factors. Cell Adh Migr, 8(4), 418-428. doi:10.4161/19336918.2014.969998

Hu, B., Cheng, J. W., Hu, J. W., Li, H., Ma, X. L., Tang, W. G., . . . Yang, X. R. (2019). KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition. Journal of Cancer, 10(17), 3914-3925. doi:10.7150/jca.31448

Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. Cancer Cell, 15(3), 195-206. doi:https://doi.org/10.1016/j.ccr.2009.01.023

Li, C., & Balazsi, G. (2018). A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst Biol Appl, 4, 34. doi:10.1038/s41540-018-0068-x

Lin, X., Chai, G., Wu, Y., Li, J., Chen, F., Liu, J., . . . Wang, H. (2019). RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun, 10(1), 2065. doi:10.1038/s41467-019-09865-9

Menendez-Menendez, J., Hermida-Prado, F., Granda-Diaz, R., Gonzalez, A., Garcia-Pedrero, J. M., Del-Rio-Ibisate, N., . . . Martinez-Campa, C. (2019). Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin. Cancers (Basel), 11(7). doi:10.3390/cancers11071011

Ota, I., Masui, T., Kurihara, M., Yook, J. I., Mikami, S., Kimura, T., . . . Kitahara, T. (2016). Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells. Oncol Rep, 35(1), 261-266. doi:10.3892/or.2015.4348

Peinado, H., Olmeda, D., & Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, 7(6), 415-428. doi:10.1038/nrc2131

Qualtrough, D., Rees, P., Speight, B., Williams, A. C., & Paraskeva, C. (2015). The Hedgehog Inhibitor Cyclopamine Reduces beta-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells. Cancers (Basel), 7(3), 1885-1899. doi:10.3390/cancers7030867

Rosmaninho, P., Mükusch, S., Piscopo, V., Teixeira, V., Raposo, A. A., Warta, R., . . . Castro, D. S. (2018). Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. The EMBO Journal, 37(15), e97115. doi:10.15252/embj.201797115

Wang, Y., Shi, J., Chai, K., Ying, X., & Zhou, B. P. (2013). The Role of Snail in EMT and Tumorigenesis. Current cancer drug targets, 13(9), 963-972. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24168186

Wawruszak, A., Kalafut, J., Okon, E., Czapinski, J., Halasa, M., Przybyszewska, A., . . . Stepulak, A. (2019). Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells. Cancers (Basel), 11(2). doi:10.3390/cancers11020148

Xue, Y., Zhang, L., Zhu, Y., Ke, X., Wang, Q., & Min, H. (2019). Regulation of Proliferation and Epithelial-to-Mesenchymal Transition (EMT) of Gastric Cancer by ZEB1 via Modulating Wnt5a and Related Mechanisms. Medical science monitor : international medical journal of experimental and clinical research, 25, 1663-1670. doi:10.12659/MSM.912338