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Relationship: 2069

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

Chronic ROS leads to Porcupine-induced Wnt secretion and Wnt signaling activation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Do not cite Under Review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 Moderate 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 Moderate

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

ROS production causes tissue damage (Gao, Zhou, Lin, Paus, & Yue, 2019). ROS production is involved in Wnt-driven tumorigenesis (Myant et al., 2013). The prolonged ROS induces inflammation leading to carcinogenesis (Vallée & Lecarpentier, 2018). 

Injury causes the Porcupine-induced Wnt secretion (Saha et al., 2016).

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

Sustained ROS increase caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling. Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018).

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 balance of ROS signaling is important, and dual effects of ROS should be taken in consideration. The ROS may enhance Wnt/beta-catenin proliferating pathways to promote tumorigenesis, while ROS may disrupt tumor progression by different pro-apoptotic mechanisms (Pérez et al., 2017). It is also known that Wnt signaling induces ROS signaling (Cheung et al., 2016). Wnt/beta-catenin signaling control by ROS needs to be further investigated (Caliceti, Nigro, Rizzo, & Ferrari, 2014).

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

GPX2, an activator of Wnt/beta-catenin signaling, is identified as a key regulator of intracellular H2O2 levels and an inhibitor of apoptosis (Wang et al., 2019).

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

ROS induces inflammatory responses (Bhattacharyya, Chattopadhyay, Mitra, & Crowe, 2014). Oxidant induces ROS generation and p38 MAPK activation in macrophages (Conway & Kinter, 2006). ROS induce tissue damage in cardiac myocytes (Miller & Cheung, 2016; Yang et al., 2006).

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

For the colony formation assay, cells were treated with 400 microM/L H2O2 for 1 week, where the medium was changed every three days (Wang 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 reduction in ROS levels in the human serum albumin-treated cerebral ischemia/reperfusion-induced injury may be mediated by Wnt/beta-catenin signaling (Tang, Shen, Zhang, Yang, & Liu, 2019).

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

Prolonged ROS induces inflammation and tissue damage in Homo sapiens (Vallée & Lecarpentier, 2018). 

References

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

Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014). Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiological reviews, 94(2), 329-354. doi:10.1152/physrev.00040.2012

Caliceti, C., Nigro, P., Rizzo, P., & Ferrari, R. (2014). ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology. BioMed research international, 2014, 318714-318714. doi:10.1155/2014/318714

Cheung, E. C., Lee, P., Ceteci, F., Nixon, C., Blyth, K., Sansom, O. J., & Vousden, K. H. (2016). Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes & development, 30(1), 52-63. doi:10.1101/gad.271130.115

Conway, J. P., & Kinter, M. (2006). Dual role of peroxiredoxin I in macrophage-derived foam cells. The Journal of biological chemistry, 281(38), 27991-28001. doi:10.1074/jbc.M605026200

Gao, Q., Zhou, G., Lin, S.-J., Paus, R., & Yue, Z. (2019). How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models. Experimental dermatology, 28(4), 413-418. doi:10.1111/exd.13846

Miller, B. A., & Cheung, J. Y. (2016). TRPM2 protects against tissue damage following oxidative stress and ischaemia-reperfusion. The Journal of physiology, 594(15), 4181-4191. doi:10.1113/JP270934

Myant, K. B., Cammareri, P., McGhee, E. J., Ridgway, R. A., Huels, D. J., Cordero, J. B., . . . Sansom, O. J. (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell stem cell, 12(6), 761-773. doi:10.1016/j.stem.2013.04.006

Pérez, S., Taléns-Visconti, R., Rius-Pérez, S., Finamor, I., & Sastre, J. (2017). Redox signaling in the gastrointestinal tract. Free radical biology & medicine, 104, 75-103. doi:10.1016/j.freeradbiomed.2016.12.048

Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7, 13096-13096. doi:10.1038/ncomms13096

Tang, Y., Shen, J., Zhang, F., Yang, F.-Y., & Liu, M. (2019). Human serum albumin attenuates global cerebral ischemia/reperfusion-induced brain injury in a Wnt/β-Catenin/ROS signaling-dependent manner in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 115, 108871-108871. doi:10.1016/j.biopha.2019.108871

Vallée, A., & Lecarpentier, Y. (2018). Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. Frontiers in immunology, 9, 745-745. doi:10.3389/fimmu.2018.00745

Wang, Y., Cao, P., Alshwmi, M., Jiang, N., Xiao, Z., Jiang, F., . . . Li, S. (2019). GPX2 suppression of H(2)O(2) stress regulates cervical cancer metastasis and apoptosis via activation of the β-catenin-WNT pathway. OncoTargets and therapy, 12, 6639-6651. doi:10.2147/OTT.S208781

Yang, K. T., Chang, W. L., Yang, P. C., Chien, C. L., Lai, M. S., Su, M. J., & Wu, M. L. (2006). Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death & Differentiation, 13(10), 1815-1826. doi:10.1038/sj.cdd.4401813