This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 298

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Chronic reactive oxygen species leading to human treatment-resistant gastric cancer

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Chronic ROS leading to human treatment-resistant gastric cancer

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

W1siziisijiwmjavmduvmdgvmnixndhozdm1m19bt1ayothfzglhz3jhbtvfof8ymc5kuecixsxbinailcj0ahvtyiisijuwmhg1mdaixv0?sha=2a9c11cdad05e5d7

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Shihori Tanabe¹⁾, Sabina Quader²⁾, Ryuichi Ono³⁾, Horacio Cabral⁴⁾, Kazuhiko Aoyagi⁵⁾, Akihiko Hirose¹⁾, Hiroshi Yokozaki⁶⁾, Hiroki Sasaki⁷⁾, Ed Perkins⁸⁾

¹Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

²Innovation Centre of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan

³Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

⁴Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Japan

⁵Department of Clinical Genomics, National Cancer Center Research Institute, Japan

⁶Department of Pathology, Kobe University of Graduate School of Medicine, Japan

⁷Department of Translational Oncology, National Cancer Center Research Institute, Japan

⁸Environmental Laboratory, US Army Engineer Research and Development Center, United States

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Shihori Tanabe (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Shihori Tanabe

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help

Author status	OECD status	OECD project	SAAOP status
Open for comment. Do not cite	EAGMST Under Review	1.58	Included in OECD Work Plan

This AOP was last modified on November 09, 2021 02:38

Revision dates for related pages

Page	Revision Date/Time
Epithelial-mesenchymal transition	May 13, 2021 01:37
Treatment-resistant gastric cancer	May 13, 2021 02:10
Chronic reactive oxygen species	November 09, 2021 00:35
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion	May 13, 2021 22:29
Proliferation / beta-catenin activation	May 13, 2021 01:36
Increases in cellular reactive oxygen species	May 10, 2022 21:44
Chronic ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion	May 13, 2021 02:22
Increases in cellular ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion	April 27, 2022 01:24
Sustained tissue damage, macrophage activation and Wnt secretion leads to Proliferation / beta-catenin activation	November 09, 2021 01:23
Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition	November 09, 2021 01:58
Epithelial-mesenchymal transition leads to Resistant gastric cancer	May 13, 2021 03:08
Wnt	May 29, 2019 03:59
WNT2	May 29, 2019 03:59
Porcupine	January 19, 2020 21:19
Wntless	January 19, 2020 21:20
Ionizing Radiation	May 07, 2019 12:12
ferric nitrilotriacetate	May 27, 2020 02:40

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The injury or sustained reactive oxygen species (ROS) causes resistance in human gastric cancer. This AOP entitled “Chronic reactive oxygen species leading to human treatment-resistant gastric cancer” consists of MIE (KE1753) as chronic ROS, followed by KE1 (KE1754) as sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion, KE2 (KE1755) as proliferation / beta-catenin activation, KE3 (KE1650) as epithelial-mesenchymal transition (EMT), and AO (KE1651) as human treatment-resistant gastric cancer. 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.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1753

Chronic reactive oxygen species

Chronic ROS

KE	1940	Increases in cellular reactive oxygen species	Increases in cellular ROS
KE	1754	Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion	Sustained tissue damage, macrophage activation and Wnt secretion
KE	1755	Proliferation / beta-catenin activation	Proliferation / beta-catenin activation
KE	1650	Epithelial-mesenchymal transition	Epithelial-mesenchymal transition

1651

Treatment-resistant gastric cancer

Resistant gastric cancer

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Chronic ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion	adjacent	Moderate	Moderate
Increases in cellular ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion	adjacent	Moderate	Moderate
Sustained tissue damage, macrophage activation and Wnt secretion leads to Proliferation / beta-catenin activation	adjacent	Moderate	Moderate
Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition	adjacent	Moderate	Moderate
Epithelial-mesenchymal transition leads to Resistant gastric cancer	adjacent	Moderate	Moderate

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
Wnt
WNT2
Porcupine
Wntless
Ionizing Radiation
ferric nitrilotriacetate

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
All life stages	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Unspecific	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

1. Support for Biological Plausibility of KERs
MIE => KE1: Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion	Biological Plausibility of the MIE => KE1 is moderate.
	Rationale: Sustained ROS increases 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).
KE1 => KE2: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation	Biological Plausibility of the KE1 => KE2 is moderate.
	Rationale: Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilize the beta-catenin (Clevers & Nusse, 2012).
KE2 => KE3: Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)	Biological Plausibility of the KE2 => KE3 is moderate.
	Rationale: Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induces 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; W. 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).
KE3 => AO: Epithelial-mesenchymal transition (EMT) leads to human treatment-resistant gastric cancer	Biological Plausibility of the KE3 => AO is moderate.
	Rationale: Some population of the cells exhibiting EMT demonstrates the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).
	EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). The increase in 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 are 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.
	Rationale for Essentiality of KEs in the AOP: The sustained tissue damage, macrophage activation and Wnt are essential for the subsequent beta-catenin activation and cancer resistance.
KE2: Proliferation / beta-catenin activation	Essentiality of the KE2 is moderate.
KE2: Proliferation / beta-catenin activation	Rationale for Essentiality of KEs in the AOP: Proliferation and beta-catenin activation are essential for the Wnt-induced cancer resistance.
KE3: Epithelial-mesenchymal transition (EMT)	Essentiality of the KE3 is moderate.
KE3: Epithelial-mesenchymal transition (EMT)	Rationale for Essentiality of KEs in the AOP: EMT is essential for the Wnt-induced cancer promotion and resistance to anti-cancer drug.
3. Empirical support for KERs
MIE => KE1: Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion	Empirical Support of the MIE => KE1 is moderate.
	Rationale: Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019).
	ROS signaling induces Wnt/beta-catenin signaling (Pérez et al., 2017).
KE1 => KE2: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation	Empirical Support of the KE1 => KE2 is moderate.
	Rationale: Sustained ROS increases 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, which then activates beta-catenin leading to proliferation.
	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: Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)	Empirical Support of the KE2 => KE3 is moderate.
	Rationale: Proliferation and beta-catenin activation induces the key transcription factors in EMT. Translocation of beta-catenin into the nucleus by Wnt/beta-catenin signaling pathway activation promotes EMT.
	The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced increase in phosphorylated beta-catenin, decrease in beta-catenin and Snail (Sohn et al., 2019).
	The garcinol, which has an anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibits EMT (Ahmad et al., 2012).
	The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in a decrease in beta-catenin and Twist expression in human glioblastoma cells (W. Yang et al., 2019).
	Histone deacetylase inhibitors affect 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: Epithelial-mesenchymal transition (EMT) leads to human treatment-resistant gastric cancer	Empirical Support of the KE3 => AO is moderate.
	Rationale: EMT induces the expression of genes such as transporters of anti-cancer drug, which promotes anti-cancer drug resistance. EMT induces migration and metastasis of cancer cells, and share the phenotype of cancer stem cells, which is one of the hallmarks of human treatment-resistant gastric cancer (Tanabe et al., 2020a, 2020b).
	EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in the resistance to doxorubicin (Saxena, Stephens, Pathak, & Rangarajan, 2011; Shibue & Weinberg, 2017).
	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 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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Homo sapiens

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

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 (Tanabe, 2015c).

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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).

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

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)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

AOP entitled “Chronic reactive oxygen species leading to human treatment-resistant gastric cancer” 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

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

Ahmad, A., Sarkar, S. H., Bitar, B., Ali, S., Aboukameel, A., Sethi, S., . . . Sarkar, F. H. (2012). Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther, 11(10), 2193-2201. doi:10.1158/1535-7163.MCT-12-0232-T

Ashoka, A. H., Ali, F., Tiwari, R., Kumari, R., Pramanik, S. K., & Das, A. (2020). Recent Advances in Fluorescent Probes for Detection of HOCl and HNO. ACS omega, 5(4), 1730-1742. doi:10.1021/acsomega.9b03420

Banziger, C., Soldini, D., Schutt, C., Zipperlen, P., Hausmann, G., & Basler, K. (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell, 125(3), 509-522. doi:10.1016/j.cell.2006.02.049

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

Bhanot, P., Brink, M., Samos, C. H., Hsieh, J.-C., Wang, Y., Macke, J. P., . . . Nusse, R. (1996). A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 382, 225. doi:10.1038/382225a0

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

Bovolenta, P., Esteve, P., Ruiz, J. M., Cisneros, E., & Lopez-Rios, J. (2008). Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci, 121(Pt 6), 737-746. doi:10.1242/jcs.026096

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

Cao, T. T., Xiang, D., Liu, B. L., Huang, T. X., Tan, B. B., Zeng, C. M., . . . Fu, L. (2017). FZD7 is a novel prognostic marker and promotes tumor metastasis via WNT and EMT signaling pathways in esophageal squamous cell carcinoma. Oncotarget, 8(39), 65957-65968. doi:10.18632/oncotarget.19586

Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y.-H., Byers, L. A., . . . Qin, F. X.-F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nature communications, 5, 5241-5241. doi:10.1038/ncomms6241

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

Ching, W., & Nusse, R. (2006). A dedicated Wnt secretion factor. Cell, 125(3), 432-433. doi:10.1016/j.cell.2006.04.018

Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127(3), 469-480. doi:10.1016/j.cell.2006.10.018

Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. doi:10.1016/j.cell.2012.05.012

Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., . . . Ishii, H. (2016). Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Sci Rep, 6, 36289. doi:10.1038/srep36289

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

De, A. (2011). Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin (Shanghai), 43(10), 745-756. doi:10.1093/abbs/gmr079

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

Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965

Du, J., Zu, Y., Li, J., Du, S., Xu, Y., Zhang, L., . . . Yang, C. (2016). Extracellular matrix stiffness dictates Wnt expression through integrin pathway. Sci Rep, 6, 20395. doi:10.1038/srep20395

Ellwanger, K., Saito, H., Clement-Lacroix, P., Maltry, N., Niedermeyer, J., Lee, W. K., . . . Niehrs, C. (2008). Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol Cell Biol, 28(15), 4875-4882. doi:10.1128/MCB.00222-08

Fang, C. X., Ma, C. M., Jiang, L., Wang, X. M., Zhang, N., Ma, J. N., . . . Zhao, Y. D. (2018). p38 MAPK is Crucial for Wnt1- and LiCl-Induced Epithelial Mesenchymal Transition. Curr Med Sci, 38(3), 473-481. doi:10.1007/s11596-018-1903-4

Foulquier, S., Daskalopoulos, E. P., Lluri, G., Hermans, K. C. M., Deb, A., & Blankesteijn, W. M. (2018). WNT Signaling in Cardiac and Vascular Disease. Pharmacol Rev, 70(1), 68-141. doi:10.1124/pr.117.013896

Funato, Y., Michiue, T., Asashima, M., & Miki, H. (2006). The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled. Nature Cell Biology, 8(5), 501-508. doi:10.1038/ncb1405

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

Gu, H., Huang, T., Shen, Y., Liu, Y., Zhou, F., Jin, Y., . . . Wei, Y. (2018). Reactive Oxygen Species-Mediated Tumor Microenvironment Transformation: The Mechanism of Radioresistant Gastric Cancer. Oxidative medicine and cellular longevity, 2018, 5801209-5801209. doi:10.1155/2018/5801209

Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. Front Oncol, 7, 295. doi:10.3389/fonc.2017.00295

Hatsell, S., Rowlands, T., Hiremath, M., & Cowin, P. (2003). Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia, 8(2), 145-158. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14635791

Hodge, D. Q., Cui, J., Gamble, M. J., & Guo, W. (2018). Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition. Sci Rep, 8(1), 841. doi:10.1038/s41598-018-19364-4

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

Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J., & Gan, X. (2018). Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/beta-catenin pathway. J Biol Chem, 293(51), 19710-19724. doi:10.1074/jbc.RA118.004434

Huang, J. Q., Wei, F. K., Xu, X. L., Ye, S. X., Song, J. W., Ding, P. K., . . . Gong, L. Y. (2019). SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/beta-catenin pathway. J Transl Med, 17(1), 143. doi:10.1186/s12967-019-1895-2

Inukai, T., Inoue, A., Kurosawa, H., Goi, K., Shinjyo, T., Ozawa, K., . . . Look, A. T. (1999). SLUG, a ces-1-Related Zinc Finger Transcription Factor Gene with Antiapoptotic Activity, Is a Downstream Target of the E2A-HLF Oncoprotein. Molecular Cell, 4(3), 343-352. doi:https://doi.org/10.1016/S1097-2765(00)80336-6

Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. C. (2012). Structural basis of Wnt recognition by Frizzled. Science, 337(6090), 59-64. doi:10.1126/science.1222879

Jia, D., Park, J. H., Jung, K. H., Levine, H., & Kaipparettu, B. A. (2018). Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells, 7(3). doi:10.3390/cells7030021

Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell, 58(3), 522-533. doi:10.1016/j.molcel.2015.03.015

Katoh, M. (2001). Molecular cloning and characterization of human WNT3. Int J Oncol, 19(5), 977-982. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11604997

Katoh, M. (2017). Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). International journal of oncology, 51(5), 1357-1369. doi:10.3892/ijo.2017.4129

Kaufhold, S., & Bonavida, B. (2014). Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res, 33, 62. doi:10.1186/s13046-014-0062-0

Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M. G., Brumwell, A. N., . . . Chapman, H. A. (2006). Alveolar epithelial cell mesenchymal transition develops <em>in vivo</em> during pulmonary fibrosis and is regulated by the extracellular matrix. Proceedings of the National Academy of Sciences, 103(35), 13180. doi:10.1073/pnas.0605669103

Kim, M., Kim, S. H., Lim, J. W., & Kim, H. (2019). Lycopene induces apoptosis by inhibiting nuclear translocation of beta-catenin in gastric cancer cells. J Physiol Pharmacol, 70(4). doi:10.26402/jpp.2019.4.11

Korswagen, H. C. (2006). Regulation of the Wnt/β-catenin pathway by redox signaling. Developmental Cell, 10(6), 687-688. doi:https://doi.org/10.1016/j.devcel.2006.05.007

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

Kusserow, A., Pang, K., Sturm, C., Hrouda, M., Lentfer, J., Schmidt, H. A., . . . Holstein, T. W. (2005). Unexpected complexity of the Wnt gene family in a sea anemone. Nature, 433(7022), 156-160. doi:10.1038/nature03158

Kwon, Y. J., Baek, H. S., Ye, D. J., Shin, S., Kim, D., & Chun, Y. J. (2016). CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/beta-Catenin Signaling via Sp1 Upregulation. PLoS One, 11(3), e0151598. doi:10.1371/journal.pone.0151598

Lai, S. L., Chien, A. J., & Moon, R. T. (2009). Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res, 19(5), 532-545. doi:10.1038/cr.2009.41

Lazarova, D., & Bordonaro, M. (2017). ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC. Journal of Cancer, 8(8), 1453-1459. doi:10.7150/jca.18762

Lee, D. Y., Kang, S., Lee, Y., Kim, J. Y., Yoo, D., Jung, W., . . . Jon, S. (2020). PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood. Theranostics, 10(5), 1997-2007. doi:10.7150/thno.39662

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

MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1), 9-26. doi:10.1016/j.devcel.2009.06.016

Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., . . . Weinberg, R. A. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704-715. doi:10.1016/j.cell.2008.03.027

Marjanovic, N. D., Weinberg, R. A., & Chaffer, C. L. (2013). Cell plasticity and heterogeneity in cancer. Clinical chemistry, 59(1), 168-179. doi:10.1373/clinchem.2012.184655

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

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

Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., . . . Ambs, S. (2018). ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest, 128(1), 323-340. doi:10.1172/JCI93815

Mo, M.-L., Li, M.-R., Chen, Z., Liu, X.-W., Sheng, Q., & Zhou, H.-M. (2013). Inhibition of the Wnt palmitoyltransferase porcupine suppresses cell growth and downregulates the Wnt/β-catenin pathway in gastric cancer. Oncology letters, 5(5), 1719-1723. doi:10.3892/ol.2013.1256

Mohammed, M. K., Shao, C., Wang, J., Wei, Q., Wang, X., Collier, Z., . . . Lee, M. J. (2016). Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 3(1), 11-40. doi:10.1016/j.gendis.2015.12.004

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

Naujok, O., Lentes, J., Diekmann, U., Davenport, C., & Lenzen, S. (2014). Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes, 7, 273. doi:10.1186/1756-0500-7-273

Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci U S A, 114(16), 4147-4152. doi:10.1073/pnas.1618293114

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

Pearlman, R. L., Montes de Oca, M. K., Pal, H. C., & Afaq, F. (2017). Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. Cancer Lett, 391, 125-140. doi:10.1016/j.canlet.2017.01.029

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

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

Pez, F., Lopez, A., Kim, M., Wands, J. R., Caron de Fromentel, C., & Merle, P. (2013). Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol, 59(5), 1107-1117. doi:10.1016/j.jhep.2013.07.001

Pirozzi, G., Tirino, V., Camerlingo, R., Franco, R., La Rocca, A., Liguori, E., . . . Rocco, G. (2011). Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One, 6(6), e21548-e21548. doi:10.1371/journal.pone.0021548

Polakis, P. (2012). Wnt signaling in cancer. Cold Spring Harb Perspect Biol, 4(5). doi:10.1101/cshperspect.a008052

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

Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434(7035), 843-850. doi:10.1038/nature03319

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

Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016a). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7(1), 13096. doi:10.1038/ncomms13096

Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016b). 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

Saito-Diaz, K., Chen, T. W., Wang, X., Thorne, C. A., Wallace, H. A., Page-McCaw, A., & Lee, E. (2013). The way Wnt works: components and mechanism. Growth Factors, 31(1), 1-31. doi:10.3109/08977194.2012.752737

Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell death & disease, 2(7), e179-e179. doi:10.1038/cddis.2011.61

Sciacovelli, M., & Frezza, C. (2017). Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J, 284(19), 3132-3144. doi:10.1111/febs.14090

Semenov, M. V., Zhang, X., & He, X. (2008). DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation. J Biol Chem, 283(31), 21427-21432. doi:10.1074/jbc.M800014200

Shen, M., Bai, D., Liu, B., Lu, X., Hou, R., Zeng, C., . . . Yin, T. (2018). Dysregulated Txnip-ROS-Wnt axis contributes to the impaired ischemic heart repair in diabetic mice. Biochimica et biophysica acta. Molecular basis of disease, 1864(12), 3735-3745. doi:10.1016/j.bbadis.2018.09.029

Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol, 14(10), 611-629. doi:10.1038/nrclinonc.2017.44

Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in Metastasis and Therapy Resistance. J Clin Med, 5(2). doi:10.3390/jcm5020017

Sohn, S. H., Kim, B., Sul, H. J., Kim, Y. J., Kim, H. S., Kim, H., . . . Zang, D. Y. (2019). INC280 inhibits Wnt/beta-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification. BMC Res Notes, 12(1), 125. doi:10.1186/s13104-019-4163-x

Stump, B., Shrestha, S., Lamattina, A. M., Louis, P. H., Cho, W., Perrella, M. A., . . . El-Chemaly, S. (2019). Glycogen synthase kinase 3-beta inhibition induces lymphangiogenesis through beta-catenin-dependent and mTOR-independent pathways. PLoS One, 14(4), e0213831. doi:10.1371/journal.pone.0213831

Suarez-Carmona, M., Lesage, J., Cataldo, D., & Gilles, C. (2017). EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 11(7), 805-823. doi:10.1002/1878-0261.12095

Sun, J., Yang, X., Zhang, R., Liu, S., Gan, X., Xi, X., . . . Sun, Y. (2017). GOLPH3 induces epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in epithelial ovarian cancer. Cancer Med, 6(4), 834-844. doi:10.1002/cam4.1040

Taelman, V. F., Dobrowolski, R., Plouhinec, J. L., Fuentealba, L. C., Vorwald, P. P., Gumper, I., . . . De Robertis, E. M. (2010). Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell, 143(7), 1136-1148. doi:10.1016/j.cell.2010.11.034

Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. World journal of stem cells, 5(3), 61-67. doi:10.4252/wjsc.v5.i3.61

Tanabe, S. (2014). Role of mesenchymal stem cells in cell life and their signaling. World journal of stem cells, 6(1), 24-32. doi:10.4252/wjsc.v6.i1.24

Tanabe, S. (2015a). Origin of cells and network information. World journal of stem cells, 7(3), 535-540. doi:10.4252/wjsc.v7.i3.535

Tanabe, S. (2015b). Signaling involved in stem cell reprogramming and differentiation. World journal of stem cells, 7(7), 992-998. doi:10.4252/wjsc.v7.i7.992

Tanabe, S. (2015c). Overview of gene regulation in stem cell network to identify therapeutic targets utilizing genome databases. Insights Stem Cells, 1(1).

Tanabe, S. (2017). Molecular markers and networks for cancer and stem cells. J Embryol Stem Cell Res, 1(1).

Tanabe, S. (2018). Wnt Signaling and Epithelial-Mesenchymal Transition Network in Cancer. Res J Oncol, 2(2).

Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2014). Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition. Int J Oncol, 44(6), 1955-1970. doi:10.3892/ijo.2014.2387

Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. World journal of stem cells, 7(1), 208-222. doi:10.4252/wjsc.v7.i1.208

Tanabe, S., Kawabata, T., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Gene expression and pathway analysis of CTNNB1 in cancer and stem cells. World J Stem Cells, 8(11), 384-395. doi:10.4252/wjsc.v8.i11.384

Tanabe, S., Komatsu, M., Kazuhiko, A., Yokozaki, H., & Sasaki, H. (2015). Implications of epithelial-mesenchymal transition in gastric cancer. Translational Gastrointestinal Cancer, 4(4), 258-264. Retrieved from http://tgc.amegroups.com/article/view/6996

Tanabe S, Quader S, Cabral H, Ono R. (2020a). Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. Front Pharmacol. Jun 17;11:904. doi: 10.3389/fphar.2020.00904. PMID: 32625096; PMCID: PMC7311659.

Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, Yokozaki H, Sasaki H. (2020b). Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer. Cancers (Basel). Dec 18;12(12):3833. doi: 10.3390/cancers12123833. PMID: 33353109; PMCID: PMC7765985.

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

Vikram, A., Kim, Y.-R., Kumar, S., Naqvi, A., Hoffman, T. A., Kumar, A., . . . Irani, K. (2014). Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species. Arteriosclerosis, thrombosis, and vascular biology, 34(10), 2301-2309. doi:10.1161/ATVBAHA.114.304338

Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). doi:10.1042/BSR20171092

Wang, H. X., Li, T. Y., & Kidder, G. M. (2010). WNT2 regulates DNA synthesis in mouse granulosa cells through beta-catenin. Biol Reprod, 82(5), 865-875. doi:10.1095/biolreprod.109.080903

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

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004763/

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

Wendt, M. K., Smith, J. A., & Schiemann, W. P. (2010). Transforming growth factor-beta-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene, 29(49), 6485-6498. doi:10.1038/onc.2010.377

Willert, K., & Nusse, R. (2012). Wnt proteins. Cold Spring Harb Perspect Biol, 4(9), a007864. doi:10.1101/cshperspect.a007864

Wu, W.-S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., & Look, A. T. (2005). Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma. Cell, 123(4), 641-653. doi:https://doi.org/10.1016/j.cell.2005.09.029