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Aop: 298

AOP Title

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

Short name:

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Chronic ROS leading to human treatment-resistant gastric cancer

Graphical Representation

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Authors

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

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

Point of Contact

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Shihori Tanabe   (email point of contact)

Contributors

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  • Shihori Tanabe

Status

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Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome Under Development 1.58 Included in OECD Work Plan


This AOP was last modified on October 13, 2020 05:35

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Revision dates for related pages

Page Revision Date/Time
Epithelial-mesenchymal transition March 23, 2020 04:18
Treatment-resistant gastric cancer May 07, 2020 04:04
Chronic reactive oxygen species September 29, 2020 21:21
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion September 29, 2020 21:20
Proliferation/ beta-catenin activation September 29, 2020 21:25
Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion September 29, 2020 22:05
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion leads to Proliferation/ beta-catenin activation September 29, 2020 21:32
Proliferation/ beta-catenin activation leads to Epithelial-mesenchymal transition September 29, 2020 21:42
Epithelial-mesenchymal transition leads to Resistant gastric cancer September 29, 2020 21:44
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

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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 treatment-resistant gastric cancer” 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 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.


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
1 MIE 1753 Chronic reactive oxygen species Chronic ROS
2 KE 1754 Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion
3 KE 1755 Proliferation/ beta-catenin activation Proliferation/ beta-catenin activation
4 KE 1650 Epithelial-mesenchymal transition Epithelial-mesenchymal transition
5 AO 1651 Treatment-resistant gastric cancer Resistant gastric cancer

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion adjacent Moderate Moderate
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion leads to Proliferation/ beta-catenin activation adjacent High Moderate
Proliferation/ beta-catenin activation leads to Epithelial-mesenchymal transition adjacent Moderate Moderate
Epithelial-mesenchymal transition leads to Resistant gastric cancer adjacent High Moderate

Network View

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Stressors

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Name Evidence Term
Wnt High
WNT2 High
Porcupine Moderate
Wntless Moderate
Ionizing Radiation Moderate
ferric nitrilotriacetate Not Specified

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: Aop298 overall assessment 5 8 20

1. Support for Biological Plausibility of KER

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 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)..

KE1 => KE2:
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation

Biological Plausibility of the KE1 => KE2 is high.
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, 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; 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 high.
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). 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.
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.
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.
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 high.
Rationale: Dishevelled (DVL), a positive regulator of Wnt signaling, form the complex with FZD and lead to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang et al., 2015).

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: 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, 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:
Epithelial-mesenchymal transition (EMT) leads to human treatment-resistant gastric cancer

Empirical Support of the KE3 => AO is moderate.
Rationale: EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in the resistant 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 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 (Tanabe, 2015c).


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 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

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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

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

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

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

Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. Cell Death Dis, 10(3), 208. doi:10.1038/s41419-019-1449-9

Yu, J., & Virshup, David M. (2014). Updating the Wnt pathways. Bioscience Reports, 34(5). doi:10.1042/BSR20140119

Zeisberg, M., & Neilson, E. G. (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest, 119(6), 1429-1437. doi:10.1172/JCI36183

Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. Proc Natl Acad Sci U S A, 115(44), E10362-E10369. doi:10.1073/pnas.1808575115

Zhang, J., Tian, X. J., & Xing, J. (2016). Signal Transduction Pathways of EMT Induced by TGF-beta, SHH, and WNT and Their Crosstalks. J Clin Med, 5(4). doi:10.3390/jcm5040041

Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle, 14(4), 481-487. doi:10.1080/15384101.2015.1006048

Zhang, Z., Wang, X., Cheng, S., Sun, L., Son, Y.-O., Yao, H., . . . Shi, X. (2011). Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicology and Applied Pharmacology, 256(2), 114-121. doi:https://doi.org/10.1016/j.taap.2011.07.016

Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. doi:10.1371/journal.pone.0160414

Ziv, E., Yarmohammadi, H., Boas, F. E., Petre, E. N., Brown, K. T., Solomon, S. B., . . . Erinjeri, J. P. (2017). Gene Signature Associated with Upregulation of the Wnt/beta-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization. J Vasc Interv Radiol, 28(3), 349-355 e341. doi:10.1016/j.jvir.2016.11.004