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Relationship: 2614

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

EMT leads to Metastasis, Breast Cancer

Upstream event

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

EMT

Downstream event

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

Metastasis, Breast Cancer

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
Alcohol Induced DNA damage and mutations leading to Metastatic Breast Cancer	adjacent	High	High	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development

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
human and other cells in culture	human and other cells in culture	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

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

Sex	Evidence
Female	High

Life Stage Applicability

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

Term	Evidence
Adult, reproductively mature	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

Upstream event: Increased, EMT

Downstream event: Metastasis

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

The “epithelial–mesenchymal transition” (EMT), a key developmental regulatory program, has been reported to play critical and intricate roles in promoting tumor invasion and metastasis in epithelium-derived carcinomas in recent years. The EMT program allows stationary and polarized epithelial cells, which are connected laterally via several types of junctions and normally interact with the basement membrane via their basal surfaces to maintain apical–basal polarity, to undergo multiple biochemical changes that enable them to disrupt cell–cell adherence, lose apical–basal polarity, dramatically remodel the cytoskeleton, and acquire mesenchymal characteristics such as enhanced migratory capacity, invasiveness, elevated resistance to apoptosis and greatly increased production of ECM components. (Boyer et al., 1993).Some of the cells undergoing EMT have the characteristics of cancer stem cells (CSCs), which are linked to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).Cancer metastasis and cancer therapeutic resistance are linked to the EMT phenomenon (Smith & Bhowmick, 2016; Tanabe, 2013). EMT causes the cell to escape from the basement membrane and metastasize by increasing the production of enzymes that breakdown extracellular matrix components and decreasing adherence to the basement membrane (Smith & Bhowmick, 2016). Therapy resistance is linked to morphological alterations seen during EMT (Smith & Bhowmick, 2016).

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

Biological Plausibility

EMT is marked by a decrease in E-cadherin and β- -catenin translocation into the nucleus and an increase in vimentin, fibronectin, and N-cadherin expression (Irani et al., 2018,Tanabe et al., 2016). EMT is a master mechanism in cancer cells that allows them to lose their epithelial characteristics and gain mesenchymal-like qualities. EMT is the most crucial step in initiating metastasis, including metastasis to lymph nodes, because tumour cell movement is a pre-requisite for the metastatic process (Da et al., 2017). Multiple signalling pathways cause cancer cells to lose their cell-to-cell connections and cellular polarity during EMT, increasing their motility and invasive ness (Huang et al., 2017). MMPs cause E-cadherin to be cleaved, which increases tumour cell motility and invasion (Pradella et al., 2017).

Invasiveness and medication resistance are linked to the morphological and physiological changes associated with EMT (Shibue & Weinberg, 2017). In initial tumours, EMT-activated carcinoma cells penetrate the surrounding stroma (Shibue & Weinberg, 2017). EMT-activated carcinoma cells interact with the extracellular matrix protein to activate focal adhesion kinase and extracellular signal-related kinase, followed by TGFbeta and canonical and/or noncanonical Wnt pathways to develop cancer stem cell (CSC) traits, which contribute to drug resistance (Shibue & Weinberg, 2017).

Drug efflux and cell proliferation are slowed by EMT-associated downregulation of several apoptotic signalling pathways, resulting in general resistance of carcinoma cells to anti-cancer drugs (Shibue & Weinberg, 2017).Snail, an EMT-related transcription factor, promotes the production of the AXL receptor tyrosine kinase, which allows cancer cells to survive by activating AXL signalling when its ligand, growth arrest-specific protein 6 (GAS6), binds to it (Shibue & Weinberg, 2017).

EMT-activated cells are resistant to the deadly effects of cytotoxic T cells, which include increased expression of programmed cell death 1 ligand (PD-L1), which binds to the inhibitory immune-checkpoint receptor programmed cell death protein 1 (PD-1) on the cell surface of cytotoxic T cells(Shibue & Weinberg, 2017).

The reversing process of EMT, which names as a mesenchymal-epithelial transition (MET), maybe one of the candidates for the anti-cancer therapy, where the plasticity of the cell phenotype is of importance and under investigation (Shibue & Weinberg, 2017).

Empirical Evidence

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

Incidence concordance

By inhibiting PUMA (also known as BBC3, encoding Bcl-2-binding component 3) and conferring resistance to p53-mediated apoptosis of hematopoietic progenitors, Slug/Snai2, a ces-1-related zinc finger transcription factor gene, confers resistance to p53-mediated apoptosis of hematopoietic progenitors (Inukai et al., 1999; Shibue & Weinberg, 2017; W.-S. Wu et al., 2005).TGFbeta-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties by inducing the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in doxorubicin resistance (Saxena et al.,2011; Shibue & Weinberg, 2017). (Pirozzi et al., 2011; Shibue & Weinberg, 2017).Cancer metastasis and resistance to dendritic cell-mediated immunotherapy are promoted by snail-driven EMT (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009).EMT induced by the zinc finger E-box-binding homeobox (ZEB1) relieves 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 lymphocytes (CTL), resulting in immunosuppression and metastasis of CD8+ T cells (Chen et al., 2014).
Wnt signalling is important for embryonic development, and genetic abnormalities in this network have been linked to colorectal cancer(Gujral et al.,2014). The Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are enhanced in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade malignancies, and their expression correlates with epithelial-mesenchymal transition markers (EMT)(They created an anti-Fzd2 antibody that decreases tumour growth and metastasis in xenografts by reducing cell migration and invasion(Support for essentiality). Patients with malignancies that exhibit high levels of Fzd2 and Wnt5a/b may benefit from blocking this pathway, according to the researchers.
In breast, colon, liver, and 186 lung cancer cell lines, researchers discovered a link between Fzd2 and its ligands Wnt5a/b and mesenchymal markers.
- Fzd2 mRNA expression is significantly increased in late stages (stages III and IV) of primary liver and lung cancers compared with normal tissue
-Fzd2 regulated cell migration.
- Fzd2 signaling regulates EMT program
-expression of Fzd2 in Huh7 cells decreased levels of the epithelial markers E-cadherin and Occludin and increased levels of the mesenchymal markers Foxc1 and Vimentin.
- Exposing cells to an inhibitor of Wnt secretion (C59) decreased Stat3 transcriptional activity in FOCUS cells 2- to 4-fold, whereas overexpressing Fzd2 in Huh7 cells increased Stat3 activity 2-fold.
Cui et al discovered a link between metastasis and the expression of ROR1, a type I receptor tyrosine kinase–like orphan receptor that is expressed throughout embryogenesis and by a variety of malignancies but not by normal postpartum tissues(Cui et al.,2013). ROR1 expression has been linked to the epithelial–mesenchymal transition (EMT), which occurs during embryogenesis and cancer metastasis, according to their findings. Breast adenocarcinomas with high ROR1 expression were more likely to have gene expression profiles consistent with EMT and had greater rates of recurrence and metastasis than those with low ROR1 expression. Suppressing ROR1 expression in metastasis-prone breast cancer cell lines MDA-MB-231, HS-578T, or BT549 decreased expression of proteins associated with EMT (e.g., vimentin, SNAIL-1/2, and ZEB1), increased expression of E-cadherin, epithelial cytokeratins (e.g., CK-19), and tight junction proteins (e.g., ZO-1), and impaired their migration/invasion capacity in vitro.( Support for essentiality)
-Conversely, transfection of MCF-7 cells to express ROR1 reduced expression of E-cadherin and CK-19, but enhanced the expression of SNAIL-1/2 and vimentin. Treatment of MDA-MB-231 with a monoclonal antibody specific for ROR1 induced downmodulation of vimentin and inhibited cancer cell migration and invasion in vitro and tumor metastasis in vivo.
- ROR1 associates with metastatic cancer phenotypes
- ROR1 is associated with early metastatic relapse in breast adenocarcinoma
- Silencing ROR1 inhibits orthotopic lung metastasis
- Silencing ROR1 inhibits experimental lung and bone metastasis
- An anti-ROR1 antibody inhibits cancer metastasis(Support for essentiality)
At 37°C, monoclonal antibodies (mAb) specific for ROR1's extracellular domain were created, and one (D10) was chosen to elicit fast downmodulation of surface ROR1 . ROR1 internalisation was observed in MDA-MB-231 cells treated with D10, as determined by confocal microscopy . As measured by flow cytometry with a separate mAb specific for a unique, non–cross-blocking epitope of ROR1, this resulted in a considerable reduction in ROR1 . D10 treatment of MDA-MB-231 reduced cytoplasmic vimentin expression , which was bound to ROR1 in coimmunoprecipitation studies . In vitro, D10 treatment significantly reduced the ability of MDA-MB-231 to migrate and invade . D10 may also be able to stop other ROR1 cancer cell lines from migrating or invading.
Chen et al investigated the potential function of MDM2 in ovarian cancer SKOV3 cells' EMT and metastasis(Chen et al.,2015).
Wound-healing and transwell tests were used to mimic MDM2's regulatory effects on cell motility. By displaying the expression levels of epithelial marker E-cadherin as well as critical components of the Smad pathway, the impacts on EMT transition and Smad pathway were explored. The connection of MDM2 expression levels with the stages of 104 ovarian cancer patients was explored using an immunohistochemical assay to assess the clinical relevance of their findings.
Results show that MDM2 plays a significant role in driving EMT and motility in ovarian SKOV3 cells by promoting the activation of the TGF-b-Smad pathway, which leads to increased snail/slug transcription and a decrease of E-cadherin levels.
Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, but is reduced by MDM2 N-terminal deletion, as evidenced by Nutlin-3a, the N-terminal targeting agent's inhibitory effects on EMT. MDM2 expression levels are substantially correlated with ovarian cancer stages, and increased MDM2 expression in combination with TGFB is associated with a bad prognosis and predicts a high risk of ovarian cancer patients.
This research suggests that MDM2 activates the Smad pathway to promote EMT in ovarian cancer metastasis, and that targeting MDM2's N-terminal can reprogram EMT and limit cancer cell mobility.
HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colo rectal cancer (CRC), is mostly unknown.Liu and colleagues used immunofluorescence, immunohistochemistry (IHC), and western blot to examine the levels of HOXD9 protein expression. Colony formation and EdU in-corporation, CCK-8, wound scratch and transwell invasion assays, and animal models were used to determine the in vivo and in vitro roles of HOXD9 in CRC. In CRC, HOXD9 expression was higher than in matched healthy tissues (Liu et al.,2020). High HOXD9 expression has been linked to advanced stages of cancer, tumour differentiation, lymph node metastasis, and other serious invasions, as well as a poor prognosis, according to the American Joint Committee on Cancer (AJCC). In CRC cells, HOXD9 promoted proliferation, motility, and EMT processes in vitro. TGF-1 also stimulated the expression of HOXD9, which was dosage dependent, and HOXD9 downregulation suppressed TGF-1-induced EMT. Through orthotopic implantation, HOXD9 promoted the invasiveness and metastasis of CRC cells in vivo.The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo.
Twist1, Snail1, Snail2, ZEB1, and ZEB2 are among a group of transcription factors that have been demonstrated to promote tumour spread by inducing epithelial mesenchymal transition (EMT). However, it is unknown whether these transcription factors activate the EMT program separately or in concert. Twist1 requires direct induction of Snail2 to induce EMT, according to the study by Casas et al. Twist1's capacity to decrease E-cadherin transcription is totally blocked when Snail2 is knocked off. Twist1 induces Snail2 transcription by binding to an evolutionarily conserved E-box on the proximal promoter. Twist1-induced cell invasion and distant metastasis in mice require Snail2 induction. Twist1 and Snail2 expression in human breast cancers are significantly linked.Results of the study by Casas et al show that Twist1 needs to induce Snail2 to suppress the epithelial branch of the EMT program and that Twist1 and Snail2 act together to promote EMT and tumor metastasis in human mammary epithelial cell lines (Casas et al.,2012).
The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c-MYC target gene and is up-regulated in colorectal cancer (CRC) and a variety of other tumour types at the same time as c-MYC. A combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic studies were used to characterise AP4 DNA binding and mRNA expression across the genome. Hundreds of AP4 target genes were identified as activated and repressed as a result. SNAIL, E-cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7 were among the AP4 target genes, which included markers of stemness (LGR5 and CD44) and epithelial–mesenchymal transition (EMT) such as SNAIL, E-cadherin/CDH1, OCLN, VIM, and FN1. As a result, AP4 activation promoted EMT and increased CRC cell motility and invasion. Down-regulation of AP4 hindered migration and invasion by causing mesenchymal–epithelial transition (Jackstadt et al.,2013).
EMT, migration, and invasion produced by ectopic expression of c-MYC also needed AP4 induction. Lung metastasis in mice was reduced when AP4 was inhibited in CRC cells. Increased AP4 expression was linked to liver metastases and poor patient survival in primary CRC. These findings point to AP4 as a novel EMT regulator that plays a role in CRC and maybe other carcinomas' metastatic processes.

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

Whenever cell phenotype plasticity is crucial and under investigation, the reverse of EMT, known as the mesenchymal-epithelial transition (MET), may be one of the prospects for anti-cancer therapy (Shibue & Weinberg, 2017).

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

In EMT-activated cells, ABC transporters linked to drug resistance are overexpressed (Saxena et al., 2011). In EMT-activated cells, the expression of PD-L1, which binds to PD-1 on cytotoxic T cells, is upregulated, inhibiting cancer immunity and increasing resistance to cancer therapy (Shibue & Weinberg, 2017).

Quantitative Understanding of the Linkage

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

	Method/ measurement reference	Reliability	Strength of evidence	Assay fit for purpose	Repeatability/ reproducibility	Direct measure
Cell line,humans,Human cell line studies	qRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, bioluminesence imaging,wound healing assay,Wound scratch & Transwell assay, Microarray,Immunofluorescence, Immunohistochemistry (table 1)	Yes	Strong	Yes	Yes	Yes

Response-response Relationship

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

TGFbeta and Twist induce EMT by upregulating the expression of EMT markers such Snail, Vimentin, N-cadherin, and ABC transporters like ABCA3, ABCC1, ABCC3, and ABCC10 (Saxena et al., 2011).In the treatment with about 0.3, 3, 30 mM of doxorubicin, human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrate increased cell viability compared to control HMLE, dose-dependently (Saxena et al., 2011).

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

When Twist/FOXC2/Snail overexpressed HMLE is treated with doxorubicin for 48 hours, cell viability increases compared to control HMLE (Saxena et al., 2011).When Twist or Zeb1 were inhibited with small interference RNA (siRNA), cell viability was reduced relative to control MDAMB231 cells treated with doxorubicin for 48 hours (Saxena et al., 2011).

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

Understanding the association between EMT and cancer malignancy necessitates further research into the EMT-cancer stem cells (CSC) relationship. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSCs, resulting in tumorigenic potential renewal (Marjanovic, Weinberg, & Chaffer, 2013; Shibue & Weinberg, 2017).The plastic CSC theory demonstrates bidirectional conversions between non-CSCs and CSCs, which could help EMT-activated cells acquire cancer malignancy (Marjanovic et al., 2013).

Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. Kong et al reported a novel lncRNA, LINC01133 that was downregulated by TGF- β, which could inhibit epithelial–mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC) cells (Kong et al.,2016). SRSF6, an alternative splicing factor that interacts directly with LINC01133, was found to enhance EMT and metastasis in CRC cells even when LINC01133 was not present. The study also found that the EMT process in CRC cells was regulated by LINC01133 in the presence of SRSF6. In vivo, the ability of LINC01133 to prevent metastasis was confirmed. Furthermore, clinical data revealed that LINC01133 expression was favourably correlated with E-cadherin and negatively correlated with Vimentin, and that low LIINC01133 expression in tumours was associated with poor CRC survival. These findings show that LINC01133, by directly binding to SRSF6 as a target mimic and inhibiting EMT and metastasis, could be used as a predictive biomarker and an effective target for anti-metastasis therapy in CRC.
MiR-148a inhibited Met expression directly by binding to its 30-UTR, according to Zhang et al's findings. Furthermore, reintroducing miR-148a reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT, by inhibiting Met's downstream signalling, such as activating phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3b-Ser9 (Zhang et al.,2015). MiR-148a, when combined, may suppress hepatoma cell EMT and metastasis by adversely regulating Met/Snail signalling.

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

EMT induces cancer invasion, metastasis (Homo sapiens)(P. Zhang et al., 2015).

EMT is related to cancer drug resistance in MCF-7 human breast cancer cells (Homo sapiens)(B. Du & Shim, 2016).

References

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

BOYER, B., & THIERY, J. P. (1993). Epithelium‐mesenchyme interconversion as example of epithelial plasticity. Apmis, 101(1‐6), 257-268.

Chen, S. P., Liu, B. X., Xu, J., Pei, X. F., Liao, Y. J., Yuan, F., & Zheng, F. (2015). MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC cancer, 15(1), 1-13.

Cui, B., Zhang, S., Chen, L., Yu, J., Widhopf, G. F., Fecteau, J. F., ... & Kipps, T. J. (2013). Targeting ROR1 inhibits epithelial–mesenchymal transition and metastasis. Cancer research, 73(12), 3649-3660.

Chen, Y., Wang, D. D., Wu, Y. P., Su, D., Zhou, T. Y., Gai, R. H., ... & Yang, B. (2017). MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. British journal of cancer, 117(8), 1192-1201..

Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C. J., & Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer research, 71(1), 245-254.

Chen, L., Mai, W., Chen, M., Hu, J., Zhuo, Z., Lei, X., ... & Zhang, D. (2017). Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacological research, 123, 130-142.

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(1), 1-12.

Da, C., Wu, K., Yue, C., Bai, P., Wang, R., Wang, G., ... & Hou, P. (2017). N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways. Oncotarget, 8(5), 8131.

Du, B., & Shim, J. S. (2016). Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules, 21(7), 965.

Gao, J., Yang, Y., Qiu, R., Zhang, K., Teng, X., Liu, R., & Wang, Y. (2018). Proteomic analysis of the OGT interactome: novel links to epithelial–mesenchymal transition and metastasis of cervical cancer. Carcinogenesis, 39(10), 1222-1234.

Gumireddy, K., Li, A., Gimotty, P. A., Klein-Szanto, A. J., Showe, L. C., Katsaros, D., ... & Huang, Q. (2009). KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nature cell biology, 11(11), 1297-1304.
Gujral, T. S., Chan, M., Peshkin, L., Sorger, P. K., Kirschner, M. W., & MacBeath, G. (2014). A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell, 159(4), 844-856.

Huang, Y., Zhao, M., Xu, H., Wang, K., Fu, Z., Jiang, Y., & Yao, Z. (2014). RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis. Oncotarget, 5(16), 6734.

Huang, R., & Zong, X. (2017). Aberrant cancer metabolism in epithelial–mesenchymal transition and cancer metastasis: Mechanisms in cancer progression. Critical reviews in oncology/hematology, 115, 13-22.

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.
Irani, S., & Dehghan, A. (2018). The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. Journal of International Society of Preventive & Community Dentistry, 8(2), 110.
Jackstadt, R., Röh, S., Neumann, J., Jung, P., Hoffmann, R., Horst, D., ... & Hermeking, H. (2013). AP4 is a mediator of epithelial–mesenchymal transition and metastasis in colorectal cancer. Journal of Experimental Medicine, 210(7), 1331-1350.
Kong, J., Sun, W., Li, C., Wan, L., Wang, S., Wu, Y., ... & Lai, M. (2016). Long non-coding RNA LINC01133 inhibits epithelial–mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. Cancer letters, 380(2), 476-484.
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.
Liang, Y. J., Wang, Q. Y., Zhou, C. X., Yin, Q. Q., He, M., Yu, X. T., ... & Zhao, Q. (2013). MiR-124 targets Slug to regulate epithelial–mesenchymal transition and metastasis of breast cancer. Carcinogenesis, 34(3), 713-722.
Liu, Y., Wang, G., Yang, Y., Mei, Z., Liang, Z., Cui, A., ... & Cui, L. (2016). Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner. Oncogene, 35(21), 2789-2800.

Liu, M., Xiao, Y., Tang, W., Li, J., Hong, L., Dai, W., ... & Xiang, L. (2020). HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma. Cancer medicine, 9(11), 3932-3943.

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

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.

Pradella, D., Naro, C., Sette, C., & Ghigna, C. (2017). EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Molecular cancer, 16(1), 1-19.
Sarkar, T. R., Battula, V. L., Werden, S. J., Vijay, G. V., Ramirez-Peña, E. Q., Taube, J. H., ... & Mani, S. A. (2015). GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer. Oncogene, 34(23), 2958-2967.
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.
Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nature reviews Clinical oncology, 14(10), 611-629.
Shiota, M., Zardan, A., Takeuchi, A., Kumano, M., Beraldi, E., Naito, S., ... & Gleave, M. E. (2012). Clusterin mediates TGF-β–induced epithelial–mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer research, 72(20), 5261-5272.
Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in metastasis and therapy resistance. Journal of clinical medicine, 5(2), 17.
Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. World journal of stem cells, 5(3), 61.
Tanabe, S. (2015). Origin of cells and network information. World journal of stem cells, 7(3), 535.
Tanabe, S. (2015). Signaling involved in stem cell reprogramming and differentiation. World journal of stem cells, 7(7), 992.
Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Regulation of CTNNB1 signaling in gastric cancer and stem cells. World journal of gastrointestinal oncology, 8(8), 592–598.
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.
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