API

Event: 1650

Key Event Title

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Epithelial-mesenchymal transition

Short name

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Epithelial-mesenchymal transition

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
cell


Organ term

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Organ term
organ


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Chronic ROS leading to human gastric cancer KeyEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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Epithelial-mesenchymal transition (EMT) is a phenomenon in which the cells transit from epithelial-like into mesenchymal-like phenotypes (S. Tanabe, 2017; Shihori Tanabe, Komatsu, Kazuhiko, Yokozaki, & Sasaki, 2015). In cancer, cells exhibiting EMT features contribute into the metastasis and drug resistance.

It is known that D-2-hydroxyglurate induces EMT(Guerra et al., 2017; Jia, Park, Jung, Levine, & Kaipparettu, 2018; Mishra et al., 2018; Sciacovelli & Frezza, 2017). D-2-hydroxyglurate, an inhibitor of Jumonji-family histone demethylase, increased the trimethylation of histone H3 lysine 4 (H3K4) in the promoter region of the ZEB1, followed by the induction of EMT (Colvin et al., 2016).

Wnt5a induces EMT and metastasis in non-small-cell lung cancer (Wang, Tang, Gong, Zhu, & Liu, 2017).

EMT is related to Wnt/beta-catenin signaling and important for cancer (S. Tanabe, Kawabata, Aoyagi, Yokozaki, & Sasaki, 2016)

TGFb induces EMT (Wendt, Smith, & Schiemann, 2010).

ZEB is one of the important transcription factors for EMT regulation (Zhang, Sun, & Ma, 2015).

SNAI1 (Snail) is an important transcription factor for cell differentiation and survival, and the phosphorylation and nuclear localization of Snail1 induced by Wnt signaling pathways are critical for the regulation of EMT (Kaufhold & Bonavida, 2014).

Transcription factors SNAI1 and TWIST1 induce EMT (Hodge, Cui, Gamble, & Guo, 2018) (Mani et al., 2008)

It is suggested that Sp1, a transcription factor involved in cell growth and metastasis, is induced by cytochrome P450 1B1 (CYP1B1), and promotes EMT, which leads to cell proliferation and metastasis (Kwon et al., 2016).


How It Is Measured or Detected

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  • EMT can be detected by immunostaining with pro-surfactant protein-C (pro-SPC) and N-cadherin in idiopathic pulmonary fibrosis (IPF) lung in vivo (Kim et al., 2006).
  • TGFbeta induces EMT, which can be detected by immunostaining with vimentin in lung aloevela in vivo (Kim et al., 2006).

Domain of Applicability

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  • Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in Homo sapiens (Wang et al., 2017).
  • WNT2 expression lead to EMT induction in Homo sapiens (Zhou et al., 2016).
  • EMT is induced in cancer and involved in cancer metastasis in Homo sapiens (Suarez-Carmona, Lesage, Cataldo, & Gilles, 2017) (Du & Shim, 2016).

Evidence for Perturbation by Stressor



GOLPH3

GOLPH3 induces EMT (Sun et al., 2017).


LiCl

LiCl induces EMT (Fang et al., 2018).


D-2-hydroxyglutarate

D-2-hydroxyglutarate induces EMT (Colvin et al., 2016).


References

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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