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Epithelial-Mesenchymal Transition-Inducing Factors Involved in the Progression of Lung Cancers

  • Nam, Min-Woo (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Kim, Cho-Won (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Choi, Kyung-Chul (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University)
  • Received : 2021.11.26
  • Accepted : 2022.01.05
  • Published : 2022.05.01

Abstract

Although there have been advances in cancer therapy and surgical improvement, lung cancer has the lowest survival rate (19%) at all stages. This is because most patients are diagnosed with concurrent metastasis, which occurs due to numerous related reasons. Especially, lung cancer is one of the most common and malignant cancers in the world. Although there are advanced therapeutic strategies, lung cancer remains one of the main causes of cancer death. Recent work has proposed that epithelial-mesenchymal transition (EMT) is the main cause of metastasis in most cases of human cancers including lung cancer. EMT involves the conversion of epithelial cells, wherein the cells lose their epithelial abilities and become mesenchymal cells involved in embryonic development, such as gastrulation and neural crest formation. In addition, recent research has indicated that EMT contributes to altering the cancer cells into cancer stem cells (CSCs). Although EMT is important in the developmental stages, this process also activates lung cancer progression, including complicated and diverse signaling pathways. Despite the numerous investigations on signaling pathways involved in the progression of lung cancer, this malignancy is considered critical for treatment. EMT in lung cancer involves many transcription factors and inducers, for example, Snail, TWIST, and ZEB are the master regulators of EMT. EMT-related factors and signaling pathways are involved in the progression of lung cancer, proposing new approaches to lung cancer therapy. In the current review, we highlight the signaling pathways implicated in lung cancer and elucidate the correlation of these pathways, indicating new insights to treat lung cancer and other malignancies.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Program (2020R1A2C2006060) and the Global Research and Development Center (GRDC) Program (2017K1A4A3014959) through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science and ICT. This study was also supported by Regional Innovation Strategy (RIS; #1345329680) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE).

References

  1. Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M. and Nieto, M. A. (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119, 1438-1449. https://doi.org/10.1172/JCI38019
  2. Arnold, S. J. and Robertson, E. J. (2009) Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell Biol. 10, 91-103. https://doi.org/10.1038/nrm2618
  3. Balzac, F., Avolio, M., Degani, S., Kaverina, I., Torti, M., Silengo, L., Small, J. V. and Retta, S. F. (2005) E-cadherin endocytosis regulates the activity of Rap1: a traffic light GTPase at the crossroads between cadherin and integrin function. J. Cell Sci. 118, 4765-4783. https://doi.org/10.1242/jcs.02584
  4. Barbera, M. J., Puig, I., Dominguez, D., Julien-Grille, S., Guaita-Esteruelas, S., Peiro, S., Baulida, J., Franci, C., Dedhar, S., Larue, L. and Garcia de Herreros, A. (2004) Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23, 7345-7354. https://doi.org/10.1038/sj.onc.1207990
  5. Barrallo-Gimeno, A. and Nieto, M. A. (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151-3161. https://doi.org/10.1242/dev.01907
  6. Basch, M. L., Bronner-Fraser, M. and Garcia-Castro, M. I. (2006) Specification of the neural crest occurs during gastrulation and requires Pax7. Nature 441, 218-222. https://doi.org/10.1038/nature04684
  7. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. and Crabtree, G. R. (1997) Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930-1934. https://doi.org/10.1126/science.275.5308.1930
  8. Bhowmick, N. A., Zent, R., Ghiassi, M., McDonnell, M. and Moses, H. L. (2001) Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J. Biol. Chem. 276, 46707-46713. https://doi.org/10.1074/jbc.M106176200
  9. Boutet, A., Esteban, M. A., Maxwell, P. H. and Nieto, M. A. (2007) Reactivation of Snail genes in renal fibrosis and carcinomas: a process of reversed embryogenesis? Cell Cycle 6, 638-642. https://doi.org/10.4161/cc.6.6.4022
  10. Bracken, C. P., Gregory, P. A., Kolesnikoff, N., Bert, A. G., Wang, J., Shannon, M. F. and Goodall, G. J. (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846-7854. https://doi.org/10.1158/0008-5472.CAN-08-1942
  11. Bronner-Fraser, M. (2002) Molecular analysis of neural crest formation. J. Physiol. Paris 96, 3-8. https://doi.org/10.1016/S0928-4257(01)00074-2
  12. Bronner, M. E. (2012) Formation and migration of neural crest cells in the vertebrate embryo. Histochem. Cell Biol. 138, 179-186. https://doi.org/10.1007/s00418-012-0999-z
  13. Buckingham, M., Bajard, L., Chang, T., Daubas, P., Hadchouel, J., Meilhac, S., Montarras, D., Rocancourt, D. and Relaix, F. (2003) The formation of skeletal muscle: from somite to limb. J. Anat. 202, 59-68. https://doi.org/10.1046/j.1469-7580.2003.00139.x
  14. Carlsson, P. and Mahlapuu, M. (2002) Forkhead transcription factors: key players in development and metabolism. Dev. Biol. 250, 1-23. https://doi.org/10.1006/dbio.2002.0780
  15. Castanon, I. and Baylies, M. K. (2002) A twist in fate: evolutionary comparison of Twist structure and function. Gene 287, 11-22. https://doi.org/10.1016/S0378-1119(01)00893-9
  16. Chilosi, M., Poletti, V., Zamo, A., Lestani, M., Montagna, L., Piccoli, P., Pedron, S., Bertaso, M., Scarpa, A., Murer, B., Cancellieri, A., Maestro, R., Semenzato, G. and Doglioni, C. (2003) Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol. 162, 1495-1502. https://doi.org/10.1016/S0002-9440(10)64282-4
  17. Chin, V. L. and Lim, C. L. (2019) Epithelial-mesenchymal plasticity-engaging stemness in an interplay of phenotypes. Stem Cell Investig. 6, 25. https://doi.org/10.21037/sci.2019.08.08
  18. De Craene, B., Gilbert, B., Stove, C., Bruyneel, E., van Roy, F. and Berx, G. (2005) The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 65, 6237-6244. https://doi.org/10.1158/0008-5472.CAN-04-3545
  19. De Robertis, E. M., Wessely, O., Oelgeschlager, M., Brizuela, B., Pera, E., Larrain, J., Abreu, J. and Bachiller, D. (2001) Molecular mechanisms of cell-cell signaling by the Spemann-Mangold organizer. Int. J. Dev. Biol. 45, 189-197.
  20. Duband, J. L., Monier, F., Delannet, M. and Newgreen, D. (1995) Epithelium-mesenchyme transition during neural crest development. Acta Anat. (Basel) 154, 63-78. https://doi.org/10.1159/000147752
  21. Eger, A., Stockinger, A., Park, J., Langkopf, E., Mikula, M., Gotzmann, J., Mikulits, W., Beug, H. and Foisner, R. (2004) beta-Catenin and TGFbeta signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23, 2672-2680. https://doi.org/10.1038/sj.onc.1207416
  22. Ezin, A. M., Fraser, S. E. and Bronner-Fraser, M. (2009) Fate map and morphogenesis of presumptive neural crest and dorsal neural tube. Dev. Biol. 330, 221-236. https://doi.org/10.1016/j.ydbio.2009.03.018
  23. Fan, J. M., Ng, Y. Y., Hill, P. A., Nikolic-Paterson, D. J., Mu, W., Atkins, R. C. and Lan, H. Y. (1999) Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int. 56, 1455-1467. https://doi.org/10.1046/j.1523-1755.1999.00656.x
  24. Fazilaty, H., Rago, L., Kass Youssef, K., Ocana, O. H., Garcia-Asencio, F., Arcas, A., Galceran, J. and Nieto, M. A. (2019) A gene regulatory network to control EMT programs in development and disease. Nat. Commun. 10, 5115. https://doi.org/10.1038/s41467-019-13091-8
  25. Frixen, U. H., Behrens, J., Sachs, M., Eberle, G., Voss, B., Warda, A., Lochner, D. and Birchmeier, W. (1991) E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol. 113, 173-185. https://doi.org/10.1083/jcb.113.1.173
  26. Fujita, Y., Krause, G., Scheffner, M., Zechner, D., Leddy, H. E., Behrens, J., Sommer, T. and Birchmeier, W. (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat. Cell Biol. 4, 222-231. https://doi.org/10.1038/ncb758
  27. Fuxe, J., Vincent, T. and Garcia de Herreros, A. (2010) Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 9, 2363-2374. https://doi.org/10.4161/cc.9.12.12050
  28. Gravdal, K., Halvorsen, O. J., Haukaas, S. A. and Akslen, L. A. (2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin. Cancer Res. 13, 7003-7011. https://doi.org/10.1158/1078-0432.ccr-07-1263
  29. Grille, S. J., Bellacosa, A., Upson, J., Klein-Szanto, A. J., van Roy, F., Lee-Kwon, W., Donowitz, M., Tsichlis, P. N. and Larue, L. (2003) The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 63, 2172-2178.
  30. Guilford, P., Hopkins, J., Harraway, J., McLeod, M., McLeod, N., Harawira, P., Taite, H., Scoular, R., Miller, A. and Reeve, A. E. (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392, 402-405. https://doi.org/10.1038/32918
  31. Hao, J., Zhang, Y., Deng, M., Ye, R., Zhao, S., Wang, Y., Li, J. and Zhao, Z. (2014) MicroRNA control of epithelial-mesenchymal transition in cancer stem cells. Int. J. Cancer 135, 1019-1027. https://doi.org/10.1002/ijc.28761
  32. Hartwell, K. A., Muir, B., Reinhardt, F., Carpenter, A. E., Sgroi, D. C. and Weinberg, R. A. (2006) The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc. Natl. Acad. Sci. U.S.A. 103, 18969-18974. https://doi.org/10.1073/pnas.0608636103
  33. Hay, E. D. (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn. 233, 706-720. https://doi.org/10.1002/dvdy.20345
  34. Hodge, D. R., Hurt, E. M. and Farrar, W. L. (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur. J. Cancer 41, 2502-2512. https://doi.org/10.1016/j.ejca.2005.08.016
  35. Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., Williams, E. D. and Thompson, E. W. (2007) Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J. Cell. Physiol. 213, 374-383. https://doi.org/10.1002/jcp.21223
  36. Iwano, M., Fischer, A., Okada, H., Plieth, D., Xue, C., Danoff, T. M. and Neilson, E. G. (2001) Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol. Ther. 3, 149-159. https://doi.org/10.1006/mthe.2000.0251
  37. Iwano, M., Plieth, D., Danoff, T. M., Xue, C., Okada, H. and Neilson, E. G. (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341-350. https://doi.org/10.1172/JCI15518
  38. Kalluri, R. and Neilson, E. G. (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776-1784. https://doi.org/10.1172/JCI200320530
  39. Karafiat, V., Dvorakova, M., Krejci, E., Kralova, J., Pajer, P., Snajdr, P., Mandikova, S., Bartunek, P., Grim, M. and Dvorak, M. (2005) Transcription factor c-Myb is involved in the regulation of the epithelial-mesenchymal transition in the avian neural crest. Cell. Mol. Life Sci. 62, 2516-2525. https://doi.org/10.1007/s00018-005-5297-7
  40. Karafiat, V., Dvorakova, M., Pajer, P., Cermak, V. and Dvorak, M. (2007) Melanocyte fate in neural crest is triggered by Myb proteins through activation of c-kit. Cell. Mol. Life Sci. 64, 2975-2984. https://doi.org/10.1007/s00018-007-7330-5
  41. Kim, B. N., Ahn, D. H., Kang, N., Yeo, C. D., Kim, Y. K., Lee, K. Y., Kim, T. J., Lee, S. H., Park, M. S., Yim, H. W., Park, J. Y., Park, C. K. and Kim, S. J. (2020) TGF-beta induced EMT and stemness characteristics are associated with epigenetic regulation in lung cancer. Sci. Rep. 10, 10597. https://doi.org/10.1038/s41598-020-67325-7
  42. Kim, C. F., Jackson, E. L., Woolfenden, A. E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R. T. and Jacks, T. (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823-835. https://doi.org/10.1016/j.cell.2005.03.032
  43. Lamouille, S., Xu, J. and Derynck, R. (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178-196. https://doi.org/10.1038/nrm3758
  44. Lander, R., Nordin, K. and LaBonne, C. (2011) The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. J. Cell Biol. 194, 17-25. https://doi.org/10.1083/jcb.201012085
  45. Lee, J. M., Dedhar, S., Kalluri, R. and Thompson, E. W. (2006a) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 172, 973-981. https://doi.org/10.1083/jcb.200601018
  46. Lee, T. K., Poon, R. T., Yuen, A. P., Ling, M. T., Kwok, W. K., Wang, X. H., Wong, Y. C., Guan, X. Y., Man, K., Chau, K. L. and Fan, S. T. (2006b) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin. Cancer Res. 12, 5369-5376. https://doi.org/10.1158/1078-0432.ccr-05-2722
  47. Leptin, M. (1999) Gastrulation in Drosophila: the logic and the cellular mechanisms. EMBO J. 18, 3187-3192. https://doi.org/10.1093/emboj/18.12.3187
  48. Leptin, M. and Affolter, M. (2004) Drosophila gastrulation: identification of a missing link. Curr. Biol. 14, R480-R482. https://doi.org/10.1016/j.cub.2004.06.016
  49. Li, Y., Yang, J., Dai, C., Wu, C. and Liu, Y. (2003) Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J. Clin. Invest. 112, 503-516. https://doi.org/10.1172/JCI200317913
  50. Lim, S., Becker, A., Zimmer, A., Lu, J., Buettner, R. and Kirfel, J. (2013) SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. PLoS ONE 8, e66558. https://doi.org/10.1371/journal.pone.0066558
  51. Liu, Y., Lu, X., Huang, L., Wang, W., Jiang, G., Dean, K. C., Clem, B., Telang, S., Jenson, A. B., Cuatrecasas, M., Chesney, J., Darling, D. S., Postigo, A. and Dean, D. C. (2014) Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. Nat. Commun. 5, 5660. https://doi.org/10.1038/ncomms6660
  52. Maiuthed, A., Chantarawong, W. and Chanvorachote, P. (2018) Lung cancer stem cells and cancer stem cell-targeting natural compounds. Anticancer Res. 38, 3797-3809. https://doi.org/10.21873/anticanres.12663
  53. Mani, S. A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., Kutok, J. L., Hartwell, K., Richardson, A. L. and Weinberg, R. A. (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl. Acad. Sci. U.S.A. 104, 10069-10074. https://doi.org/10.1073/pnas.0703900104
  54. Monsoro-Burq, A. H., Wang, E. and Harland, R. (2005) Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Dev. Cell 8, 167-178. https://doi.org/10.1016/j.devcel.2004.12.017
  55. Nishitani, Y., Iwano, M., Yamaguchi, Y., Harada, K., Nakatani, K., Akai, Y., Nishino, T., Shiiki, H., Kanauchi, M., Saito, Y. and Neilson, E. G. (2005) Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int. 68, 1078-1085. https://doi.org/10.1111/j.1523-1755.2005.00500.x
  56. Okada, H., Ban, S., Nagao, S., Takahashi, H., Suzuki, H. and Neilson, E. G. (2000) Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int. 58, 587-597. https://doi.org/10.1046/j.1523-1755.2000.00205.x
  57. Okada, H., Danoff, T. M., Kalluri, R. and Neilson, E. G. (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am. J. Physiol. 273, F563-F574.
  58. Okada, H., Strutz, F., Danoff, T. M., Kalluri, R. and Neilson, E. G. (1996) Possible mechanisms of renal fibrosis. Contrib. Nephrol. 118, 147-154. https://doi.org/10.1159/000425088
  59. Oloumi, A., McPhee, T. and Dedhar, S. (2004) Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase. Biochim. Biophys. Acta 1691, 1-15. https://doi.org/10.1016/j.bbamcr.2003.12.002
  60. Otsuki, Y., Saya, H. and Arima, Y. (2018) Prospects for new lung cancer treatments that target EMT signaling. Dev. Dyn. 247, 462-472. https://doi.org/10.1002/dvdy.24596
  61. Pan, J., Fang, S., Tian, H., Zhou, C., Zhao, X., Tian, H., He, J., Shen, W., Meng, X., Jin, X. and Gong, Z. (2020) lncRNA JPX/miR-33a-5p/ Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/beta-catenin signaling. Mol. Cancer 19, 9. https://doi.org/10.1186/s12943-020-1133-9
  62. Pece, S. and Gutkind, J. S. (2002) E-cadherin and Hakai: signalling, remodeling or destruction? Nat. Cell Biol. 4, E72-E74. https://doi.org/10.1038/ncb0402-e72
  63. Peinado, H., Olmeda, D. and Cano, A. (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415-428. https://doi.org/10.1038/nrc2131
  64. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H. and Christofori, G. (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190-193. https://doi.org/10.1038/32433
  65. Pires, B. R., Mencalha, A. L., Ferreira, G. M., de Souza, W. F., Morgado-Diaz, J. A., Maia, A. M., Correa, S. and Abdelhay, E. S. (2017) NF-kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS ONE 12, e0169622. https://doi.org/10.1371/journal.pone.0169622
  66. Polakis, P. (2000) Wnt signaling and cancer. Genes Dev. 14, 1837-1851. https://doi.org/10.1101/gad.14.15.1837
  67. Prudkin, L., Liu, D. D., Ozburn, N. C., Sun, M., Behrens, C., Tang, X., Brown, K. C., Bekele, B. N., Moran, C. and Wistuba, I. I. (2009) Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod. Pathol. 22, 668-678. https://doi.org/10.1038/modpathol.2009.19
  68. Sato, R., Semba, T., Saya, H. and Arima, Y. (2016) Concise review: stem cells and epithelial-mesenchymal transition in cancer: biological implications and therapeutic targets. Stem Cells 34, 1997-2007. https://doi.org/10.1002/stem.2406
  69. Sauka-Spengler, T. and Bronner-Fraser, M. (2008) A gene regulatory network orchestrates neural crest formation. Nat. Rev. Mol. Cell Biol. 9, 557-568. https://doi.org/10.1038/nrm2428
  70. Seo, J., Ha, J., Kang, E. and Cho, S. (2021) The role of epithelial-mesenchymal transition-regulating transcription factors in anti-cancer drug resistance. Arch. Pharm. Res. 44, 281-292. https://doi.org/10.1007/s12272-021-01321-x
  71. Shaw, A. T. and Solomon, B. (2011) Targeting anaplastic lymphoma kinase in lung cancer. Clin. Cancer Res. 17, 2081-2086. https://doi.org/10.1158/1078-0432.ccr-10-1591
  72. Shih, J. Y., Tsai, M. F., Chang, T. H., Chang, Y. L., Yuan, A., Yu, C. J., Lin, S. B., Liou, G. Y., Lee, M. L., Chen, J. J., Hong, T. M., Yang, S. C., Su, J. L., Lee, Y. C. and Yang, P. C. (2005) Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin. Cancer Res. 11, 8070-8078. https://doi.org/10.1158/1078-0432.CCR-05-0687
  73. Shin, S. Y., Rath, O., Zebisch, A., Choo, S. M., Kolch, W. and Cho, K. H. (2010) Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res. 70, 6715-6724. https://doi.org/10.1158/0008-5472.CAN-10-1377
  74. Strutz, F., Okada, H., Lo, C. W., Danoff, T., Carone, R. L., Tomaszewski, J. E. and Neilson, E. G. (1995) Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol. 130, 393-405. https://doi.org/10.1083/jcb.130.2.393
  75. Strutz, F., Zeisberg, M., Ziyadeh, F. N., Yang, C. Q., Kalluri, R., Muller, G. A. and Neilson, E. G. (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 61, 1714-1728. https://doi.org/10.1046/j.1523-1755.2002.00333.x
  76. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A. and Bray, F. (2021) Global cancer statistics 2020: GLO-BOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209-249. https://doi.org/10.3322/caac.21660
  77. Tepass, U. (1996) Crumbs, a component of the apical membrane, is required for zonula adherens formation in primary epithelia of Drosophila. Dev. Biol. 177, 217-225. https://doi.org/10.1006/dbio.1996.0157
  78. Tepass, U., Theres, C. and Knust, E. (1990) crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 61, 787-799. https://doi.org/10.1016/0092-8674(90)90189-l
  79. Teschendorff, A. E., Journee, M., Absil, P. A., Sepulchre, R. and Caldas, C. (2007) Elucidating the altered transcriptional programs in breast cancer using independent component analysis. PLoS Comput. Biol. 3, e161. https://doi.org/10.1371/journal.pcbi.0030161
  80. Thiery, J. P., Acloque, H., Huang, R. Y. and Nieto, M. A. (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890. https://doi.org/10.1016/j.cell.2009.11.007
  81. Thiery, J. P. and Sleeman, J. P. (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131-142. https://doi.org/10.1038/nrm1835
  82. Timmerman, L. A., Grego-Bessa, J., Raya, A., Bertran, E., Perez-Pomares, J. M., Diez, J., Aranda, S., Palomo, S., McCormick, F., Izpisua-Belmonte, J. C. and de la Pompa, J. L. (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99-115. https://doi.org/10.1101/gad.276304
  83. Tucker, G. C., Duband, J. L., Dufour, S. and Thiery, J. P. (1988) Cell-adhesion and substrate-adhesion molecules: their instructive roles in neural crest cell migration. Development 103 Suppl, 81-94. https://doi.org/10.1242/dev.103.Supplement.81
  84. Ungefroren, H., Witte, D. and Lehnert, H. (2018) The role of small GT-Pases of the Rho/Rac family in TGF-beta-induced EMT and cell motility in cancer. Dev. Dyn. 247, 451-461. https://doi.org/10.1002/dvdy.24505
  85. Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C. H. and Moustakas, A. (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol. Biol. Cell 16, 1987-2002. https://doi.org/10.1091/mbc.E04-08-0658
  86. Wang, D., Dai, C., Li, Y. and Liu, Y. (2011) Canonical Wnt/beta-catenin signaling mediates transforming growth factor-beta1-driven podocyte injury and proteinuria. Kidney Int. 80, 1159-1169. https://doi.org/10.1038/ki.2011.255
  87. Wang, G., Guo, X., Hong, W., Liu, Q., Wei, T., Lu, C., Gao, L., Ye, D., Zhou, Y., Chen, J., Wang, J., Wu, M., Liu, H. and Kang, J. (2013) Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation. Proc. Natl. Acad. Sci. U.S.A. 110, 2858-2863. https://doi.org/10.1073/pnas.1212769110
  88. Wang, J., Sridurongrit, S., Dudas, M., Thomas, P., Nagy, A., Schneider, M. D., Epstein, J. A. and Kaartinen, V. (2005) Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev. Biol. 286, 299-310. https://doi.org/10.1016/j.ydbio.2005.07.035
  89. Wellner, U., Schubert, J., Burk, U. C., Schmalhofer, O., Zhu, F., Sonntag, A., Waldvogel, B., Vannier, C., Darling, D., zur Hausen, A., Brunton, V. G., Morton, J., Sansom, O., Schuler, J., Stemmler, M. P., Herzberger, C., Hopt, U., Keck, T., Brabletz, S. and Brabletz, T. (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487-1495. https://doi.org/10.1038/ncb1998
  90. Weston, J. A. (1970) The migration and differentiation of neural crest cells. Adv. Morphog. 8, 41-114. https://doi.org/10.1016/B978-0-12-028608-9.50006-5
  91. Wu, D. and Wang, X. (2015) Application of clinical bioinformatics in lung cancer-specific biomarkers. Cancer Metastasis Rev. 34, 209-216. https://doi.org/10.1007/s10555-015-9564-2
  92. Xie, L., Law, B. K., Chytil, A. M., Brown, K. A., Aakre, M. E. and Moses, H. L. (2004) Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 6, 603-610. https://doi.org/10.1593/neo.04241
  93. Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R. A., Come, C., Savagner, P., Gitelman, I., Richardson, A. and Weinberg, R. A. (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927-939. https://doi.org/10.1016/j.cell.2004.06.006
  94. Yang, Z., Rayala, S., Nguyen, D., Vadlamudi, R. K., Chen, S. and Kumar, R. (2005) Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res. 65, 3179-3184. https://doi.org/10.1158/0008-5472.CAN-04-3480
  95. Zeisberg, M., Bonner, G., Maeshima, Y., Colorado, P., Muller, G. A., Strutz, F. and Kalluri, R. (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am. J. Pathol. 159, 1313-1321. https://doi.org/10.1016/S0002-9440(10)62518-7
  96. Zhang, P., Sun, Y. and Ma, L. (2015) ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 14, 481-487. https://doi.org/10.1080/15384101.2015.1006048
  97. Zhang, Y. and Weinberg, R. A. (2018) Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front. Med. 12, 361-373. https://doi.org/10.1007/s11684-018-0656-6
  98. Zhou, B. P., Deng, J., Xia, W., Xu, J., Li, Y. M., Gunduz, M. and Hung, M. C. (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 6, 931-940. https://doi.org/10.1038/ncb1173
  99. Zhou, J. J., Meng, Z., Zhou, Y., Cheng, D., Ye, H. L., Zhou, Q. B., Deng, X. G. and Chen, R. F. (2016) Hepatitis C virus core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma. Oncol. Rep. 36, 582-588. https://doi.org/10.3892/or.2016.4775