DOI QR코드

DOI QR Code

Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer

  • Liu, Xia (Department of Pathology,The First Affiliated Hospital of Inner Mongolia Medical University) ;
  • Yun, Fen (Department of Pathology,The First Affiliated Hospital of Inner Mongolia Medical University) ;
  • Shi, Lin (Department of Pathology,The First Affiliated Hospital of Inner Mongolia Medical University) ;
  • Li, Zhe-Hai (The Third Affiliated Hospital of Inner Mongolia Medical University) ;
  • Luo, Nian-Rong (Physical Examination Center, the Inner Mongolia Autonomous Region People's Hospital) ;
  • Jia, Yong-Feng (Department of Pathology,The First Affiliated Hospital of Inner Mongolia Medical University)
  • Published : 2015.10.06

Abstract

The epithelial-mesenchymal transition (EMT) is a cellular process though which an epithelial phenotype can be converted into a phenotype of mesenchymal cells. Under physiological conditions EMT is important for embryogenesis, organ development, wound repair and tissue remodeling. However, EMT may also be activated under pathologic conditions, especially in carcinogenesis and metastatic progression. Major signaling pathways involved in EMT include transforming growth factor ${\beta}(TGF-{\beta})$, Wnt, Notch, Hedgehog and other signaling pathways. These pathways are related to several transcription factors, including Twist, Smads and zinc finger proteins snail and slug. These interact with each other to provide crosstalk between the relevant signaling pathways. This review lays emphasis on studying the relationship between EMT and signaling pathways in carcinogenesis and metastatic progression.

Keywords

EMT;signaling pathway;cancer

Acknowledgement

Supported by : National Natural Science Foundation of China

References

  1. Attisano L, Wrana JL (2002). Signal transduction by the TGF-$\beta$ superfamily. Science, 296, 1646-7. https://doi.org/10.1126/science.1071809
  2. Beachy PA, Karhadkar SS, Berman DM (2004). Tissue repair and stem cell renewal in carcinogenesis. Nature, 432, 324-31. https://doi.org/10.1038/nature03100
  3. Cano A, Perez-Moreno MA, Rodrigo I, et al (2000). The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol, 2, 76-83. https://doi.org/10.1038/35000025
  4. Chen T, Nie H, Gao X, et al (2014a). Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multiwalled carbon nanotubes via TGF-beta/Smad signaling pathway. Toxicol Lett, 226, 150-62. https://doi.org/10.1016/j.toxlet.2014.02.004
  5. Chen X, Ye S, Xiao W, et al (2014b). ERK1/2 pathway mediates epithelial-mesenchymal transition by cross-interacting with TGFbeta/Smad and Jagged/Notch signaling pathways in lens epithelial cells. Int J Mol Med, 33, 1664-70.
  6. Clevers H, Nusse R (2012). Wnt/beta-catenin signaling and disease. Cell, 149, 1192-205. https://doi.org/10.1016/j.cell.2012.05.012
  7. Gnemmi V, Bouillez A, Gaudelot K, et al (2014). MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/beta-catenin pathway and interaction with SNAIL promoter. Cancer Lett, 346, 225-36. https://doi.org/10.1016/j.canlet.2013.12.029
  8. Guo J, Fu Z, Wei J, et al (2015). PRRX1 promotes epithelialmesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer. Med Oncol, 32, 393. https://doi.org/10.1007/s12032-014-0393-x
  9. Hassan WA, Yoshida R, Kudoh S, et al (2014). Notch1 controls cell invasion and metastasis in small cell lung carcinoma cell lines. Lung Cancer, 86, 304-10. https://doi.org/10.1016/j.lungcan.2014.10.007
  10. Hay ED (1982). Interaction of embryonic surface and cytoskeleton with extracellular matrix. Am J Anat, 165, 1-12. https://doi.org/10.1002/aja.1001650102
  11. Heldin CH, Landstrom M, Moustakas A (2009). Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol, 21, 166-76. https://doi.org/10.1016/j.ceb.2009.01.021
  12. Hiraga R, Kato M, Miyagawa S, et al (2013). Nox4-derived ROS signaling contributes to TGF-beta-induced epithelialmesenchymal transition in pancreatic cancer cells. Anticancer Res, 33, 4431-8.
  13. Hofman P, Vouret-Craviari V (2012). Microbes-induced EMT at the crossroad of inflammation and cancer. Gut Microbes, 3, 176-85. https://doi.org/10.4161/gmic.20288
  14. Hu S, Yu W, Lv TJ, et al (2014). Evidence of TGF-beta1 mediated epithelial-mesenchymal transition in immortalized benign prostatic hyperplasia cells. Mol Membr Biol, 31, 103-10. https://doi.org/10.3109/09687688.2014.894211
  15. Huynh TT, Rao YK, Lee WH, et al (2014). Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/beta-catenin signaling pathway and epithelialmesenchymal transition. Toxicol In Vitro, 28, 552-61. https://doi.org/10.1016/j.tiv.2014.01.002
  16. Ishida T, Hijioka H, Kume K, et al (2013). Notch signaling induces EMT in OSCC cell lines in a hypoxic environment. Oncol Lett, 6, 1201-6.
  17. Joost S, Almada LL, Rohnalter V, et al (2012). GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells. Cancer Res, 72, 88-99.
  18. Kalluri R, Neilson EG (2003). Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest, 112, 1776-84. https://doi.org/10.1172/JCI200320530
  19. Kalluri R, Weinberg RA (2009). The basics of epithelialmesenchymal transition. J Clin Invest, 119, 1420-8. https://doi.org/10.1172/JCI39104
  20. Karhadkar SS, Bova GS, Abdallah N, et al (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 431, 707-12. https://doi.org/10.1038/nature02962
  21. Katsuno Y, Lamouille S, Derynck R (2013). TGF-beta signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol, 25, 76-84. https://doi.org/10.1097/CCO.0b013e32835b6371
  22. Lan A, Qi Y, Du J (2014). Akt2 mediates TGF-beta1-induced epithelial to mesenchymal transition by deactivating GSK3beta/snail signaling pathway in renal tubular epithelial cells. Cell Physiol Biochem, 34, 368-82. https://doi.org/10.1159/000363006
  23. Lei J, Ma J, Ma Q, et al (2013). Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer, 12, 66. https://doi.org/10.1186/1476-4598-12-66
  24. Li H, Wang Z, Zhang W, et al (2015). VGLL4 inhibits EMT in part through suppressing Wnt/beta-catenin signaling pathway in gastric cancer. Med Oncol, 32, 83. https://doi.org/10.1007/s12032-015-0539-5
  25. Li LC, Peng Y, Liu YM, et al (2014). Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by gamma-secretase inhibitor DAPT. Oncol Lett, 7, 2160-4.
  26. Liu JK, Chen WC, Ji XZ, et al (2015). Correlation of overexpression of nestin with expression of epithelialmesenchymal transition-related proteins in gastric adenocarcinoma. Asian Pac J Cancer Prev, 16, 2777-83. https://doi.org/10.7314/APJCP.2015.16.7.2777
  27. Liu L, Chen X, Wang Y, et al (2014). Notch3 is important for TGF-beta-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1. Cancer Gene Ther, 21, 364-72. https://doi.org/10.1038/cgt.2014.39
  28. Logan CY, Nusse R (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 20, 781-810. https://doi.org/10.1146/annurev.cellbio.20.010403.113126
  29. Luo WR, Chen XY, Li SY, et al (2012). Neoplastic spindle cells in nasopharyngeal carcinoma show features of epithelial mesenchymal transition. Histopathol, 61, 113-22. https://doi.org/10.1111/j.1365-2559.2012.04205.x
  30. Massague J (2008). TGFbeta in Cancer. Cell, 134, 215-30. https://doi.org/10.1016/j.cell.2008.07.001
  31. Miele L, Golde T, Osborne B (2006a). Notch signaling in cancer. Curr Mol Med, 6, 905-18. https://doi.org/10.2174/156652406779010830
  32. Miele L, Miao H, Nickoloff BJ (2006b). NOTCH signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets, 6, 313-23. https://doi.org/10.2174/156800906777441771
  33. Moustakas A, Heldin CH (2007). Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci, 98, 1512-20. https://doi.org/10.1111/j.1349-7006.2007.00550.x
  34. Nelson WJ (2008). Regulation of cell-cell adhesion by the cadherin-catenin complex. Biochem Soc Trans, 36, 149-55. https://doi.org/10.1042/BST0360149
  35. Nusse R, Fuerer C, Ching W, et al (2008). Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol, 73, 59-66. https://doi.org/10.1101/sqb.2008.73.035
  36. Penton AL, Leonard LD, Spinner NB (2012). Notch signaling in human development and disease. Semin Cell Dev Biol, 23, 450-7. https://doi.org/10.1016/j.semcdb.2012.01.010
  37. Romero-Gallo J, Sozmen EG, Chytil A, et al (2005). Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene, 24, 3028-41. https://doi.org/10.1038/sj.onc.1208475
  38. Schinner S, Willenberg HS, Schott M, et al (2009). Pathophysiological aspects of Wnt-signaling in endocrine disease. Eur J Endocrinol, 160, 731-7. https://doi.org/10.1530/EJE-08-0831
  39. Takeyama Y, Sato M, Horio M, et al (2010). Knockdown of ZEB1, a master epithelial-to-mesenchymal transition (EMT) gene, suppresses anchorage-independent cell growth of lung cancer cells. Cancer Lett, 296, 216-24. https://doi.org/10.1016/j.canlet.2010.04.008
  40. Taskin S, Dunder I, Erol E, et al (2012). Roles of E-cadherin and cyclooxygenase enzymes in predicting different survival patterns of optimally cytoreduced serous ovarian cancer patients. Asian Pac J Cancer Prev, 13, 5715-9. https://doi.org/10.7314/APJCP.2012.13.11.5715
  41. Teglund S, Toftgard R (2010). Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta, 1805, 181-208.
  42. Wang T, Xuan X, Pian L, et al (2014a). Notch-1-mediated esophageal carcinoma EC-9706 cell invasion and metastasis by inducing epithelial-mesenchymal transition through Snail. Tumour Biol, 35, 1193-201. https://doi.org/10.1007/s13277-013-1159-3
  43. Wang ZS, Shen Y, Li X, et al (2014b). Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer. Tumour Biol, 35, 1357-63. https://doi.org/10.1007/s13277-013-1185-1
  44. Wei W, Chua MS, Grepper S, et al (2010). Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer, 126, 2426-36.
  45. Yang J, Weinberg RA (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell, 14, 818-29. https://doi.org/10.1016/j.devcel.2008.05.009
  46. Xia YY, Yin L, Jiang N, et al (2015). Downregulating HMGA2 attenuates epithelial-mesenchymal transition-induced invasion and migration in nasopharyngeal cancer cells. Biochem Biophys Res Commun, 463, 357-63. https://doi.org/10.1016/j.bbrc.2015.05.068
  47. Yue D, Li H, Che J, et al (2014). Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res, 33, 34. https://doi.org/10.1186/1756-9966-33-34
  48. Zaid KW (2014). Immunohistochemical assessment of E-cadherin and beta-catenin in the histological differentiations of oral squamous cell carcinoma. Asian Pac J Cancer Prev, 15, 8847-53. https://doi.org/10.7314/APJCP.2014.15.20.8847
  49. Zhang HY, Wang ZQ, Li YY, et al (2014). Transforming growth factor-beta1-induced epithelial-mesenchymal transition in human esophageal squamous cell carcinoma via the PTEN/ PI3K signaling pathway. Oncol Rep, 32, 2134-42.
  50. Zhang X, Zhao X, Shao S, et al (2015). Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role. Int J Oncol, 46, 1141-8.
  51. Zhao ZL, Ma SR, Wang WM, et al (2015). Notch signaling induces epithelial-mesenchymal transition to promote invasion and metastasis in adenoid cystic carcinoma. Am J Transl Res, 7, 162-74.
  52. Zhou Q, Wang Y, Peng B, et al (2013). The roles of Notch1 expression in the migration of intrahepatic cholangiocarcinoma. BMC Cancer, 13, 244. https://doi.org/10.1186/1471-2407-13-244
  53. Zhu QC, Gao RY, Wu W, et al (2013). Epithelial-mesenchymal transition and its role in the pathogenesis of colorectal cancer. Asian Pac J Cancer Prev, 14, 2689-98. https://doi.org/10.7314/APJCP.2013.14.5.2689
  54. Zong D, Yin L, Zhong Q, et al (2015). ZNF 488 enhances the invasion and tumorigenesis in nasopharyngeal carcinoma via the wnt signaling pathway involving epithelial mesenchymal transition. Cancer Res Treat.

Cited by

  1. Mesenchymal Stromal Cells Epithelial Transition Induced by Renal Tubular Cells-Derived Extracellular Vesicles vol.11, pp.7, 2016, https://doi.org/10.1371/journal.pone.0159163
  2. Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer vol.35, pp.1, 2016, https://doi.org/10.1186/s13046-016-0449-1
  3. Leukemia inhibitory factor receptor negatively regulates the metastasis of pancreatic cancer cells in vitro and in vivo vol.36, pp.2, 2016, https://doi.org/10.3892/or.2016.4865
  4. TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma vol.45, pp.7, 2016, https://doi.org/10.1111/jop.12406
  5. Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review) vol.48, pp.6, 2016, https://doi.org/10.3892/ijo.2016.3480
  6. extracts reverses TGF-β1-induced epithelial-mesenchymal transition in human lung adenocarcinoma cells and suppresses tumor growth in vivo vol.32, pp.7, 2017, https://doi.org/10.1002/tox.22410
  7. MicroRNAs and signaling networks involved in epithelial-mesenchymal transition pp.00219541, 2018, https://doi.org/10.1002/jcp.27489
  8. Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration vol.233, pp.12, 2018, https://doi.org/10.1002/jcp.26947