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Gastric Cancer: Epithelial Mesenchymal Transition

  • Yoon Jin ChoiEmail author
  • Hyeon Jang
Chapter
  • 1.4k Downloads

Abstract

An epithelial-mesenchymal transition (EMT) induces loss of epithelial cell polarity and change of cell phenotype from typical cubical shape into fibroblast-like shape. Since the ability to migrate is obtained as a result of EMT, this has been an essential mechanism for cancer invasion and metastatic spreads. During EMT process, E-cadherin, a typical epithelial cell marker, is decreased, and hallmarks of mesenchymal cells are increased. Most studies about EMT in oncologic field have been focused on the role of EMT hallmarks as a prognostic marker. However, recent evidence has shown that EMT plays an important role in tumorigenesis and progression. In addition, EMT has taken center stage as the convergence point between inflammation and cancer.

This review will highlight the general concept of EMT, brief summary of the regulators and signal pathways involved in EMT, and the association between EMT and cancer including both carcinogenesis and progression. We also investigate the role of EMT in gastric cancer related with Helicobacter pylori infection.

Keywords

Helicobacter pylori Epithelial-mesenchymal transition Cancer stem cell 

References

  1. 1.
    Wu J, Mlodzik M. A quest for the mechanism regulating global planar cell polarity of tissues. Trends Cell Biol. 2009;19:295–305.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Beyer Nardi N, da Silva Meirelles L. Mesenchymal stem cells: isolation, in vitro expansion and characterization. Handb Exp Pharmacol. 2006;174:249–82.CrossRefPubMedGoogle Scholar
  3. 3.
    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Kong D, Li Y, Wang Z, Sarkar FH. Cancer stem cells and epithelial-to-mesenchymal transition (EMT)-phenotypic cells: are they cousins or twins? Cancers. 2011;3:716–29.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest. 2009;119:1417–9.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S. Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101:293–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Savagner P, Boyer B, Valles AM, Jouanneau J, Thiery JP. Modulations of the epithelial phenotype during embryogenesis and cancer progression. Cancer Treat Res. 1994;71:229–49.CrossRefPubMedGoogle Scholar
  11. 11.
    Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98:1512–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Wells RG. Epithelial to mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology. 2010;51:737–40.PubMedPubMedCentralGoogle Scholar
  13. 13.
    López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1:303–14.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Park SM, Kim SM, Han JH. The role of epithelial-mesenchymal transition in the gastroenterology. Korean J Gastroenterol. 2010;56:69–77.CrossRefPubMedGoogle Scholar
  15. 15.
    Fidler IJ, Poste G. The “seed and soil” hypothesis revisited. Lancet Oncol. 2008;9:808–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Thompson EW, Haviv I. The social aspects of EMT-MET plasticity. Nat Med. 2011;17:1048–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002;70:537–46.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jechlinger M, Grunert S, Beug H. Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. J Mammary Gland Biol Neoplasia. 2002;7:415–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Smit MA, Peeper DS. Deregulating EMT and senescence: double impact by a single twist. Cancer Cell. 2008;14:5–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Weinberg RA. Twisted epithelial-mesenchymal transition blocks senescence. Nat Cell Biol. 2008;10:1021–3.CrossRefPubMedGoogle Scholar
  22. 22.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.CrossRefPubMedGoogle Scholar
  23. 23.
    Niessen K, Fu YX, Chang L, Hoodless PA, McFadden D, Karsan A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol. 2008;182:315–25.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Medici D, Hay ED, Olsen BR. Snail and slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell. 2008;19:4875–87.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kokudo T, Suzuki Y, Yoshimatsu Y, Yamazaki T, Watabe T, Miyazono K. Snail is required for TGF{beta}-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J Cell Sci. 2008;121:3317–24.CrossRefPubMedGoogle Scholar
  26. 26.
    Willis BC, Borok Z. TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Cell Mol Physiol. 2007;293:L525–34.CrossRefGoogle Scholar
  27. 27.
    Gupta PB, Mani S, Yang J, Hartwell K, Weinberg RA. The evolving portrait of cancer metastasis. Cold Spring Harb Symp Quant Biol. 2005;70:291–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Yang J, Mani SA, Weinberg RA. Exploring a new twist on tumor metastasis. Cancer Res. 2006;66:4549–52.CrossRefPubMedGoogle Scholar
  29. 29.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA. The Spemann organizer gene, goosecoid, promotes tumor metastasis. Proc Natl Acad Sci U S A. 2006;103:18969–74.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Oft M, Heider KH, Beug H. TGF-beta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Song J. EMT or apoptosis: a decision for TGF-beta. Cell Res. 2007;17:289–90.CrossRefPubMedGoogle Scholar
  34. 34.
    Miyazono K, ten Dijke P, Heldin CH. TGF-beta signaling by Smad proteins. Adv Immunol. 2000;75:115–57.CrossRefPubMedGoogle Scholar
  35. 35.
    Heldin CH, Miyazono K, ten Dijke P. TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–71.CrossRefPubMedGoogle Scholar
  36. 36.
    Roberts AB, Tian F, Byfield SDC, Stuelten C, Ooshima A, Saika S, et al. Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev. 2006;17:19–27.CrossRefPubMedGoogle Scholar
  37. 37.
    Piek E, Moustakas A, Kurisaki A, Heldin CH, Dijke PT. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci. 1999;112:4557–68.PubMedGoogle Scholar
  38. 38.
    Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, et al. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12:27–36.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lee YH, Albig AR, Regner MA, Schiemann BJ, Schiemann WP. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis. 2008;29:2243–51.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lehmann K, Janda E, Pierreux CE, Rytömaa M, Schulze A, McMahon M, et al. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 2000;14:2610–22.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gotzmann J, Huber H, Thallinger C, Wolschek M, Jansen B, Schulte-Hermann R, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J Cell Sci. 2002;115:1189–202.PubMedGoogle Scholar
  42. 42.
    Oft M, Peli F, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 1996;10:2462–77.CrossRefPubMedGoogle Scholar
  43. 43.
    Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol. 2002;156:299–313.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, et al. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996;86:531–42.CrossRefPubMedGoogle Scholar
  45. 45.
    Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis. 2008;29:2227–35.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stockinger A, Eger A, Wolf J, Beug H, Foisner R. E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity. J Cell Biol. 2001;154:1185–96.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gottardi CJ, Wong E, Gumbiner BM. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol. 2001;153:1049–60.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kim K, Lu Z, Hay ED. Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int. 2002;26:463–76.CrossRefPubMedGoogle Scholar
  49. 49.
    Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, et al. Notch promotes epithelial mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18:99–115.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Katoh M. Epithelial-mesenchymal transition in gastric cancer (review). Int J Oncol. 2005;27:1677–83.PubMedGoogle Scholar
  51. 51.
    Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol. 2003;14:1705–13.CrossRefPubMedGoogle Scholar
  52. 52.
    Castro Alves C, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, Carneiro, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol. 2007;211:507–15.CrossRefPubMedGoogle Scholar
  53. 53.
    He H, Chen W, Wang X, Wang C, Liu F, Shen Z, et al. Snail is an independent prognostic predictor for progression and patient survival of gastric cancer. Cancer Sci. 2012;103:1296–303.CrossRefPubMedGoogle Scholar
  54. 54.
    Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Höfler H, et al. Expression and nuclear localization of snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract. Virchows Arch. 2006;448:277–87.CrossRefPubMedGoogle Scholar
  55. 55.
    Yang Z, Zhang X, Gang H, Li X, Li Z, Wang T, et al. Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun. 2007;358:925–30.CrossRefPubMedGoogle Scholar
  56. 56.
    Yan-Qi Z, Xue-Yan G, Shuang H, Yu C, Fu-Lin G, Fei-Hu B, et al. Expression and significance of TWIST basic helix-loop-helix protein over-expression in gastric cancer. Pathology. 2007;39:470–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Sung CO, Lee KW, Han S, Kim SH. Twist1 is up-regulated in gastric cancer-associated fibroblasts with poor clinical outcomes. Am J Pathol. 2011;179:1827–38.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zhang J, Ma L. MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev. 2012;31:653–62.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Sun Q, Gu H, Zeng Y, Xia Y, Wang Y, Jing Y, et al. Hsa-mir-27a genetic variant contributes to gastric cancer susceptibility through affecting miR-27a and target gene expression. Cancer Sci. 2010;101:2241–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Liu T, Tang H, Lang Y, Liu M, Li X. MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett. 2008;273:233–42.CrossRefPubMedGoogle Scholar
  61. 61.
    Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, et al. A double- negative feedback loop between ZEB1–SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008;68:7846–54.CrossRefPubMedGoogle Scholar
  62. 62.
    MA L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol. 2010;12:247–56.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributions to epithelial cell plasticity by targeting RhoA. Mol Cell Biol. 2008;28:6773–84.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Wang FE, Zhang C, Maminishkis A, Dong L, Zhi C, Li R, et al. MicroRNA-204/211 alters epithelial physiology. FASEB J. 2010;24:1552–71.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Noto JM, Peek RM. The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis. Front Cell Infect Microbiol. 2012;1:21.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Park Y, Kim JW, Kim DS, Kim EB, Park SJ, Park JY, et al. The Bone Morphogenesis Protein-2 (BMP-2) is associated with progression to metastatic disease in gastric cancer. Cancer Res Treat. 2008;40:127–32.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA. BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp Cell Res. 2010;316:24–37.CrossRefPubMedGoogle Scholar
  68. 68.
    Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression. Exp Cell Res. 2011;317:1746–62.CrossRefPubMedGoogle Scholar
  69. 69.
    Jung H, Jun KH, Jung JH, Chin HM, Park WB. The expression of claudin-1, claudin-2, claudin-3, and claudin-4 in gastric cancer tissue. J Surg Res. 2011;167:e185–91.CrossRefPubMedGoogle Scholar
  70. 70.
    Agarwal R, Mori Y, Cheng Y, Jin Z, Olaru AV, Hamilton JP, et al. Silencing of claudin-11 is associated with increased invasiveness of gastric cancer cells. PLoS One. 2009;4:e8002.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Yoon JH, Kang YH, Choi YJ, Park IS, Nam SW, Lee JY, et al. Gastrokine 1 functions as a tumor suppressor by inhibition of epithelial-mesenchymal transition in gastric cancers. J Cancer Res Clin Oncol. 2011;137:1697–704.CrossRefPubMedGoogle Scholar
  72. 72.
    Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 2007;449:862–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Beswick EJ, Pinchuk IV, Earley RB, Schmitt DA, Reyes VE. Role of gastric epithelial cell-derived transforming growth factor β in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun. 2011;79:2737–45.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest. 2005;115:66–75.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Lindholm C, Quiding-Järbrink M, Lönroth H, Hamlet A, Svennerholm AM. Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun. 1998;66:5964–71.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Watanabe T, Takahashi A, Suzuki K, Kurusu-Kanno M, Yamaguchi K, Fujiki H, et al. Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori. Int J Cancer. 2014;10:2373–82.CrossRefGoogle Scholar
  77. 77.
    Lee DG, Kim HS, Lee YS, Kim S, Cha SY, Ota I, et al. Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity. Nat Commun. 2014;5:4423.PubMedGoogle Scholar
  78. 78.
    Yu H, Zeng J, Liang X, Wang W, Zhou Y, Sun Y, et al. Helicobacter pylori promotes epithelial–mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4. PLoS One. 2014;9:e105306.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 2007;26:4617–26.CrossRefPubMedGoogle Scholar
  80. 80.
    Franco AT, Israel DA, Washington MK, Krishna U, Fox JG, Rogers AB, et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A. 2005;102:10646–51.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Chang H, Kim N, Park JH, Nam RH, Choi YJ, Park SM, et al. Helicobacter pylori might induce TGF-β1-mediated EMT by means of cagE. Helicobacter. 2015;20:438–48.Google Scholar
  82. 82.
    Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer. 2006;94:661–71.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Perri F, Cotugno R, Piepoli A, Merla A, Quitadamo M, Gentile A, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. Am J Gastroenterol. 2007;102:1361–71.CrossRefPubMedGoogle Scholar
  84. 84.
    Chan AO, Lam SK, Wong BC, Wong WM, Yuen MF, Yeung YH, et al. Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut. 2003;52:502–6.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bessède E, Staedel C, Acuña Amador LA, Nguyen PH, Chambonnier L, Hatakeyama M, et al. Helicobacter pylori generates cells with cancer stem cell properties via epithelial–mesenchymal transition-like changes. Oncogene. 2013;8:1–9.Google Scholar
  86. 86.
    Steinestel K, Eder S, Schrader AJ, Steinestel J. Clinical significance of epithelial-mesenchymal transition. Clin Transl Med. 2014;3:17–21.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Uchikado Y, Okumura H, Ishigami S, Setoyama T, Matsumoto M, Owaki T, et al. Increased Slug and decreased E-cadherin expression is related to poor prognosis in patients with gastric cancer. Gastric Cancer. 2011;14:41–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, et al. Clinical significance of vimentin-positive gastric cancer cells. Anticancer Res. 2010;30:5239–43.PubMedGoogle Scholar
  89. 89.
    Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WH. Prognostic importance of epithelial–mesenchymal transition-related protein expression in gastric carcinoma. Histopathology. 2009;54:442–51.CrossRefPubMedGoogle Scholar
  90. 90.
    Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22:894–907.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9:582–9.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Chang YJ, Wu MS, Lin JT, Pestell RG, Blaser MJ, Chen CC. Mechanisms for Helicobacter pylori CagA-induced cyclin D1 expression that affect cell cycle. Cell Microbiol. 2006;8:1740–52.CrossRefPubMedGoogle Scholar
  93. 93.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.CrossRefPubMedGoogle Scholar
  94. 94.
    Christoffersen NR, Silahtaroglu A, Orom UA, Kauppinen S, Lund AH. miR-200b mediates post-transcriptional repression of ZFHX1B. RNA. 2007;13:1172–8.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Liang S, He L, Zhao X, Miao Y, Gu Y, Guo C, et al. MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One. 2011;6:e18409.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Zhao X, Dou W, He L, Liang S, Tie J, Liu C, et al. MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor. Oncogene. 2013;32:1363–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2016

Authors and Affiliations

  1. 1.Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea

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