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Protective effects of intestinal trefoil factor (ITF) on gastric mucosal epithelium through activation of extracellular signal-regulated kinase 1/2 (ERK1/2)

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Abstract

The rapid repair of gastric mucosa is critical upon exposure to injurious agents. Intestinal trefoil factor (ITF) is a member of the trefoil factor family domain peptides, which play an important role in the cytoprotection of gastric epithelium. However, the underlying molecular mechanisms that are responsible for ITF-induced gastric epithelial repair remain unclear. In the present study, we demonstrate that ITF enhances the proliferation and migration of GES-1 gastric endothelial cells in a dose- and time-dependent manner through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, the ITF-mediated protection of GES-1 cells from a NS398 (nonsteroidal anti-inflammatory drug) was dependent on the ERK1/2 signaling pathway. Taken together, the results provide a mechanistic explanation for ITF-mediated protection of gastric epithelial mucosa cells, suggesting that activation of the ERK1/2 signaling pathway may provide a new therapeutic strategy for repairing gastric injury.

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References

  1. Podolsky DK (1999) V. Innate mechanisms of mucosal defense and repair: the best offense is a good defense. Am J Physiol Gastrointest Liver Physiol 277(3):G495–G499

    CAS  Google Scholar 

  2. Mazzuoli S, Guglielmi FW, Antonelli E, Salemme M, Bassotti G, Villanacci V (2013) Definition and evaluation of mucosal healing in clinical practice. Dig Liver Dis 45(12):969–977

    Article  PubMed  Google Scholar 

  3. Hoffmann W (2005) TFF (trefoil factor family) peptide-triggered signals promoting restitution of mucous epithelia. Cell Mol Life Sci 62:2932–2938

    Article  CAS  PubMed  Google Scholar 

  4. Kjellev S (2009) The trefoil factor family-small peptides with multiple functionalities. Cell Mol Life Sci 66(8):1350–1369

    Article  CAS  PubMed  Google Scholar 

  5. Baus-Loncar M, Giraud AS (2005) Multiple regulatory pathways for trefoil factor (TFF) genes. Cell Mol Life Sci 62(24):2921–2931

    Article  CAS  PubMed  Google Scholar 

  6. Pan M-R, Chang H-C, Hung W-C (2008) Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 20(6):1134–1141

    Article  CAS  PubMed  Google Scholar 

  7. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410(6824):37–40

    Article  CAS  PubMed  Google Scholar 

  8. Storesund T, Hayashi K, Kolltveit KM, Bryne M, Schenck K (2008) Salivary trefoil factor 3 enhances migration of oral keratinocytes. Eur J Oral Sci 116(2):135–140

    Article  CAS  PubMed  Google Scholar 

  9. Christine R, Sylvie R, Erik B, Geneviève P, Amélie R, Gérard R, Marc B, Christian G, Samir A (2005) Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3)—and vascular endothelial growth factor-mediated cellular invasion and tumor growth. Cancer Res 65(1):195–202

    CAS  PubMed  Google Scholar 

  10. Torii S, Yamamoto T, Tsuchiya Y, Nishida E (2006) ERK MAP kinase in G1 cell cycle progression and cancer. Cancer Sci 97(8):697–702

    Article  CAS  PubMed  Google Scholar 

  11. Taupin D, Podolsky DK (2003) Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4(9):721–732

    Article  CAS  PubMed  Google Scholar 

  12. Tomisato W, Tsutsumi S, Rokutan K, Tsuchiya T, Mizushima T (2001) NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture. Am J Physiol Gastrointest Liver Physiol 281(4):G1092–G1100

    CAS  PubMed  Google Scholar 

  13. Hoffmann W (2004) Trefoil factor family (TFF) peptides: regulators of mucosal regeneration and repair, and more. Peptides 25(5):727–730

    Article  CAS  PubMed  Google Scholar 

  14. Kouznetsova I, Peitz U, Vieth M, Meyer F, Vestergaard EM, Malfertheiner P, Roessner A, Lippert H, Hoffmann W (2004) A gradient of TFF3 (trefoil factor family 3) peptide synthesis within the normal human gastric mucosa. Cell Tissue Res 316(2):155–165

    Article  CAS  PubMed  Google Scholar 

  15. Podolsky D (1999) Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides. J Gastroenterol 35:69–74

    Google Scholar 

  16. Guleng B, Han J, Yang J-Q, Huang Q-W, Huang J-K, Yang X-N, Liu J-J, Ren J-L (2012) TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells. Mol Biol Rep 39(4):4127–4134

    Article  CAS  PubMed  Google Scholar 

  17. Storesund T, Schenck K, Osmundsen H, Røed A, Helgeland K, Kolltveit KM (2009) Signal transduction and gene transcription induced by TFF3 in oral keratinocytes. Eur J Oral Sci 117(5):511–517

    Article  CAS  PubMed  Google Scholar 

  18. Göke MN, Cook JR, Kunert KS, Fini ME, Gipson IK, Podolsky DK (2001) Trefoil peptides promote restitution of wounded corneal epithelial cells. Exp Cell Res 264(2):337–344

    Article  PubMed  Google Scholar 

  19. Oertel M, Graness A, Thim L, Buhling F, Kalbacher H, Hoffmann W (2001) Trefoil factor family-peptides promote migration of human bronchial epithelial cells: synergistic effect with epidermal growth factor. Am J Respir Cell Mol Biol 25(4):418–424

    Article  CAS  PubMed  Google Scholar 

  20. De Liu, El-Hariry I, Karayiannakis A, Wilding J, Chinery R, Kmiot W, McCrea P, Gullick W, Pignatelli M (1997) Phosphorylation of beta-catenin and epidermal growth factor receptor by intestinal trefoil factor. Lab Invest 77(6):557–563

    Google Scholar 

  21. Zheng Q, Gao J, Li H, Guo W, Mao Q, Gao E, Y-q Zhu (2013) Trefoil factor 3 peptide regulates migration via a Twist-dependent pathway in gastric cell. Biochem Biophys Res Commun 438(1):6–12

    Article  CAS  PubMed  Google Scholar 

  22. Taupin D, Kinoshita K, Podolsky D (2000) Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Proc Natl Acad Sci USA 97(2):799–804

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, Malki S, Alderman BM, Grail D, Hollande F (2002) Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8(10):1089–1097

    Article  CAS  PubMed  Google Scholar 

  24. Marshall C (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80(2):179–185

    Article  CAS  PubMed  Google Scholar 

  25. Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1-to S-phase transition. Oncogene 26(22):3227–3239

    Article  CAS  PubMed  Google Scholar 

  26. Massagué J (2004) G1 cell-cycle control and cancer. Nature 432(7015):298–306

    Article  PubMed  Google Scholar 

  27. Zhong J, Cornelsen Gencay MM, Bubendorf L, Burgess JK, Parson H, Robinson BW, Tamm M, Black JL, Roth M (2006) ERK1/2 and p38 MAP kinase control MMP-2, MT1-MMP, and TIMP action and affect cell migration: a comparison between mesothelioma and mesothelial cells. J Cell Physiol 207(2):540–552

    Article  CAS  PubMed  Google Scholar 

  28. Fiorucci S, Antonelli E, Morelli A (2001) Mechanism of non-steroidal anti-inflammatory drug-gastropathy. Dig Liver Dis 33:S35–S43

    Article  CAS  PubMed  Google Scholar 

  29. Santucci L, Fiorucci S, Giansanti M, Brunori P, Di Matteo F, Morelli A (1994) Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. Gut 35(7):909–915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Chinery R, Playford RJ (1995) Combined intestinal trefoil factor and epidermal growth factor is prophylactic against indomethacin-induced gastric damage in the rat. Clin Sci 88(4):401–404

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant from the Major Projects Foundation of Nanjing Military Region (12Z32), the Medical Science Foundation for young cultivation project of PLA (13QNP038), and the Natural Science Foundation of Jinling Hospital (2013023 and 2014004).

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Correspondence to Zhizhou Yang or Shinan Nie.

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Jinfeng Lin and Zhaorui Sun have contributed equally.

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Lin, J., Sun, Z., Zhang, W. et al. Protective effects of intestinal trefoil factor (ITF) on gastric mucosal epithelium through activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Mol Cell Biochem 404, 263–270 (2015). https://doi.org/10.1007/s11010-015-2386-2

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  • DOI: https://doi.org/10.1007/s11010-015-2386-2

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