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Vol. 39, No. 4, 2007
Issue release date: June 2007
Eur Surg Res 2007;39:208–215

Association of Extracellular Cleavage of E-Cadherin Mediated by MMP-7 with HGF-Induced in vitro Invasion in Human Stomach Cancer Cells

Lee K.H. · Choi E.Y. · Hyun M.S. · Jang B.I. · Kim T.N. · Kim S.W. · Song S.K. · Kim J.H. · Kim J.-R.
Departments of aHemato-Oncology, bEnterology, cGeneral Surgery, and dBiochemistry and Molecular Biology, and eAging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea

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Background: Proteolytic shedding of the ectodomain of a variety of transmembrane proteins, including cell-to-cell adhesion molecules, has been observed in solid cancers. We have investigated whether extracellular cleavage of E-cadherin mediated by matrix metalloproteinase-7 (MMP-7) is involved in hepatocyte growth factor (HGF) induced in vitro invasion in stomach cancer cells. Methods: The effects of HGF on the expression of E-cadherin/β-catenin and MMP-7 at both the protein and mRNA levels were assessed in stomach cancer cells, NUGC-3 and MKN-28, and in cells in which the expression of MMP-7 was downregulated by transfection with a MMP-7 short hairpin RNA plasmid. Results: Treatment with HGF increased the extracellular cleavage of E-cadherin and the release of MMP-7 and reduced the level of E-cadherin in a dose- and time-dependent manner. HGF treatment repressed the phosphorylation of β-catenin in a Triton-soluble fraction, but enhanced this phosphorylation in a Triton-insoluble fraction. The association of E-cadherin with β-catenin was decreased by HGF treatment in the Triton-soluble fraction. In addition, treatment of MMP-7 short hairpin RNA transfected NUGC-3 cells with HGF resulted in no extracellular cleavage of E-cadherin and also decreased the in vitro cell invasion. Conclusions: These results suggest that incubation with HGF mediated the release of MMP-7, resulting in extracellular cleavage of E-cadherin from stomach cancer cells. This might be a key mechanism in HGF-induced in vitro invasion and metastasis.

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  1. Fidler IJ: Origin and biology of cancer metastasis. Cytometry 1989;10:673–680.
  2. Kyung HL, Myung SH, Jae RK: Invasion-metastasis by hepatocyte growth factor/c-met signalling concomitant with induction of urokinase plasminogen avtivator in human pancreatic cancer: role as therapeutic target. Cancer Res Treat 2003;35:207–212.
  3. Takeishi M: Cadherins: a molecular family important in selective cell-cell adhesion. Annu Rev Biochem 1990;59:237–252.
  4. Takeichi M: The cadherins, cell-cell molecules controlling animal morphogenesis. Development 1988;102:639–655.
  5. Chen WC, Obrink B: Cell-cell contacts mediated by E-cadherin (uvomorulin) restrict invasive behavior of L-cells. J Cell Biol 1991;114:319–327.
  6. Shiozaki H, Oka H, Inoue M, Tamura S, Monden M: E-cadherin mediated adhesion system in cancer cells. Cancer 1996;77:1605–1613.
  7. Hiscox S, Jiang WG: Hepatocyte growth factor/scatter factor disrupts epithelial tumour cell-cell adhesion: involvement of beta-catenin. Anticancer Res 1999;19:509–517.
  8. Gofuku J, Shiozaki H, Doki Y, Inoue M, Hirao M, Fukuchi N, Monden M: Characterization of soluble E-cadherin as a disease marker in gastric cancer patients. Br J Cancer 1998;78:1095–1101.
  9. Protheroe AS, Banks RE, Mzimba M, Porter WH, Southgate J, Singh PN, Bosomworth M, Harnden P, Smith PH, Whelan P, Selby PJ: Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer. Br J Cancer 1999;80:273–278.
  10. Velikova G, Banks RE, Gearing A, Hemingway I, Forbes MA, Preston SR, Hall NR, Jones M, Wyatt J, Miller K, Ward U, Al-Maskatti J, Singh SM, Finan PJ, Ambrose NS, Primrose JN, Selby PJ: Serum concentrations of soluble adhesion molecules in patients with colorectal cancer. Br J Cancer 1998;77:1857–1863.
  11. Matrisian LM: The matrix-degrading metalloproteinases. Bioessays 1992;14:455–463.
  12. Honda M, Mori M, Ueo H, Sugimachi K, Akiyoshi T: Matrix metalloproteinase-7 expression in gastric carcinoma. Gut 1996;39:444–448.
  13. Yamamoto H, Adachi Y, Itoh F, Iku S, Matsuno K, Kusano M, Arimura Y, Endo T, Hinoda Y, Hosokawa M, Imai K: Association of MMP-7 expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Cancer Res 1999;59:3313–3316.
  14. Davies G, Jiang WG, Mason MD: MMP-7 mediates extracellular cleavage of E-cadherin from prostate cancer cells: a key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion. Clin Cancer Res 2001;7:3289–3297.
  15. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W: E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 1991;113:173–185.
  16. Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F: Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991;66:107–119.
  17. Schipper JH, Frixen UH, Behrens J, Unger A, Jahnke K, Birchmeier W: E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis. Cancer Res 1991;51:6328–6337.
  18. Gabbert HE, Mueller W, Schneiders A, Meier S, Moll R, Birchmeier W, Hommel G: Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer 1996;69:184–189.
  19. Oka H, Shiozaki H, Inoue M, Kobayashi K, Tahara H, Kobayashi T, Takatsuka Y, Matsuyoshi N, Hirano S, Takeichi M, Mori T: Expression of E-cadherin adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res 1993;53:1696–1701.
  20. Krishnadath KK, Tilanus HW, Blankenstein M, Hop WC, Kremers ED, Dinjens WN, Bosman FT: Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. J Pathol 1997;182:331–338.
  21. Takayama T, Shiozaki H, Doki Y, Oka H, Inoue M, Yamamoto M, Tamura S, Shibamoto S, Ito F, Monden M: Aberrant expression and phosphorylation of beta-catenin in human colorectal cancer. Br J Cancer 1998;77:605–613.
  22. Katayama M, Hirai S, Kamihagi K, Nakagawa K, Yasumoto M, Kato I: Soluble E-cadherin fragments increased in circulation of cancer patients. Br J Cancer 1994;69:580–585.
  23. Wilson CL, Matrisian LM: Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol 1996;28:123–136.
  24. Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M: Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001;114(Pt 1):111–118.
  25. Katayama M, Hirai S, Yasumoto M, Nishikawa K, Yasumoto M, Kamihagi K, Kato I: Soluble fragments of E-cadherin cell adhesion molecule increase in urinary excretion of cancer patients, potentially indicating its shedding from epithelial tumor cells (abstract). Int J Oncol 1994;5:1049–1057.
  26. Rudolph-Owen LA, Chan R, Muller WJ, Matrisian LM: The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res 1998;58:5500–5506.
  27. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997;89:1260–1270.
  28. Noel A, Gilles C, Bajou K, Devy L, Kebers F, Lewalle JM, Maquoi E, Munaut C, Remacle A, Foidart JM: Emerging roles for proteinases in cancer. Invasion Metastasis 1997;17:221–239.
  29. Kyung HL, Eun YC, Min KK, Myung SH, Byung IJ, Tae NK, Sang WK, Sun KS, Jung HK, Jae RK: Hepatocyte growth factor/c-met signalling in regulating urokinase plasminogen activator in human stomach cancer: a potential therapeutic target for human stomach cancer. Korean J Med 2006;26:20–27.
  30. Hyun AH, Gu L, Hee JK, Yong GK, Sung HB, Jae LL, Kyung HL, Dong SK: Overexpression of c-Met protein in gastric cancer and role of uPAR as a therapeutic target. Cancer Res Treat 2003;35:9–15.
  31. Hinck L, Nathke IS, Papkoff J, Nelson WJ: Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol 1994;125:1327–1340.
  32. Davies G, Jiang WG, Mason MD: The interaction between β-catenin, GSK3β and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer. Int J Oncol 2001;18:843–847.
  33. Powell WC, Knox JD, Navre M, Grogan T, Kittelson J, Nagle RB, Bowden GT: Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 1993;53:417–422.

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