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Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma

Oncogene volume 23, pages 8509–8519 (2004)Cite this article

Abstract

Malignant transformation of melanocytes frequently coincides with loss of E-cadherin expression. Here, we show that loss of E-cadherin leads to induction of nuclear factor kappa B (NFκB) activity in melanoma cell lines. Melanoma cells show constitutively active NFκB, whereas no activity is found in primary melanocytes. After re-expression of E-cadherin in melanoma cells, strong downregulation of NFκB activity was found. Consistently, NFκB activity was induced in primary human melanocytes after inhibition of E-cadherin activity by functionally blocking anti-E-cadherin antibodies. Interestingly, re-expression of E-cadherin-blocked p38 MAPK activity and the p38 MAPK inhibitors SB203580 and SB202190 almost completely prevented NFκB activation in melanoma cells. Furthermore, cytoplasmatic β-catenin induced p38 and NFκB activation in malignant melanoma. To our knowledge, this is the first report suggesting a correlation between E-cadherin and NFκB activity in melanocytes and melanoma cells. In summary, we conclude that loss of E-cadherin and cytoplasmatic β-catenin induces p38-mediated NFκB activation, potentially revealing an important mechanism of tumorigenesis in malignant melanomas.

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Abbreviations

ELISA:

enzyme-linked immunosorbent assay

EMSA:

electrophoretic mobility shift assay

ERK:

extracellular signal-regulated protein kinase

IκB (IkappaB):

inhibitor of NFκB

IL-8:

interleukin 8

JNK:

c-jun NH2-terminal kinase

MAPK:

mitogen-activated protein kinase

Mekk1:

MAP kinase kinase1

MMP2:

matrix-metalloproteinase 2

NFκB:

nuclear factor kappa B

NHEM:

normal human epidermal melanocytes

PBS:

phosphate-buffered saline

PD98059:

2-(2′amino-3′-methoxyphenyl)-oxanaphthalen-4-one

PKB:

protein kinase B

RT:

reverse transcription

SAPK:

stress-activated protein kinase

SB202190:

4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole

SB203580:

4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole

TCF:

T-cell factor

TGFβ2:

transcriptional growth factor beta 2

References

  • Baldwin AS . (2001). J. Clin. Invest., 107, 241–246.

  • Bergmann M, Hart L, Lindsay M, Barnes PJ and Newton R . (1998). J. Biol. Chem., 273, 6607–6610.

  • Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C and van Roy F . (1995). EMBO J., 14, 6107–6115.

  • Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F and Cornelisse C . (1996). Oncogene, 13, 1919–1925.

  • Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P and Fiers W . (1996). EMBO J., 15, 1914–1923.

  • Bosserhoff AK, Hein R, Bogdahn U and Buettner R . (1996). J. Biol. Chem., 271, 490–495.

  • Carpentier I, Declercq W, Malinin NL, Wallach D, Fiers W and Beyaert R . (1998). FEBS Lett., 425, 195–198.

  • Carter AB, Knudtson KL, Monick MM and Hunninghake GW . (1999). J. Biol. Chem., 274, 30858–30863.

  • Cowin P . (1994). Proc. Natl. Acad. Sci. USA, 91, 10759–10761.

  • Davis RE, Brown KD, Siebenlist U and Staudt LM . (2001). J. Exp. Med., 194, 1861–1874.

  • Denkert C, Siegert A, Leclere A, Turzynski A and Hauptmann S . (2002). Clin. Exp. Metast., 19, 79–85.

  • Englaro W, Bertolotto C, Busca R, Brunet A, Pages G, Ortonne JP and Ballotti R . (1998). J. Biol. Chem., 273, 9966–9970.

  • Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D and Birchmeier W . (1991). J. Cell Biol., 113, 173–185.

  • Gumbiner B, Stevenson B and Grimaldi A . (1988). J. Cell Biol., 107, 1575–1587.

  • Hellerbrand C, Jobin C, Licato LL, Sartor RB and Brenner DA . (1998). Am. J. Physiol., 275, G269–G278.

  • Huang S, DeGuzman A, Bucana CD and Fidler IJ . (2000). Clin. Cancer Res., 6, 2573–2581.

  • Jacob K, Wach F, Holzapfel U, Hein R, Lengyel E, Buettner R and Bosserhoff AK . (1998). Melanoma Res., 8, 211–219.

  • Kortylewski M, Heinrich PC, Kauffmann ME, Bohm M, MacKiewicz A and Behrmann I . (2001). Biochem. J., 357, 297–303.

  • Li G, Satyamoorthy K and Herlyn M . (2001). Cancer Res., 61, 3819–3825.

  • Madrid LV, Mayo MW, Reuther JY and Baldwin Jr AS . (2001). J. Biol. Chem., 276, 18934–18940.

  • Maulik N, Sato M, Price BD and Das DK . (1998). FEBS Lett., 429, 365–369.

  • McNulty SE, Tohidian NB and Meyskens Jr FL . (2001). Pigment Cell Res., 14, 456–465.

  • Melki JR, Vincent PC, Brown RD and Clark SJ . (2000). Blood, 95, 3208–3213.

  • Nollet F, Berx G and van Roy F . (1999). Mol. Cell Biol. Res. Commun., 2, 77–85.

  • Novak A and Dedhar S . (1999). Cell Mol. Life Sci., 56, 523–537.

  • Orsulic S, Huber O, Aberle H, Arnold S and Kemler R . (1999). J. Cell Sci., 112, 1237–1245.

  • Pece S and Gutkind JS . (2000). J. Biol. Chem., 275, 41227–41233.

  • Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R and Bosserhoff AK . (2001). J. Biol. Chem., 276, 24661–24666.

  • Sanders DS, Blessing K, Hassan GA, Bruton R, Marsden JR and Jankowski J . (1999). Mol. Pathol., 52, 151–157.

  • Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als-Nielsen J, Colman DR and Hendrickson WA . (1995). Nature, 374, 327–337.

  • Shattuck-Brandt RL and Richmond A . (1997). Cancer Res., 57, 3032–3039.

  • Silye R, Karayiannakis AJ, Syrigos KN, Poole S, van Noorden S, Batchelor W, Regele H, Sega W, Boesmueller H, Krausz T and Pignatelli M . (1998). J. Pathol., 186, 350–355.

  • Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gelinas C and Rabson AB . (2002). Prostate, 52, 183–200.

  • Tamura G, Sakata K, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, Terashima M, Saito K and Satodate R . (1996a). Jpn. J. Cancer Res., 87, 1153–1159.

  • Tamura S, Shiozaki H, Miyata M, Kadowaki T, Inoue M, Matsui S, Iwazawa T, Takayama T, Takeichi M and Monden M . (1996b). Br. J. Surg., 83, 1608–1614.

  • Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz ML, Fiers W and Haegeman G . (1998). J. Biol. Chem., 273, 3285–3290.

  • Vleminckx K, Vakaet Jr L, Mareel M, Fiers W and van Roy F . (1991). Cell, 66, 107–119.

  • Wang D and Richmond A . (2001). J. Biol. Chem., 276, 3650–3659.

  • Watabe M, Nagafuchi A, Tsukita S and Takeichi M . (1994). J. Cell Biol., 127, 247–256.

  • Wesselborg S, Bauer MK, Vogt M, Schmitz ML and Schulze-Osthoff K . (1997). J. Biol. Chem., 272, 12422–12429.

  • Yang J and Richmond A . (2001). Cancer Res., 61, 4901–4909.

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Acknowledgements

We are indebted to Astrid Hamm and Claudia Abschlag for technical assistance and to Eric Fearon and Gabriele Handschuh for providing β/-γ-catenin- and pBAT-E-cadherin expression vectors, respectively. We thank Guy Haegeman for helpful discussions. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to AB.

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Author notes

  1. S Kuphal and I Poser: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, D-93053, Germany

    S Kuphal, I Poser & A K Bosserhoff

  2. Department of Medicine, University of North Carolina, USA

    C Jobin

  3. Internal Medicine I, University of Regensburg, Regensburg, D-93053, Germany

    C Hellerbrand

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  1. S Kuphal
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Correspondence to A K Bosserhoff.

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Kuphal, S., Poser, I., Jobin, C. et al. Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma. Oncogene 23, 8509–8519 (2004). https://doi.org/10.1038/sj.onc.1207831

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