Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development

Oncogene volume 20, pages 8125–8135 (2001)Cite this article

Abstract

During melanoma development, transformed cells evade keratinocyte-mediated control by downregulating cell adhesion molecules. This study investigated the regulation of cell adhesion by hepatocyte growth factor (HGF) in melanoma. Melanocytes and two melanoma lines, WM164 and WM35, expressed normal level E-cadherin and Desmoglein 1, whereas most melanomas (18 out of 20) expressed no E-cadherin and significantly reduced Desmoglein 1. Overexpression of dominant negative E-cadherin and Desmoglein in melanocytes demonstrated that both molecules contribute to adhesion between melanocytes and keratinocytes. In contrast to melanocytes, most melanomas expressed HGF. All melanocytic cells expressed the HGF receptor c-Met, and autocrine HGF caused constitutive activation of c-Met, MAPK and PI3K. When autocrine activation was induced with HGF-expressing adenovirus, E-cadherin and Desmoglein 1 were decreased in melanocytes, WM164 and WM35. MAPK inhibitor PD98059 and PI3K inhibitor wortmannin partially blocked the downregulation, suggesting that both pathways are involved in this process. c-Met was coimmunoprecipitated with E-cadherin, Desmoglein 1 and Plakoglobin, suggesting that they form a complex (es) that acts to regulate intercellular adhesion. Together, the results indicate that autocrine HGF decouples melanomas from keratinocytes by downregulating E-cadherin and Desmoglein 1, therefore frees melanoma cells from the control by keratinocytes and allows dissemination of the tumor mass.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

AKT:

murine thymoma viral (v-akt) oncogene homologue

bFGF:

basic fibroblast growth factor

DMEM:

Dulbecco's modified Eagle's medium

Dsg3ΔEC:

Desmoglein 3 mutant with extracellular domain deleted

E-cadΔEC:

E-cadherin mutant with extracellular domain deleted

ELISA:

enzyme linked immunosorbent assay

FBS:

fetal bovine serum

HGF:

hepatocyte growth factor

IGF-R1:

insulin-like growth factor receptor 1

MAPK:

mitogen-activated protein kinase

PI3K:

phosphatidyl-inositol-3-kinase.

References

  • Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H . 1994 J. Cell. Sci. 107: 3655–3663

  • Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, Buck CA . 1990 Cancer Res. 50: 6757–6764

  • Amagai M, Karpati S, Klaus-Kovtun V, Udey MC, Stanley JR . 1994 J. Invest. Dermatol. 102: 402–408

  • Amagai M, Karpati S, Prussick R, Klaus-Kovtun V, Stanley JR . 1992 J. Clin. Invest. 90: 919–926

  • Amagai M, Koch PJ, Nishikawa T, Stanley JR . 1996 J. Invest. Dermatol. 106: 351–355

  • Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM, Hughes AE . 1999 Hum. Mol. Genet. 8: 143–148

  • Bauer A, Lickert H, Kemler R, Stappert J . 1998 J. Biol. Chem. 273: 28314–28321

  • Bellusci S, Moens G, Gaudino G, Comoglio P, Nakamura T, Thiery JP, Jouanneau J . 1994 Oncogene 9: 1091–1099

  • Bornslaeger EA, Corcoran CM, Stappenbeck TS, Green KJ . 1996 J. Cell. Biol. 134: 985–1001

  • Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA . 1991b Science 251: 802–804

  • Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA . 1991a Science 251: 802–804

  • Butz S, Kemler R . 1994 FEBS Lett. 355: 195–200

  • Conn IG, Vilela MJ, Garrod DR, Crocker J, Wallace DM . 1990 Br. J. Urol. 65: 176–180

  • Cowin P, Kapprell HP, Franke WW, Tamkun J, Hynes RO . 1986 Cell 46: 1063–1073

  • Danen EH, de Vries TJ, Morandini R, Ghanem GG, Ruiter DJ, van Muijen GN . 1996 Melanoma. Res. 6: 127–131

  • De Bruin A, Muller E, Wurm S, Caldelari R, Wyder M, Wheelock MJ, Suter MM . 1999 Cell. Adhes. Commun. 7: 13–28

  • Depondt J, Shabana AH, Florescu-Zorila S, Gehanno P, Forest N . 1999 Eur. J. Oral. Sci. 107: 183–193

  • Drubin DG, Nelson WJ . 1996 Cell 84: 335–344

  • Franke WW, Goldschmidt MD, Zimbelmann R, Mueller HM, Schiller DL, Cowin P . 1989 Proc. Natl. Acad. Sci. USA 86: 4027–4031

  • Garrod D, Chidgey M, North A . 1996 Curr. Opin. Cell. Biol. 8: 670–678

  • Garrod DR . 1993 Curr. Opin. Cell. Biol. 5: 30–40

  • Gherardi E, Gray J, Stoker M, Perryman M, Furlong R . 1989 Proc. Natl. Acad. Sci. USA 86: 5844–5848

  • Green KJ, Gaudry CA . 2000 Nat. Rev. Mol. Cell. Biol. 1: 208–216

  • Gumbiner BM . 1996 Cell 84: 345–357

  • Halaban R, Rubin JS, Funasaka Y, Cobb M, Boulton T, Faletto D, Rosen E, Chan A, Yoko K, White W, Cook C, Moellmann G . 1992 Oncogene 7: 2195–2206

  • Halaban R, Rubin JS, White W . 1993 Exs. 65: 329–339

  • Hanakawa Y, Amagai M, Shirakata Y, Sayama K, Hashimoto K . 2000 J. Cell. Sci. 113: 1803–1811

  • Hendrix MJ, Seftor EA, Seftor RE, Kirschmann DA, Gardner LM, Boldt HC, Meyer M, Pe'er J, Folberg R . 1998 Am. J. Pathol. 152: 855–863

  • Hirohashi S . 1998 Am. J. Pathol. 153: 333–339

  • Hiscox S, Jiang WG . 1999a Biochem. Biophys. Res. Commun. 261: 406–411

  • Hiscox S, Jiang WG . 1999b Anticancer Res. 19: 509–517

  • Hoschuetzky H, Aberle H, Kemler R . 1994 J. Cell. Biol. 127: 1375–1380

  • Hsu MY, Meier FE, Nesbit M, Hsu JY, Van Belle P, Elder DE, Herlyn M . 2000 Am. J. Pathol. 156: 1515–1525

  • Hsu MY, Shih DT, Meier FE, Van Belle P, Hsu JY, Elder DE, Buck CA, Herlyn M . 1998 Am. J. Pathol. 153: 1435–1442

  • Hsu MY, Wheelock MJ, Johnson KR, Herlyn M . 1996 J. Investig. Dermatol. Symp. Proc. 1: 188–194

  • Imokawa G, Yada Y, Morisaki N, Kimura M . 1998 Biochem. J. 330: 1235–1239

  • Iyer A, Kmiecik TE, Park M, Daar I, Blair D, Dunn KJ, Sutrave P, Ihle JN, Bodescot M, Vande Woude GF . 1990 Cell Growth Differ. 1: 87–95

  • Johnson JP . 1999 Cancer Metastasis Rev. 18: 345–357

  • Jouneau A, Yu YQ, Pasdar M, Larue L . 2000 Pigment Cell. Res. 13: 260–272

  • Kamei T, Matozaki T, Sakisaka T, Kodama A, Yokoyama S, Peng YF, Nakano K, Takaishi K, Takai Y . 1999 Oncogene 18: 6776–6784

  • Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S . 1995 Biochem. Biophys. Res. Commun. 208: 1067–1072

  • Kanegae Y, Lee G, Sato Y, Tanaka M, Nakai M, Sakaki T, Sugano S, Saito I . 1995 Nucleic Acids Res. 23: 3816–3821

  • Kanegae Y, Takamori K, Sato Y, Lee G, Nakai M, Saito I . 1996 Gene 181: 207–212

  • Klymkowsky MW, Parr B . 1995 Cell 83: 5–8

  • Koch PJ, Franke WW . 1994 Curr. Opin. Cell. Biol. 6: 682–687

  • Koch PJ, Mahoney MG, Ishikawa H, Pulkkinen L, Uitto J, Shultz L, Murphy GF, Whitaker-Menezes D, Stanley JR . 1997 J. Cell. Biol. 137: 1091–1102

  • Kos L, Aronzon A, Takayama H, Maina F, Ponzetto C, Merlino G, Pavan W . 1999 Pigment Cell. Res. 12: 13–21

  • Kouklis PD, Hutton E, Fuchs E . 1994 J. Cell. Biol. 127: 1049–1060

  • Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM, Denning MF, Green KJ . 1997 J. Cell. Biol. 139: 773–784

  • Kowalczyk AP, Bornslaeger EA, Norvell SM, Palka HL, Green KJ . 1999 Int. Rev. Cytol. 185: 237–302

  • Krunic AL, Garrod DR, Smith NP, Orchard GS, Cvijetic OB . 1996 Acta Derm. Venereol. 76: 394–398

  • Lewis JE, Wahl JK, Sass KM, Jensen PJ, Johnson KR, Wheelock MJ . 1997 J. Cell. Biol. 136: 919–934

  • Li G, Herlyn M . 2000 Mol. Med. Today 6: 163–169

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

  • Marshall CJ . 1996 Curr. Opin. Cell. Biol. 8: 197–204

  • Mathur M, Goodwin L, Cowin P . 1994 J. Biol. Chem. 269: 14075–14080

  • Matsumoto K, Tajima H, Nakamura T . 1991 Biochem. Biophys. Res. Commun. 176: 45–51

  • Meier F, Nesbit M, Hsu MY, Martin B, Van Belle P, Elder DE, Schaumburg-Lever G, Garbe C, Walz TM, Donatien P, Crombleholme TM, Herlyn M . 2000 Am. J. Pathol. 156: 193–200

  • Meier F, Satyamoorthy K, Nesbit M, Hsu MY, Schittek B, Garbe C, Herlyn M . 1998 Front. Biosci. 3: D1005–D1010

  • Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C, Saito I . 1996 Proc. Natl. Acad. Sci. USA 93: 1320–1324

  • Moriyama T, Kataoka H, Koono M, Wakisaka S . 1999 Int. J. Mol. Med. 3: 531–536

  • Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S . 1989 Nature 342: 440–443

  • Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, Comoglio PM . 1993 Br. J. Cancer 68: 746–750

  • Noonan FP, Otsuka T, Bang S, Anver MR, Merlino G . 2000 Cancer Res. 60: 3738–3743

  • North AJ, Bardsley WG, Hyam J, Bornslaeger EA, Cordingley HC, Trinnaman B, Hatzfeld M, Green KJ, Magee AI, Garrod DR . 1999 J. Cell. Sci. 112: 4325–4336

  • Ochiai A, Akimoto S, Kanai Y, Shibata T, Oyama T, Hirohashi S . 1994 Biochem. Biophys. Res. Commun. 205: 73–78

  • Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, Ellmore N, Vieira W, Owens JW, Anver M, Merlino G . 1998 Cancer Res. 58: 5157–5167

  • Parker SL, Tong T, Bolden S, Wingo PA . 1997 CA Cancer J. Clin. 47: 5–27

  • Phaneuf D, Chen SJ, Wilson JM . 2000 Mol. Med. 6: 96–103

  • Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM . 1994 Cell 77: 261–271

  • Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK . 2001 J. Biol. Chem. 25: 25

  • Potempa S, Ridley AJ . 1998 Mol. Biol. Cell. 9: 2185–2200

  • Rickman L, Simrak D, Stevens HP, Hunt DM, King IA, Bryant SP, Eady RA, Leigh IM, Arnemann J, Magee AI, Kelsell DP, Buxton RS . 1999 Hum. Mol. Genet. 8: 971–976

  • Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, Vernon SW, Cronin K, Edwards BK . 2000 Cancer 88: 2398–2424

  • Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Koprowsk H . 1987 Int. J. Cancer 40: 687–690

  • Roh JY, Stanley JR . 1995 J. Invest. Dermatol. 104: 720–724

  • Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF . 1992 Mol. Cell. Biol. 12: 5152–5158

  • Rosen EM, Nigam SK, Goldberg ID . 1994 J. Cell. Biol. 127: 1783–1787

  • Royal I, Park M . 1995 J. Biol. Chem. 270: 27780–27787

  • Rusciano D, Lin S, Lorenzoni P, Casella N, Burger MM . 1998 Tumour Biol. 19: 335–345

  • Satyamoorthy K, DeJesus E, Linnenbach AJ, Kraj B, Kornreich DL, Rendle S, Elder DE, Herlyn M . 1997 Melanoma. Res. 7: Suppl 2 S35–S42

  • Savagner P, Yamada KM, Thiery JP . 1997 J. Cell. Biol. 137: 1403–1419

  • Scott GA, Cassidy L . 1998 J. Invest. Dermatol. 111: 243–250

  • Shinohara M, Hiraki A, Ikebe T, Nakamura S, Kurahara S, Shirasuna K, Garrod DR . 1998 J. Pathol. 184: 369–381

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

  • Smith EA, Fuchs E . 1998 J. Cell Biol. 141: 1229–1241

  • Sonnenberg E, Meyer D, Weidner KM, Birchmeier C . 1993 J. Cell Biol. 123: 223–235

  • Stanley JR . 1993 Adv. Immunol. 53: 291–325

  • Stappenbeck TS, Green KJ . 1992 J. Cell Biol. 116: 1197–1209

  • Steinberg MS . 1996 Dev. Biol. 180: 377–388

  • Stoker M, Gherardi E, Perryman M, Gray J . 1987 Nature 327: 239–242

  • Tada H, Hatoko M, Tanaka A, Kuwahara M, Muramatsu T . 2000 J. Cutan. Pathol. 27: 24–29

  • Takayama H, La Rochelle WJ, Anver M, Bockman DE, Merlino G . 1996 Proc. Natl. Acad. Sci. USA 93: 5866–5871

  • Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA, Merlino G . 1997 Proc. Natl. Acad. Sci. USA 94: 701–706

  • Takeichi M . 1995 Curr. Opin. Cell Biol. 7: 619–627

  • Takeichi M, Watabe M, Shibamoto S, Ito F . 1994 Princess Takamatsu Symp. 24: 28–37

  • Tamatani T, Hattori K, Iyer A, Tamatani K, Oyasu R . 1999 Carcinogenesis 20: 957–962

  • Tang A, Eller MS, Hara M, Yaar M, Hirohashi S, Gilchrest BA . 1994 J. Cell Sci. 107: 983–992

  • To CT, Tsao MS . 1998 Oncol. Rep. 5: 1013–1024

  • Troyanovsky SM, Leube RE . 1998 Subcell. Biochem. 31: 263–289

  • Trusolino L, Serini G, Cecchini G, Besati C, Ambesi-Impiombato FS, Marchisio PC, De Filippi R . 1998 J. Cell. Biol. 142: 1145–1156

  • Van Belle PA, Elenitsas R, Satyamoorthy K, Wolfe JT, Guerry, DT, Schuchter L, Van Belle TJ, Albelda S, Tahin P, Herlyn M, Elder DE . 1999 Hum. Pathol. 30: 562–567

  • Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J . 1997 Ciba. Found. Symp. 212: 119–130

Download references

Acknowledgements

We thank Dr James Wilson (University of Pennsylvania) for providing recombinant adenoviral vector Ad.CMV.rhHGF and Dr Izumu Saito (University of Tokyo, Japan) for AxCANCre. We also thank Rena Finko for help in cell culture and Ruth Snyder for reading the manuscript. This work was supported by National Institutes of Health Grants CA-25874, CA-76674, CA-47159, CA-80999 and CA-10815.

Author information

Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, Pennsylvania, USA

    Gang Li, Helmut Schaider, Kapaettu Satyamoorthy & Meenhard Herlyn

  2. Program of Cell and Molecular Biology, Biomedical Graduate Studies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, Pennsylvania, USA

    Gang Li

  3. Department of Dermatology, School of Medicine, Ehime University, Ehime, Japan

    Yasushi Hanakawa & Koji Hashimoto

Authors
  1. Gang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helmut Schaider
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kapaettu Satyamoorthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasushi Hanakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koji Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meenhard Herlyn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meenhard Herlyn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, G., Schaider, H., Satyamoorthy, K. et al. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 20, 8125–8135 (2001). https://doi.org/10.1038/sj.onc.1205034

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205034

Keywords

This article is cited by

Search

Advanced search

Quick links