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