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Collaborative activities of macrophage-stimulating protein and transforming growth factor-β1 in induction of epithelial to mesenchymal transition: roles of the RON receptor tyrosine kinase

Oncogene volume 23, pages 1668–1680 (2004)Cite this article

Abstract

Epithelial to mesenchymal transition (EMT) is a process occurring during embryonic development and cancer progression. Using recepteur d'origine nantais (RON)-expressing epithelial cells as a model, we showed that RON activation causes spindle-shaped morphology with increased cell motilities. These activities resemble those observed in EMT induced by transforming growth factor (TGF)-β1 or by Ras–Raf signaling. By immunofluorescent and Western blot analyses, we found that constitutive RON expression results in diminished expression of E-cadherin, redistribution of β-catenin, reorganization of actin cytoskeleton, and increased expression of vimentin, a mesenchymal filament. RON expression is also essential for TGF-β1-induced expression of α-smooth muscle actin (α-SMA), a specialized mesenchymal marker. In the study of signaling pathways responsible for RON-mediated EMT, it was found that PD98059, a MAP kinase inhibitor, blocks the collaborative activities of RON and TGF-β1 in induction of α-SMA expression and restores epithelial cells to their original morphology. Moreover, we showed that RON expression increases Smad2 gene promoter activities and protein expression, which significantly lowers TGF-β1 threshold for EMT induction. These results suggest that persistent RON expression and activation cause the loss of epithelial phenotypes. These changes, collaborating with TGF-β1 signaling, could play a critical role in epithelial transdifferentiation towards invasiveness and metastasis of certain cancers.

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References

  • Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J and Garcia De Herreros A . (2000). Nat. Cell Biol., 2, 84–89.

  • Beavon IR . (2000). Eur. J Cancer, 36, 1607–1620.

  • Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL and Moses HL . (2001). Mol. Biol. Cell., 12, 27–36.

  • Boyer B, Valles AM and Edme N . (2000). Biochem. Pharmacol., 60, 1091–1099.

  • Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA . (2000). Nat. Cell Biol., 2, 76–83.

  • Cavallaro U and Christofori G . (2001). Biochim. Biophys. Acta, 1552, 39–45.

  • Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D and van Roy F . (2001). Mol. Cell, 7, 1267–1278.

  • Comoglio PM, Tamagnone L and Boccaccio C . (1999). Exp. Cell Res., 253, 88–99.

  • de Caestecker MP, Parks WT, Frank CJ, Castagnino P, Bottaro DP, Roberts AB and Lechleider RJ . (1998). Genes Dev., 12, 1587–1592.

  • Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G and Gress TM . (2001). Cancer Res., 61, 4222–4228.

  • Elliott BE, Hung WL, Boag AH and Tuck AB . (2002). Can. J. Physiol. Pharmacol., 80, 91–102.

  • Fujimoto K, Sheng H, Shao J and Beauchamp RD . (2001). Exp. Cell Res., 266, 239–249.

  • Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, Godowski PJ and Comogio PM . (1994). EMBO. J., 13, 3524–3532.

  • Gherardi E, Gonzalez Manzano R, Cottage A, Hawker K and Aparicio S . (1997). Ciba Found. Symp., 212, 24–35.

  • Gilles C, Polette M, Mestdagt M, Nawrocki-Raby B, Ruggeri P, Birembaut P and Foidart JM . (2003). Cancer Res., 63, 2658–2664.

  • Grande M, Franzen A, Karlsson JO, Ericson LE, Heldin NE and Nilsson M . (2002). J. Cell. Sci., 115, 4227–4236.

  • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN and Larue L . (2003). Cancer Res., 63, 2172–2178.

  • Hague A, Manning AM, Hanlon KA, Huschtscha LI, Hart D and Paraskeva C . (1993). Int. J. Cancer, 55, 498–505.

  • Han S, Stuart LA and Degen SJF . (1991). Biochemistry, 30, 9768–9780.

  • Heldin CH, Miyazono K and ten Dijke P . (1997). Nature, 390, 465–471.

  • Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H and Grunert S . (2002). J. Cell Biol., 156, 299–313.

  • Lamorte L, Royal I, Naujokas M and Park M . (2002). Mol. Biol. Cell, 13, 1449–1461.

  • Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H and Downward J . (2000). Genes Dev., 14, 2610–2622.

  • Li BQ, Wang MH, Kung HF, Ronsin C, Breathnach R, Leonard EJ and Kamata T . (1995). Biochem. Biophys. Res. Commun., 216, 110–118.

  • Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P and Comoglio PM . (1998). Oncogene, 16, 2927–2933.

  • Masszi A, Di Ciano C, Sirokmany G, Arthur WT, Rotstein OD, Wang J, McCulloch CA, Rosivall L, Mucsi I and Kapus A . (2003). Am. J. Physiol. Renal Physiol., 284, 911–924.

  • Medico E, Mongiovi AM, Huff J, Jelinek MA, Follenzi A, Gaudino G, Parsons JT and Comoglio PM . (1996). Mol. Biol. Cell, 7, 495–504.

  • Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V and Arteaga CL . (2002). J. Clin. Invest., 109, 1551–1559.

  • Nicolas FJ, Lehmann K, Warne PH, Hill CS and Downward J . (2003). J. Biol. Chem., 278, 3251–3256.

  • Oft M, Akhurst RJ and Balmain A . (2002). Nat. Cell Biol., 4, 487–494.

  • Oft M, Peli J, Rudaz C, Schwarz H, Beug H and Reichmann E . (1996). Genes Dev., 10, 2462–2477.

  • Piek E, Heldin CH and Ten Dijke P . (1999b). FASEB J., 13, 2105–2124.

  • Piek E, Moustakas A, Kurisaki A, Heldin CH and ten Dijke P . (1999a). J. Cell. Sci., 112, 4557–4568.

  • Ronsin C, Muscatelli F, Mattei MG and Breathnach R . (1993). Oncogene, 8, 1195–1202.

  • Rubin JS, Bottaro DP and Aaronson SA . (1993). Biochim. Biophys. Acta, 1155, 357–364.

  • Ruiz P and Gunthert U . (1996). World J. Urol., 14, 141–150.

  • Santoro MM, Collesi C, Grisendi S, Gaudino G and Comoglio PM . (1996). Mol. Cell Biol., 16, 7072–7083.

  • Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M and Gaudino G . (1998). Oncogene, 17, 741–749.

  • Savagner P . (2001). Bioessays, 23, 912–923.

  • Serini G and Gabbiani G . (1999). Exp. Cell Res., 250, 273–283.

  • Skeel A, Yoshimura T, Showalter SD, Tanaka S, Appella E and Leonard EJ . (1991). J. Exp. Med., 173, 1227–1234.

  • Takenoshita S, Mogi A, Nagashima M, Yang K, Yagi K, Hanyu A, Nagamachi Y, Miyazono K and Hagiwara K . (1998). Genomics, 48, 1–11.

  • Thiery JP . (2002). Nat. Rev. Cancer, 2, 442–454.

  • Thiery JP and Chopin D . (1999). Cancer Metastasis Rev., 18, 31–42.

  • Vleminckx K and Kemler R . (1999). Bioessays, 21, 211–220.

  • Wang MH, Dlugosz AA, Sun Y, Suda T, Skeel A and Leonard EJ . (1996b). Exp. Cell Res., 226, 39–46.

  • Wang MH, Montero-Julian FA, Dauny I and Leonard EJ . (1996a). Oncogene, 13, 2167–2175.

  • Wang MH, Ronsin C, Gesnel MC, Coupeym L, Skeel A, Leonard EJ and Breathnach R . (1994a). Science, 266, 117–119.

  • Wang M-H, Wang D and Chen Y-Q . (2003). Carcinogenesis, 23, 1291–1300.

  • Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G and Wakefield LM . (2002). J. Clin. Invest., 109, 1607–1615.

  • Yue J and Mulder KM . (2001). Pharmacol. Therapeutics, 91, 1–34.

  • Zhou YQ, Chen YQ, Fisher JH and Wang MH . (2002). J. Biol. Chem., 277, 38104–38110.

  • Zhou YQ, He C, Chen YQ, Wang D and Wang MH . (2003). Oncogene, 22, 186–197.

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Acknowledgements

We thank Drs EJ Leonard (NCI of NIH, Frederick, MD, USA) for human MSP; K Hagiwara (Tohoku University, Sendai, Japan) for the Smad2 promoter sequence. B Hann (UCSF) for the PAI-1 promoter sequence; and A Balmain (UCSF) for ΔSmad2. We are grateful to Ms Q Tanna (Denver Health Medical Center, Denver, CO, USA) for editing the manuscript. This study was supported in part by NIH Grant R01 CA91890 to MHW and The foundation of Chang-Jiang Scholar Endowment from the Chinese Ministry of Education.

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Authors and Affiliations

  1. Laboratory of Chang-Jiang Scholar Endowment for Biomedical Sciences, Institute of Infectious Diseases and First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China

    Da Wang & Ming-Hai Wang

  2. Department of Medicine, University of Colorado School of Medicine, Cancer Center, and Denver Health Medical Center, Denver, CO, USA

    Da Wang, Qi Shen, Yi-Qing Chen & Ming-Hai Wang

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  1. Da Wang
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Correspondence to Ming-Hai Wang.

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Wang, D., Shen, Q., Chen, YQ. et al. Collaborative activities of macrophage-stimulating protein and transforming growth factor-β1 in induction of epithelial to mesenchymal transition: roles of the RON receptor tyrosine kinase. Oncogene 23, 1668–1680 (2004). https://doi.org/10.1038/sj.onc.1207282

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