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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

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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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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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