Abstract
It is well accepted that cell scattering (dispersion of clustered cells into single cells) is the initial step of tumor metastasis, and the downregulation of E-cadherin is associated with metastatic potential of tumor cells; however, the molecular mechanisms underlying loss of E-cadherin during tumor development are still poorly understood. Here, we report that hepatocyte growth factor (HGF) induced E-cadherin downregulation and cell scattering are attributed to the activation of Wnt/β-catenin signaling and transcriptional activation of matrix metalloproteinase MMP-7. Furthermore, the increased MMP-7 is secreted into the medium and cleaves the ectodomain of E-cadherin. Inhibition of HGF signal by siRNA of c-Met, blocking the β-catenin transcriptional activity through a dominant negative form of TCF4, MMP-7 knockdown by siRNA or suppression of MMP-7 enzymatic activity with a neutralization antibody allowed inhibition of HGF-induced loss of E-cadherin and HepG2 scattering. Our data presented here revealed the intrinsic mechanism of HGF activated Wnt/β-catenin signaling regulation of HepG2 cell scattering through MMP-7 transcription activation and E-cadherin degradation. The results suggest that the blocking of HGF/c-Met/β-catenin/MMP-7/E-cadherin signaling pathway might present a practical therapeutic target for interference with hepatocellular carcinoma metastasis.
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Acknowledgments
We thank Shen C. X. and Reske S. N. for their pShuttle-H1 vector. We also thank He T. C. and Vogelstein B. for their plasmid pAdEasy-1, and Dr. O. Tetsu and Dr. F. McCormick for their cDNA3 dominant negative TCF4. This work was supported by research grants from the National Natural Science Foundation of China (30800574), the Natural Science of Foundation of Jiangsu Province of China (BK2008432), the Natural Science Foundation of the Jiangsu High Education Institutions of China (07KJD180103).
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F.-Y. Pan and S.-Z. Zhang contributed equally to this work.
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Pan, FY., Zhang, SZ., Xu, N. et al. β-catenin signaling involves HGF-enhanced HepG2 scattering through activating MMP-7 transcription. Histochem Cell Biol 134, 285–295 (2010). https://doi.org/10.1007/s00418-010-0729-3
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DOI: https://doi.org/10.1007/s00418-010-0729-3