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c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase

Oncogene volume 30, pages 2003–2016 (2011)Cite this article

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Abstract

The progression and negative outcome of a variety of human carcinomas are intimately associated with aberrant activity of the c-Met oncogene. The underlying cause of this dysregulation, however, remains a subject of discussion, as the majority of cancer patients do not present with activating mutations in c-Met receptor itself. In this study, we show that the oncogenic protease matriptase is ubiquitously co-expressed with the c-Met in human squamous cell carcinomas and amplifies migratory and proliferative responses of primary epithelial cells to the cognate ligand for c-Met, pro-hepatocyte growth factor/scatter factor (proHGF/SF), through c-Met and Gab1 signaling. Furthermore, the selective genetic ablation of c-Met from matriptase-expressing keratinocytes completely negates the oncogenic potential of matriptase. In addition, matriptase-dependent carcinoma formation could be blocked by the pharmacological inhibition of the Akt–mammalian target of Rapamycin (mTor) pathway. Our data identify matriptase as an initiator of c-Met-Akt–mTor-dependent signaling axis in tumors and reveal mTor activation as an essential component of matriptase/c-Met-induced carcinogenesis. The study provides a specific example of how epithelial transformation can be promoted by epigenetic acquisition of the capacity to convert a widely available paracrine growth factor precursor to its signaling competent state.

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Acknowledgements

We thank Dr Snorri Thorgeirsson for floxed Hgfr mice. Supported by NIDCR Intramural Research Program. We thank Dr Mary Jo Danton for critically reviewing this manuscript.

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  1. Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD, USA

    R Szabo, A L Rasmussen, A B Moyer, P Kosa, J M Schafer, A A Molinolo, J S Gutkind & T H Bugge

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  1. R Szabo
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Correspondence to T H Bugge.

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Szabo, R., Rasmussen, A., Moyer, A. et al. c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase. Oncogene 30, 2003–2016 (2011). https://doi.org/10.1038/onc.2010.586

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