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

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.

• Authors: R Szabo, A L Rasmussen, A B Moyer, P Kosa, J M Schafer, A A Molinolo, J S Gutkind, T H Bugge
• Journal: Oncogene (Oncogene) Vol. 30 Issue 17 Pg. 2003-16 (Apr 28 2011) ISSN: 1476-5594 [Electronic] England
• PMID: 21217780 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Protein Precursors
• pro-hepatocyte growth factor
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Serine Endopeptidases
• matriptase

Topics

• Animals
• Carcinoma, Squamous Cell (enzymology, genetics, pathology)
• Cell Transformation, Neoplastic
• Epithelial Cells (enzymology, pathology)
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (enzymology, genetics, pathology)
• Hepatocyte Growth Factor (metabolism)
• Humans
• Keratinocytes (enzymology, metabolism, pathology)
• Mice
• Protein Precursors (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-met (deficiency, genetics, metabolism)
• Serine Endopeptidases (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation