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

• Published in: Oncogene Vol. 30; no. 17; pp. 2003 - 2016
• Main Authors: Szabo, R, Rasmussen, A L, Moyer, A B, Kosa, P, Schafer, J M, Molinolo, A A, Gutkind, J S, Bugge, T H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2011; Nature Publishing Group
• Subjects: 631/67/395; 631/80/86; 692/699/67/1536; AKT protein; Animals; Apoptosis; Biological and medical sciences; c-Met protein; Carcinogenesis; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Biology; Cell migration; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Cellular biology; Epigenetics; Epithelial cells; Epithelial Cells - enzymology; Epithelial Cells - pathology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Gene mutations; Genetic aspects; Genetic transformation; Growth factors; Head & neck cancer; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Health aspects; Hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; Human Genetics; Humans; Internal Medicine; Keratinocytes; Keratinocytes - enzymology; Keratinocytes - metabolism; Keratinocytes - pathology; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Oncology; original-article; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Paracrine signalling; Pathogenesis; Physiological aspects; Proteases; Protein Precursors - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - deficiency; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Rapamycin; Risk factors; Serine Endopeptidases - metabolism; Serine proteinase; Signal Transduction; Squamous cell carcinoma; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumors; Up-Regulation; United States; mTor; head and neck carcinoma; protease-activated signaling; hepatocyte growth factor; cell surface proteases; Enzyme; Hepatocyte growth factor; Serine; Activation; Malignant tumor; Epithelium; Carcinogenesis; Cell surface; Peptidases; Hydrolases; ENT disease; Head and neck carcinoma; Cancer
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2010.586

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.