title: 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.affiliation: Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD 20892, USA.
authors.forename: R
authors.initials: R
authors.lastname: Szabo
authors.forename: A L
authors.initials: AL
authors.lastname: Rasmussen
authors.forename: A B
authors.initials: AB
authors.lastname: Moyer
authors.forename: P
authors.initials: P
authors.lastname: Kosa
authors.forename: J M
authors.initials: JM
authors.lastname: Schafer
authors.forename: A A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
authors.forename: T H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011498:Protein Precursors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D011498:Protein Precursors; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D012697:Serine Endopeptidases; C485595:matriptase