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

Oncogene. 2011 Apr 28;30(17):2003-16. doi: 10.1038/onc.2010.586. Epub 2011 Jan 10.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

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

Substances

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