C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression

Oncotarget. 2014 Mar 30;5(6):1491-501. doi: 10.18632/oncotarget.1606.


Epithelial-mesenchymal transition (EMT) is associated with salivary adenoid cystic cancer (ACC) progression and metastasis. Here, we report that ectopic overexpression of c-kit in ACC cell lines is sufficient for acquisition of mesenchymal traits, enhanced cell invasion, along with stem cell properties defined by the presence of a CD133+/CD44+ cell subpopulation. c-kit positively regulated expression of known EMT inducers, also activating TGF-β to contribute to EMT. c-kit itself was induced by TGF-β in ACC cell lines and required for TGF-β-induced EMT. Xenograft experiments showed that c-kit cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in human specimens of ACC, we found that c-kit was abnormally overexpressed and correlated with the prognosis of ACC. Our findings define an important function for c-kit in ACC progression by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Carcinoma, Adenoid Cystic / metabolism
  • Carcinoma, Adenoid Cystic / mortality
  • Carcinoma, Adenoid Cystic / pathology*
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic / pathology*
  • Disease Progression
  • Epithelial-Mesenchymal Transition*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Genes, ras / genetics
  • Humans
  • Immunoenzyme Techniques
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Prognosis
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Salivary Gland Neoplasms / metabolism
  • Salivary Gland Neoplasms / mortality
  • Salivary Gland Neoplasms / pathology*
  • Signal Transduction
  • Survival Rate
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured


  • RNA, Messenger
  • Transforming Growth Factor beta
  • Proto-Oncogene Proteins c-kit