Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Blotting, Western
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Carcinoma, Adenoid Cystic / metabolism
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Carcinoma, Adenoid Cystic / mortality
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Carcinoma, Adenoid Cystic / pathology*
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Cell Movement
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Cell Proliferation
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Cell Transformation, Neoplastic / pathology*
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Disease Progression
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Epithelial-Mesenchymal Transition*
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Flow Cytometry
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic
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Genes, ras / genetics
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Humans
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Immunoenzyme Techniques
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Neoplasm Invasiveness
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Prognosis
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Salivary Gland Neoplasms / metabolism
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Salivary Gland Neoplasms / mortality
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Salivary Gland Neoplasms / pathology*
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Signal Transduction
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Survival Rate
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
Substances
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RNA, Messenger
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Transforming Growth Factor beta
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Proto-Oncogene Proteins c-kit