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

• Published in: Oncotarget 2014-03, Vol.5 (6), p.1491-1501
• Main Authors: Tang, Ya-ling, Fan, Yun-long, Jiang, Jian, Li, Kai-de, Zheng, Min, Chen, Wei, Ma, Xiang-rui, Geng, Ning, Chen, Qian-ming, Chen, Yu, Liang, Xin-hua
• Format: Article
• Language: English
• Subjects: 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; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; 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
• ISSN: 1949-2553; 1949-2553
• 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.