C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression.
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.
State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People's Republic of China.
Ya-ling
YL
Tang
Yun-long
YL
Fan
Jian
J
Jiang
Kai-de
KD
Li
Min
M
Zheng
Wei
W
Chen
Xiang-rui
XR
Ma
Ning
N
Geng
Qian-ming
QM
Chen
Yu
Y
Chen
Xin-hua
XH
Liang
D017209:Apoptosis; D015153:Blotting, Western; D003528:Carcinoma, Adenoid Cystic / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012468:Salivary Gland Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019009:Proto-Oncogene Proteins c-kit