Epithelial-mesenchymal transition induced by transforming growth factor-{beta}1/Snail activation aggravates invasive growth of cholangiocarcinoma.
Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-beta1 (TGF-beta1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-beta1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers, such as vimentin and S100A4. TGF-beta1 also induced the nuclear expression of Snail, and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGF-beta1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-beta1 were inhibited by the simultaneous administration of soluble TGF-beta type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced, and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-beta1/Snail activation is closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor prognosis.
Sato
Yasunori
Y
Department of Human Pathology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
Harada
Kenichi
K
Itatsu
Keita
K
Ikeda
Hiroko
H
Kakuda
Yuko
Y
Shimomura
Syuji
S
Shan Ren
Xiang
X
Yoneda
Norihide
N
Sasaki
Motoko
M
Nakanuma
Yasuni
Y
D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010641:Phenotype; D000071250:Snail Family Transcription Factors; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014183:Transplantation, Heterologous
D053539:Keratin-19; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1