title: Transforming growth factor-β and epithelial-mesenchymal transition are associated with pulmonary metastasis in adenoid cystic carcinoma.
abstract: OBJECTIVE
  Adenoid cystic carcinoma (ACC) is one of the most common malignancies of salivary glands, characterized by poor prognosis, particularly due to pulmonary metastasis. We previously reported that transforming growth factor (TGF)-β1 promoted ACC cell migration and invasion via the Smad pathway in vitro. The aim of this study was to establish the underlying mechanisms.
  
  
  METHODS
  TGF-β1, phospho-Smad2 and β-catenin expression in ACC tissues derived from patients was evaluated by immunohistochemistry. The role of TGF- β1 on the invasive capacity of ACC cells was determined by transwell assays in SACC-83 cells transfected with TGF-β1 and TGF-β type II dominant-negative receptor (TβRIIDN) plasmids or silenced by TGF-β1 siRNA. Expression of the epithelial-mesenchymal transition (EMT) markers, β-catenin, E-cadherin and Nectin-1, was determined by real-time PCR and immunochemistry. In vivo investigations were performed by inoculating nude mice with the transfected ACC cells and examining metastasis in bilateral lung tissues by immunohistochemistry.
  
  
  RESULTS
  Overexpression of TGF-β1 and phospho-Smad2, and reduced expression of membrane β-catenin, were closely associated with lung metastasis in ACC. Furthermore, the EMT markers were downregulated. In vitro, cells transfected with TGF-β1 exhibited altered morphology and increased invasive capacity compared to TβRIIDN-transfected cells or TGF-β1 siRNA silenced cells. In vivo, mice inoculated with TGF-β1 transfected ACC cells exhibited more metastases than other cells.
  
  
  CONCLUSIONS
  TGF-β1, phospho-Smad2 and β-catenin were significantly correlated with ACC metastasis. Blockade of TGF-β signaling by TβRIIDN or siRNA may offer potential gene therapies against pulmonary metastasis in patients with ACC.
authors: Laboratory of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Nandajie, Haidian District, Beijing 100081, PR China.
authors: Ling
authors: L
authors: Dong
authors: Xi-Yuan
authors: XY
authors: Ge
authors: Yi-Xiang
authors: YX
authors: Wang
authors: Lin-Qian
authors: LQ
authors: Yang
authors: Sheng-Lin
authors: SL
authors: Li
authors: Guang-Yan
authors: GY
authors: Yu
authors: Yan
authors: Y
authors: Gao
authors: Jia
authors: J
authors: Fu
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D003528:Carcinoma, Adenoid Cystic / Q000378:metabolism* / Q000556:secondary; D015815:Cell Adhesion Molecules / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D000075983:Nectins; D009374:Neoplasms, Experimental; D060888:Real-Time Polymerase Chain Reaction; D012468:Salivary Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin
keywords: ACC; Adenoid cystic carcinoma; CAMs; Ca(2+)-independent immunoglobulin-like cell adhesion molecules; EMT; Epithelial–mesenchymal transition; Gene therapy; H-score; Pulmonary metastasis; ROC; TGF-β1; Transforming growth factor-β1; adenoid cystic carcinoma; epithelial–mesenchymal transition; immunohistochemical score; membrane expression of β-catenin; p-Smad2; phospho-Smad2; receiver operating characteristic; transforming growth factor; β-catenin RM