title: Bone morphogenetic protein-4-induced epithelial-mesenchymal transition and invasiveness through Smad1-mediated signal pathway in squamous cell carcinoma of the head and neck.
abstract: OBJECTIVE
  Bone morphogenetic proteins (BMPs) have recently been shown to be involved in the genesis and progression of a wide variety of carcinomas. The present study was undertaken to estimate the effect of BMP-4 on squamous cell carcinoma of the head and neck (SCCHN) in tissue and cell levels.
  
  
  METHODS
  In this study, immunohistochemistry, Western blotting and RT-PCR were utilized to detect the expression of BMP-4, Smad1 and phosphorylated Smad1 in SCCHN tissues or SCCHN cell lines. Those three proteins in tissues were further correlated with prognosis of SCCHN by Kaplan-Meier analysis. The epithelial-mesenchymal transition (EMT)-associated changes in SCCHN cells were detected after stimulation by human BMP-4 recombinant protein and knockdown of Smad1 gene. Meanwhile, the effect on invasiveness and migration was evaluated by invasion and scratch assays, respectively.
  
  
  RESULTS
  BMP-4 and p-Smad1 protein were overexpressed in SCCHN tissues with cervical lymph node metastasis, which was significantly higher than those without metastasis. The expression of BMP-4 and p-Smad1 protein was negatively correlated with the prognosis of SCCHN. BMP-4 promoted the invasiveness and migration through EMT, which was demonstrated by morphological alterations, loss of E-cadherin, increase of vimentin and activation of the Smad1 signal pathway. Knockdown of Smad1 expression suppressed BMP-4 induced EMT in both cell lines and weakened the invasiveness and migration of Tu686 and Tu212 in vitro.
  
  
  CONCLUSIONS
  Our results demonstrate that BMP-4 protein may contribute to the malignant metastasis of SCCHN, which presents as a novel prognostic marker and a potential therapeutic target for patients with SCCHN.
authors.affiliation: Department of Otolaryngology, Xiangya Hospital, Central South University, Xiangya Road, Changsha, Hunan, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.forename: Chang-Yun
authors.initials: CY
authors.lastname: Yu
authors.forename: Jin-Jie
authors.initials: JJ
authors.lastname: Sun
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xing-Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Lei-Ming
authors.initials: LM
authors.lastname: Pi
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Tian
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism* / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects / Q000235:genetics; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D015820:Cadherins; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D014746:Vimentin