title: HIF-1α induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells.
abstract: OBJECTIVE
  To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1α or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1α and VE-cadherin, ephrinA2 (EphA2) and laminin5γ2 (LN5γ2) was measured by Western blot and real-time polymerase chain reaction.
  
  
  RESULTS
  Knockdown of HIF-1α inhibited cell proliferation (32.3% ± 6.1% for Eca109 cells and 38.6% ± 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1α or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5γ2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1α-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5γ2 (P < 0.05), while HIF-1α expression was unchanged. The time for xenograft tumor formation was 6 ± 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1α Neo control short hairpin RNA (shRNA) vector, and 8.4 ± 2.1 d for Eca109 cells transfected with an shRNA against HIF-1α. Knockdown of HIF-1α inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo.
  
  
  CONCLUSIONS
  HIF-1α may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5γ2.
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Tang
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Zhang
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Jin
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Gui-Jun
authors.initials: GJ
authors.lastname: He
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hao
authors.affiliation: Na-Na Tang, Hong Zhu, Hong-Jie Zhang, Wei-Feng Zhang, Hai-Lin Jin, Lu Wang, Pin Wang, Gui-Jun He, Bo Hao, Rui-Hua Shi, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Shi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018716:Molecular Mimicry; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D036104:Receptor, EphA2; D000099152:Cadherin 5; C497442:HIF1A protein, human; C400567:LAMC2 protein, human
keywords: Esophageal squamous cell carcinoma; Hypoxia-inducible factor-1α; RNA interference; VE-cadherin; Vasculogenic mimicry