title: ZEB2 promotes vasculogenic mimicry by TGF-β1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma.
abstract: OBJECTIVE
  Zinc finger E-box binding homeobox 2 (ZEB2), an epithelial-mesenchymal transition (EMT) regulator, has been involved in invasion and metastasis of human tumor. Although EMT may be involved in vasculogenic mimicry (VM) formation, no reports describing the relation between ZEB2 and VM are available. We hypothesize that ZEB2 may promote VM formation in hepatocellular carcinoma (HCC).
  
  
  RESULTS
  Paraffin-embedded tumor tissue samples from 92 patients were immunostained with anti-ZEB2 antibody. We found that the ZEB2 nuclear expression was significantly associated with VM formation and metastasis. Patients with VM and ZEB2 nuclear expression had a shorter survival period than those without expression. In vitro, ZEB2 overexpression significantly enhanced cell motility, invasiveness, and VM formation of HepG2 cells. ZEB2 upregulation also increased VE-cadherin, Flt-1, and Flk-1 expression and activated MMPs. ZEB2 knockdown inhibited cell motility, invasiveness, and VM formation in Bel7402 cells. ZEB2 knockdown also decreased VE-cadherin, Flt-1, and Flk-1 expression and MMP activity. In addition, EMT in HepG2 cells was induced by TGF-β1 treatment, and the kinetics of expression of EMT markers and regulators were assessed by Western blot analysis. The expression of ZEB2 increased significantly, and VM formation was promoted.
  
  
  CONCLUSIONS
  ZEB2 can promote VM formation through the EMT pathway. Our findings may represent a novel therapeutic target in HCC.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China. Electronic address: yangzhihong321@sina.com.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin 300060, China; Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China. Electronic address: baocunsun@gmail.com.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: dylylnj@163.com.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China. Electronic address: xiulanzhao01@163.com.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: xuemingzhao@163.com.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China; Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, China. Electronic address: qiang00gu@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: jindananan@163.com.
authors.forename: Jindan
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: xueyidongdong@126.com.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: fangliu112233@163.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China. Electronic address: yongwangwywy@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018398:Homeodomain Proteins; D020782:Matrix Metalloproteinases; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099152:Cadherin 5; C492363:ZEB2 protein, human; C501162:FLT1 protein, human
keywords: Epithelial–mesenchymal transition; Hepatocellular carcinoma; TGF-β1; Vasculogenic mimicry; Zinc finger E-box binding homeobox 2