ZEB2 promotes vasculogenic mimicry by TGF-β1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

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. W...

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Veröffentlicht in:Experimental and molecular pathology 2015-06, Vol.98 (3), p.352-359
Hauptverfasser: Yang, Zhihong, Sun, Baocun, Li, Yanlei, Zhao, Xiulan, Zhao, Xueming, Gu, Qiang, An, Jindan, Dong, Xueyi, Liu, Fang, Wang, Yong
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Sprache:eng
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Zusammenfassung: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). 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. ZEB2 can promote VM formation through the EMT pathway. Our findings may represent a novel therapeutic target in HCC. •ZEB2 nuclear expression was associated with VM formation and metastasis in human hepatocellular carcinoma samples.•ZEB2 overexpression enhanced cell motility, invasiveness, and VM formation of hepatocellular carcinoma cells.•Knockdown of ZEB2 reduced tumor cell migration, invasion, VM formation, and endothelium related markers expression.•Epithelial–mesenchymal transition in hepatocellular carcinoma cells was induced by TGF-β1 treatment.•ZEB2 can promote VM formation through the EMT pathway.
ISSN:0014-4800
1096-0945
DOI:10.1016/j.yexmp.2015.03.030