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HIF-1alpha induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells

Periodical: World J Gastroenterol ISBN: 1007-9327  Number: 47  Date: 2014/12/31  Language: eng  Pages: 17894-904

Authors:Tang, N. N., Zhu, H., Zhang, H. J., Zhang, W. F., Jin, H. L., Wang, L., Wang, P., He, G. J., Hao, B., Shi, R. H.
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Abstract
AIM: To investigate whether hypoxia inducible factor (HIF)-1alpha 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-1alpha 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-1alpha and VE-cadherin, ephrinA2 (EphA2) and laminin5gamma2 (LN5gamma2) was measured by Western blot and real-time polymerase chain reaction. RESULTS: Knockdown of HIF-1alpha 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-1alpha or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5gamma2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1alpha-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5gamma2 (P < 0.05), while HIF-1alpha expression was unchanged. The time for xenograft tumor formation was 6 +/- 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1alpha Neo control short hairpin RNA (shRNA) vector, and 8.4 +/- 2.1 d for Eca109 cells transfected with an shRNA against HIF-1alpha. Knockdown of HIF-1alpha inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo. CONCLUSION: HIF-1alpha may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5gamma2.
Keywords
Gastric cancer, Helicobacter pylori

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CellLine: Eca109
  Morphology: Cancerous
  Origin: Esophagus
  Species: Human
Scaffold Form: gel/hydrogel
Scaffold Material: Matrigel (TM)
Scaffold Origin: synthetic