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Effect of HIF-1α-EphA2 Pathway on Vasculogenic Mimicry in Esophageal Squamous Cell Carcinoma

Author: WangPin
Tutor: ShiRuiHua
School: Nanjing Medical University
Course: Department of Gastroenterology,
Keywords: Esophageal squamous cell carcinoma Hypoxia-inducible factor 1-α Vasculogenic mimicry EphA2 RNA interference Hypoxia
CLC: R735.1
Type: Master's thesis
Year: 2011
Downloads: 40
Quote: 0
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Abstract

Background: Esophageal cancer is one of the common malignant tumors of the gastrointestinal tract, China is a high incidence of esophageal, and its esophageal cancer mortality rate ranks first in the world. Pathological type of esophageal squamous cell carcinoma, accounting for about 95 percent of esophageal cancer. Esophageal squamous cell carcinoma has progressed rapidly, early metastasis, poor prognosis. The pathogenesis of esophageal squamous cell carcinoma is not clear. Our previous study found that esophageal squamous cell carcinoma internal hypoxic environment, angiogenesis, and vascular mimicry may be an important factor in promoting the rapid progression of the tumor. The study confirmed the hypoxia-inducible factor-1α (Hypoxia inducible factor-1α, HIF-1α) gene expression and is associated with poor prognosis in patients with esophageal squamous cell carcinoma cells. HIF-1α is a nuclear transcription factor exists in mammals through hypoxia-inducible gene regulation to maintain the body's ability to adapt to hypoxia, involved in angiogenesis and cell growth, differentiation, and apoptosis multiple regard, while it and tumor angiogenesis, metastasis and infiltration of closely related. Vascular mimicry (vasculogenic mimicry, VM) is involved in tumor microcirculation endothelial cells surrounded by the malignant cells rather than vascular-like structures. VM eased ischemia and hypoxia in the tumor microenvironment, tumor invasion, metastasis and prognosis of patients, and the traditional anti-tumor vascular treatment ineffective. Preliminary studies suggest that overexpression of HIF-1α in esophageal squamous cell carcinoma may have some connection with the formation of malignant tumors VM. EphA2 plays a key role in the the VM formation process in. EphA2 is Eph receptor tyrosine kinase family of a low expression in normal tissue cells and its ligand ephrin-A binding, negative regulation of cell adhesion and proliferation of spotty Eph-ephrin signal transduction mechanisms; EphA2 overexpression or dysfunction can cause malignant cells to promote tumor cell migration, invasion and remodeling of the surrounding matrix, eventually leading to some highly malignant tumor vascular endothelial cells to form capillary-like structure formation of angiogenesis as well as tumor cells mimicry. Our previous studies suggest that HIF-1α may directly or indirectly regulate EphA2 expression to affect the formation of esophageal squamous cell carcinoma VM, this study revealed that regulatory pathways. Objective: To investigate the normal partial pressure of oxygen and hypoxic conditions, HIF-1α in esophageal cancer cells, EphA2 expression changes and esophageal cancer cell lines in vitro three-dimensional culture and between HIF-1α, EphA2 interaction . Esophageal carcinoma cell line Eca109 and TE13, RT-PCR, western blot method: 1. Cultured under normal partial pressure of oxygen (19% O2) and hypoxic conditions (1% O2) comparative observation of HIF-1α, EphA2 expression changes 2 Matrigel in vitro three-dimensional culture analog angiogenesis to form a number of changes intended to observe the normal-state model partial pressure of oxygen and hypoxic conditions Eca109 and TE13 cell lumen. construct the EphA2 miRNA interference plasmids were transfected Eca109 cells and TE13 cells, RT- PCR and western blot were used to detect the transfected cells, EphA2 inhibition efficiency; 4. HIF-1αmiRNA transfection Eca109 cells and TE13 cells, respectively, in hypoxia and the observed EphA2 expression changes in the normal oxygen partial pressure on cells in vitro three-dimensional culture impact; to 5 of EphA2 miRNA transfection Eca109 cells and TE13 cells, HIF-1α expression changes were observed in hypoxic and normal oxygen partial pressure and the impact of culture in vitro three-dimensional; 1 under hypoxic conditions Eca109 cells and TE13 cells, HIF-1α and EphA2 expression significantly improve the Matrigel cultured in vitro, significantly higher than normal oxygen partial pressure lumen formation of tumor cells under hypoxic conditions. 2. EphA2 miRNA interference plasmid to suppress Eca109 and TE13 EphA2 mRNA expression; 3. Both normal partial pressure of oxygen or hypoxic conditions, miRNA effectively inhibit the expression of HIF-1α, EphA2 expression decreased number of lumen decline significant decline more under hypoxic conditions. Effective inhibition of EphA2 expression of miRNA under normoxic and hypoxic conditions, did not affect the expression of HIF-1α change, but it can significantly reduce the number of lumen formation in vitro three-dimensional culture and more obvious decline under normoxic conditions ; 5 under hypoxic conditions, HIF-1α inhibition of tubular structure is stronger than EphA2 inhibition; under normal oxygen concentration, EphA2 inhibits tubular structure is stronger than HIF-1α inhibition. Conclusion 1. Esophageal cancer cells TE13 and Eca109 of HIF-1α and structural EphA2 expression, but the hypoxic environment can significantly induced HIF-1α, EphA2 enhanced expression, and the emergence of the lumen increase in the number of in vitro three-dimensional culture models; 2. Environment oxygen concentration affect esophageal squamous cell carcinoma cells in vitro lumen formation of three-dimensional culture an important factor in the hypoxic environment induced cancer lumen formation related to changes in expression of HIF-1α and EphA2 gene. Inhibition of HIF-1α expression enables EphA2 expression decreased, while the inhibition of the EphA2 no obvious effect on the expression of HIF-1α, suggesting that HIF-1α upstream genes in this pathway, and possible regulation of EphA2 expression. Under hypoxic conditions, HIF-1α-EphA2 pathway for esophageal squamous cell carcinoma VM play an important role in the regulation; between HIF-1α and EphA2 may also exist more complex network structure. HIF-1α in the hypoxic environment is more critical in the normal oxygen concentration EphA2 more direct impact on the VM.

Effect of HIF-1α-EphA2 Pathway on Vasculogenic Mimicry in Esophageal Squamous Cell Carcinoma

Abstract

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