Effect of endothelial PAS domain protein 1 and hypoxia inducible factor 1αon vascular endothelial growth factor expression in human pancreatic carcinoma

摘要

Background Transcription factors hypoxia inducible factor 1α (HIF 1α) and endothelial PAS domain protein 1 (EPAS1)promote the transcription of vascular endothelial growth factor (VEGF).VEGF enhances angiogenesis and vascular permeability of tumours,which promotes tumour growth and facilitates entry of cancer cells into blood circulation and metastasizing.This study examined whether HIF 1α and EPAS1 stimulated angiogenesis through activation of VEGF in human pancreatic carcinoma.Methods Specimens from pancreatic carcinoma and healthy parts of same pancreas were taken from 60 patients.Real time quantitative reverse transcription polymerase chain reaction estimated expression of HIF 1α,EPAS1,and VEGF mRNAs.Western blotting and immunohistochemical,streptavidin peroxidase method assessed expression of HIF 1α,EPAS1,and VEGF proteins.Microvessel density (MVD) was assessed.Results Highly significant increases in expression of EPAS1,VEGF,and MVD were found in pancreatic carcinoma tissue but not in normal pancreatic tissue:VEGF at mRNA and protein levels (t=17.32,P=0.0001;t=98.41,P=0.0001);EPAS1 protein level (t=22.51,P=0.0001).Expression of HIF 1α was similar in pancreatic carcinoma and normal pancreatic tissues at both mRNA and protein levels.Significant correlations were observed between EPAS1 and VEGF (r=0.736,P=0.0041),between VEGF and MVD (r=0.858,P=0.0001),and between EPAS1 and MVD (r=0.641,P=0.0003).No significant correlations were observed between HIF 1α and VEGF,or between HIF 1α and MVD.MVD and expression of EPAS1 and VEGF were significantly related with TNM staging,so was EPAS1 and VEGF with size of tumour.Conclusions EPAS1 and VEGF,but not HIF1α,are overexpressed in pancreatic carcinoma.The expression of EPAS1 is correlated with that of VEGF and MVD.EPAS1 may be involved in the angiogenesis of pancreatic carcinoma by upregulating the expression of VEGF.Targeting EPAS1 may be a new method of antiangiogenic tumour therapy for pancreatic carcinoma.