Influence of vascular endothelial growth factor single nucleotide polymorphisms             on non-small cell lung cancer tumor angiogenesis.
Vascular endothelial growth factor (VEGF) plays an important role in tumor             angiogenesis. Several studies have reported that genomic VEGF polymorphisms may             influence VEGF synthesis. To evaluate the role of VEGF single nucleotide polymorphisms             (SNPs), we examined the expression of several angiogenesis-related proteins [VEGF,             hypoxia-inducible factor-1α (HIF-1α) and delta-like ligand 4 (Dll4)] and the spread             of microvessels in resected non-small cell lung cancer (NSCLC). Blood and tumor             tissue from 83 patients with NSCLC were examined for VEGF -460T/C (rs833061) and             VEGF +405G/C (rs2010963) SNPs using the SNaPshot method. Immunohistochemical staining             was performed to measure protein expression and microvessel density (MVD). VEGF -460T/C             and +405G/C SNPs showed no association with VEGF or HIF-1α expression and MVD.             Patients with VEGF -460TT and the TC genotype had significantly higher MVD compared             to those with the CC genotypes. Furthermore, patients with the VEGF -460TT genotype             had significantly higher Dll4 expression compared to those with the TC or CC genotypes,             while the VEGF +405G/C SNP displayed no association with Dll4 expression and MVD.             These findings indicate that the VEGF -460T/C SNP may have a functional influence             on tumor angiogenesis in NSCLC. We hypothesize that VEGF SNPs may influence angiogenesis             through Dll4.
Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan. amaeda@med.kawasaki-m.ac.jp
Ai
A
Maeda
Masao
M
Nakata
Koichiro
K
Yasuda
Takuro
T
Yukawa
Shinsuke
S
Saisho
Riki
R
Okita
Yuji
Y
Hirami
Katsuhiko
K
Shimizu
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A