1. Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
2. Division of Clinical Pharmacokinetics, Department of General Therapeutics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
3. Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
4. Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
5. Department of Endoscopy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
6. Center for Integrative Education of Pharmacy Frontier (Frontier Education Center), Graduate School of Pharmaceutical Sciences, Kyoto University 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
Background: Previously, MDR1 T-129C polymorphism, encoding multidrug resistant transporter MDR1/P-glycoprotein, was reported to be predictive of poorly-differentiated colorectal adenocarcinomas. Here, VEGF T-1498C, C-634G and C-7T polymorphisms, encoding vascular endothelial growth factor (VEGF), were investigated in terms of their association with differentiation grade.
Methods: VEGF genotypes were determined by TaqManR MGB probe based polymerase chain reaction and evaluated were confirmed by direct sequencing in 36 Japanese patients.
Results: VEGF T-1498C, but not C-634G or C-7T, was predictive of poorly-differentiated ones, and thereby a poor prognosis (p = 0.064 for genotype, p = 0.037 for allele), and this effect can be explained by that on VEGF expression. Treatment of a colorectal adenocarcinoma cell line, HCT-15, with sodium butyrate, a typical differentiating agent, resulted in an increase of alkaline phosphatase activity and MDR1 mRNA expression, but in a decrease of VEGF mRNA expression. The transfection of VEGF small interfering RNA (siRNA) induced the expression of MDR1 mRNA to 288-332% of the control level, whereas MDR1 siRNA had no effect on VEGF mRNA expression.
Conclusions: VEGF T-1498C polymorphism is also a candidate marker predictive of poorly-differentiated colorectal adenocarcinomas, but further investigations with a large number of patients should be addressed to draw a conclusion.
Keywords: colorectal adenocarcinoma, vascular endothelial growth factor, differentiation, genetic polymorphism, predictive marker