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VEGF T-1498C polymorphism, a predictive marker of differentiation of colorectal adenocarcinomas in Japanese.

Yamamori M, Taniguchi M, Maeda S, Nakamura T, Okamura N, Kuwahara A, Iwaki K, Tamura T, Aoyama N, Markova S, Kasuga M, Okumura K, Sakaeda T - Int J Med Sci (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT

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 TaqMan(R) 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.

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Related in: MedlinePlus

Effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. HCT-15 cells were treated with 1 or 5 mM NaB for 24, 48, and 72 hr, and ALP activity and VEGF mRNA levels were assessed. The results were expressed as the mean ± SD of 4 independent experiments. (A) ALP activity, (B) VEGF mRNA. Open column: control (0 mM NaB), closed column: 1 mM NaB, hatched column: 5 mM NaB. *: p < 0.05, when compared with the control experiment.
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Figure 1: Effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. HCT-15 cells were treated with 1 or 5 mM NaB for 24, 48, and 72 hr, and ALP activity and VEGF mRNA levels were assessed. The results were expressed as the mean ± SD of 4 independent experiments. (A) ALP activity, (B) VEGF mRNA. Open column: control (0 mM NaB), closed column: 1 mM NaB, hatched column: 5 mM NaB. *: p < 0.05, when compared with the control experiment.

Mentions: Compared with adjacent noncancerous colorectal tissues, VEGF mRNA expression was up-regulated, but MDR1 mRNA expression was down-regulated in colorectal adenocarcinomas, suggesting their linkage 5, 6. Fig. 1 shows the effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. ALP activity increased in a NaB-concentration and treatment time-dependent manner, and VEGF mRNA expression was suppressed as ALP activity increased. In our previous report, treatment with NaB resulted in an up-regulation of MDR1 mRNA expression 6. Fig. 2 shows the effects of transfecting VEGF siRNA on the mRNA expression of VEGF and MDR1 in HCT-15 cells. VEGF mRNA expression was suppressed; indicating a successful transfection of VEGF siRNA, and under these conditions, MDR1 mRNA expression was increased to 288-332% of the control level. Fig. 3 shows the effects of transfecting MDR1 siRNA on the mRNA expression of VEGF and MDR1. MDR1 mRNA expression was suppressed, but VEGF mRNA expression was not altered. It should be that scramble siRNA for VEGF and MDR1 had no effect on the expression of either mRNA (data not shown). Taken together, it could be said that VEGF itself or the factors resulting in production of VEGF had a suppressive effect on MDR1 expression, suggesting that cancer patients with a higher VEGF expression will show a relatively high sensitivity for MDR1 substrates, including vinca-alkaloids, anthracyclines and taxanes. Considering that a number of factors affect MDR1 expression 35-40, VEGF expression and/or genetic polymorphisms of VEGF were thought to be superior.


VEGF T-1498C polymorphism, a predictive marker of differentiation of colorectal adenocarcinomas in Japanese.

Yamamori M, Taniguchi M, Maeda S, Nakamura T, Okamura N, Kuwahara A, Iwaki K, Tamura T, Aoyama N, Markova S, Kasuga M, Okumura K, Sakaeda T - Int J Med Sci (2008)

Effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. HCT-15 cells were treated with 1 or 5 mM NaB for 24, 48, and 72 hr, and ALP activity and VEGF mRNA levels were assessed. The results were expressed as the mean ± SD of 4 independent experiments. (A) ALP activity, (B) VEGF mRNA. Open column: control (0 mM NaB), closed column: 1 mM NaB, hatched column: 5 mM NaB. *: p < 0.05, when compared with the control experiment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2293643&req=5

Figure 1: Effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. HCT-15 cells were treated with 1 or 5 mM NaB for 24, 48, and 72 hr, and ALP activity and VEGF mRNA levels were assessed. The results were expressed as the mean ± SD of 4 independent experiments. (A) ALP activity, (B) VEGF mRNA. Open column: control (0 mM NaB), closed column: 1 mM NaB, hatched column: 5 mM NaB. *: p < 0.05, when compared with the control experiment.
Mentions: Compared with adjacent noncancerous colorectal tissues, VEGF mRNA expression was up-regulated, but MDR1 mRNA expression was down-regulated in colorectal adenocarcinomas, suggesting their linkage 5, 6. Fig. 1 shows the effect of NaB on ALP activity and VEGF mRNA expression in HCT-15 cells. ALP activity increased in a NaB-concentration and treatment time-dependent manner, and VEGF mRNA expression was suppressed as ALP activity increased. In our previous report, treatment with NaB resulted in an up-regulation of MDR1 mRNA expression 6. Fig. 2 shows the effects of transfecting VEGF siRNA on the mRNA expression of VEGF and MDR1 in HCT-15 cells. VEGF mRNA expression was suppressed; indicating a successful transfection of VEGF siRNA, and under these conditions, MDR1 mRNA expression was increased to 288-332% of the control level. Fig. 3 shows the effects of transfecting MDR1 siRNA on the mRNA expression of VEGF and MDR1. MDR1 mRNA expression was suppressed, but VEGF mRNA expression was not altered. It should be that scramble siRNA for VEGF and MDR1 had no effect on the expression of either mRNA (data not shown). Taken together, it could be said that VEGF itself or the factors resulting in production of VEGF had a suppressive effect on MDR1 expression, suggesting that cancer patients with a higher VEGF expression will show a relatively high sensitivity for MDR1 substrates, including vinca-alkaloids, anthracyclines and taxanes. Considering that a number of factors affect MDR1 expression 35-40, VEGF expression and/or genetic polymorphisms of VEGF were thought to be superior.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT

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 TaqMan(R) 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.

Show MeSH
Related in: MedlinePlus