Skip to main content

Advertisement

Log in

The importance of −460 C/T and +405 G/C single nucleotide polymorphisms to the function of vascular endothelial growth factor A in colorectal cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The present study investigated the functional influence of the single nucleotide polymorphisms (SNPs) −460 C/T and +405 G/C at vascular endothelial growth factor A (VEGF-A), mRNA and protein levels in colorectal cancer (CRC) and normal colorectal tissue.

Methods

Blood and tissue were collected from 113 patients surgically resected for colorectal cancer. SNPs were analysed from genomic DNA by PCR, the VEGF-A gene expression analysis was performed by RT–PCR and protein analysis by ELISA.

Results

The T-allele in the −460 C/T SNP and the C-allele in the +405 G/C SNP were associated with significantly lower VEGF-A protein levels in normal colorectal tissue. There were no differences in protein levels in the malignant tissue according to genotypes. No differences were observed at the gene expression levels either.

Conclusion

The results indicate that the two SNPs have a functional influence on the VEGF-A protein levels in normal colorectal tissue. The possible clinical implications of the findings need further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Altomare DF, Rotelli MT, Pentimone A, Rossiello MR, Martinelli E, Guglielmi A, De FM, Marino F, Memeo V, Colucci M, Semeraro N (2007) Tissue factor and vascular endothelial growth factor expression in colorectal cancer: relation with cancer recurrence. Colorectal Dis 9(2):133–138

    Article  CAS  PubMed  Google Scholar 

  • Andre T, Kotelevets L, Vaillant JC, Coudray AM, Weber L, Prevot S, Parc R, Gespach C, Chastre E (2000) Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. Int J Cancer 86(2):174–181

    Article  CAS  PubMed  Google Scholar 

  • Broll R, Erdmann H, Duchrow M, Oevermann E, Schwandner O, Markert U, Bruch HP, Windhovel U (2001) Vascular endothelial growth factor (VEGF)—a valuable serum tumour marker in patients with colorectal cancer? Eur J Surg Oncol 27(1):37–42

    Article  CAS  PubMed  Google Scholar 

  • Cheung N, Wong MP, Yuen ST, Leung SY, Chung LP (1998) Tissue-specific expression pattern of vascular endothelial growth factor isoforms in the malignant transformation of lung and colon. Hum Pathol 29(9):910–914

    Article  CAS  PubMed  Google Scholar 

  • Cressey R, Wattananupong O, Lertprasertsuke N, Vinitketkumnuen U (2005) Alteration of protein expression pattern of vascular endothelial growth factor (VEGF) from soluble to cell-associated isoform during tumourigenesis. BMC Cancer 5:128

    Article  PubMed  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  • Ferroni P, Spila A, Martini F, D’Alessandro R, Mariotti S, Del MG, Graziano P, Buonomo O, Guadagni F, Roselli M (2005) Prognostic value of vascular endothelial growth factor tumor tissue content of colorectal cancer. Oncology 69(2):145–153

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1):4–6

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Closas M, Malats N, Real FX, Yeager M, Welch R, Silverman D, Kogevinas M, Dosemeci M, Figueroa J, Chatterjee N, Tardon A, Serra C, Carrato A, Garcia-Closas R, Murta-Nascimento C, Rothman N, Chanock SJ (2007) Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet 3(2):e29

    Article  PubMed  Google Scholar 

  • George ML, Tutton MG, Janssen F, Arnaout A, Abulafi AM, Eccles SA, Swift RI (2001) VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia 3(5):420–427

    Article  CAS  PubMed  Google Scholar 

  • Hofmann G, Langsenlehner U, Renner W, Langsenlehner T, Yazdani-Biuki B, Clar H, Gerger A, Wehrschuetz M, Samonigg H, Krippl P (2007) Common single nucleotide polymorphisms in the vascular endothelial growth factor gene and colorectal cancer risk. J Cancer Res Clin Oncol 134(5):591–595

    Article  PubMed  Google Scholar 

  • Holt RC, Ralph SA, Webb NJ, Watson CJ, Clark AG, Mathieson PW, Brenchley PE (2003) Steroid-sensitive nephrotic syndrome and vascular endothelial growth factor gene polymorphisms. Eur J Immunogenet 30(1):1–3

    Article  CAS  PubMed  Google Scholar 

  • Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267(36):26031–26037

    CAS  PubMed  Google Scholar 

  • Howell WM, Bateman AC, Turner SJ, Collins A, Theaker JM (2002) Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma. Genes Immun 3(4):229–232

    Article  CAS  PubMed  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

    Article  CAS  PubMed  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844

    Article  CAS  PubMed  Google Scholar 

  • Kim JG, Chae YS, Sohn SK, Cho YY, Moon JH, Park JY, Jeon SW, Lee IT, Choi GS, Jun SH (2008) Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with colorectal cancer. Clin Cancer Res 14(1):62–66

    Article  CAS  PubMed  Google Scholar 

  • Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E (2004) VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 46(3):293–298

    Article  PubMed  Google Scholar 

  • Ku KT, Wan L, Peng HC, Tsai MH, Tsai CH, Tsai FJ (2005) Vascular endothelial growth factor gene −460 C/T polymorphism is a biomarker for oral cancer. Oral Oncol 41(5):497–502

    Article  CAS  PubMed  Google Scholar 

  • Kumar H, Heer K, Lee PW, Duthie GS, MacDonald AW, Greenman J, Kerin MJ, Monson JR (1998) Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer. Clin Cancer Res 4(5):1279–1285

    CAS  PubMed  Google Scholar 

  • Kuramochi H, Hayashi K, Uchida K, Miyakura S, Shimizu D, Vallbohmer D, Park S, Danenberg KD, Takasaki K, Danenberg PV (2006) Vascular endothelial growth factor messenger RNA expression level is preserved in liver metastases compared with corresponding primary colorectal cancer. Clin Cancer Res 12(1):29–33

    Article  CAS  PubMed  Google Scholar 

  • Lin CC, Wu HC, Tsai FJ, Chen HY, Chen WC (2003) Vascular endothelial growth factor gene −460 C/T polymorphism is a biomarker for prostate cancer. Urology 62(2):374–377

    Article  PubMed  Google Scholar 

  • Lu H, Shu XO, Cui Y, Kataoka N, Wen W, Cai Q, Ruan ZX, Gao YT, Zheng W (2005) Association of genetic polymorphisms in the VEGF gene with breast cancer survival. Cancer Res 65(12):5015–5019

    Article  CAS  PubMed  Google Scholar 

  • Park JE, Keller GA, Ferrara N (1993) The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4(12):1317–1326

    CAS  PubMed  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  • Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E (2000) A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res 37(6):443–448

    Article  CAS  PubMed  Google Scholar 

  • Schneider S, Park DJ, Yang D, El-Khoueiry A, Sherrod A, Groshen S, Streeter O, Iqbal S, Danenberg KD, Lenz HJ (2006) Gene expression in tumor-adjacent normal tissue is associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation. Pharmacogenet Genomics 16(8):555–563

    Article  CAS  PubMed  Google Scholar 

  • Spindler KL, Lindebjerg J, Nielsen JN, Olsen DA, Bisgard C, Brandslund I, Jakobsen A (2006) Epidermal growth factor receptor analyses in colorectal cancer: a comparison of methods. Int J Oncol 29(5):1159–1165

    CAS  PubMed  Google Scholar 

  • Takahashi H, Shibuya M (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 109(3):227–241

    Article  CAS  Google Scholar 

  • Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77(6):998–1002

    CAS  PubMed  Google Scholar 

  • Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12(8):1232–1235

    Article  CAS  PubMed  Google Scholar 

  • Yamamori M, Sakaeda T, Nakamura T, Okamura N, Tamura T, Aoyama N, Kamigaki T, Ohno M, Shirakawa T, Gotoh A, Kuroda Y, Matsuo M, Kasuga M, Okumura K (2004) Association of VEGF genotype with mRNA level in colorectal adenocarcinomas. Biochem Biophys Res Commun 325(1):144–150

    Article  CAS  PubMed  Google Scholar 

  • Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R (2000) The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer 83(1):63–68

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are very thankful for the technical assistance provided by Lone Frischknecht, Lone Hartmann Hansen, Sara Egsgaard and Birgit Roed Sørensen and for the proofreading by Karin Larsen.

Conflict of interest statement

None of the authors had any conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Torben F. Hansen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hansen, T.F., Spindler, KL.G., Lorentzen, K.A. et al. The importance of −460 C/T and +405 G/C single nucleotide polymorphisms to the function of vascular endothelial growth factor A in colorectal cancer. J Cancer Res Clin Oncol 136, 751–758 (2010). https://doi.org/10.1007/s00432-009-0714-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0714-1

Keywords

Navigation