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beta-Catenin regulates vascular endothelial growth factor expression in colon cancer
- Source :
- Cancer research. 63(12)
- Publication Year :
- 2003
-
Abstract
- To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.
- Subjects :
- Vascular Endothelial Growth Factor A
Genes, APC
Colon
Recombinant Fusion Proteins
Endothelial Growth Factors
Adenocarcinoma
Transfection
Oligodeoxyribonucleotides, Antisense
Mice
Tumor Cells, Cultured
Animals
Humans
RNA, Messenger
RNA, Neoplasm
Intestinal Mucosa
Growth Substances
Promoter Regions, Genetic
beta Catenin
Lymphokines
Binding Sites
Vascular Endothelial Growth Factors
Mice, Mutant Strains
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Cytoskeletal Proteins
Genes, ras
Adenomatous Polyposis Coli
Colonic Neoplasms
Trans-Activators
Intercellular Signaling Peptides and Proteins
Fibroblast Growth Factor 2
Signal Transduction
Subcellular Fractions
Subjects
Details
- ISSN :
- 00085472
- Volume :
- 63
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.pmid..........6ed23bdee706edcfac51cf717e1a3d45