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.
MeSH terms
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Adenocarcinoma / blood supply
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Adenocarcinoma / etiology
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenomatous Polyposis Coli / genetics
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Adenomatous Polyposis Coli / metabolism
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Animals
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Binding Sites
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Colon / metabolism
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Colonic Neoplasms / blood supply
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Colonic Neoplasms / etiology
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / physiology*
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Fibroblast Growth Factor 2 / analysis
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Genes, APC
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Genes, ras
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Growth Substances / genetics
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Humans
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Intercellular Signaling Peptides and Proteins / biosynthesis*
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Intercellular Signaling Peptides and Proteins / genetics
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Intestinal Mucosa / metabolism
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Lymphokines / biosynthesis*
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Lymphokines / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Promoter Regions, Genetic / genetics*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Recombinant Fusion Proteins / physiology
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Signal Transduction
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Subcellular Fractions / chemistry
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transfection
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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beta Catenin
Substances
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Endothelial Growth Factors
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Growth Substances
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Neoplasm Proteins
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Oligodeoxyribonucleotides, Antisense
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RNA, Messenger
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RNA, Neoplasm
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Recombinant Fusion Proteins
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Trans-Activators
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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beta Catenin
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Fibroblast Growth Factor 2