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[Cancer Research 63, 3145-3153, June 15, 2003]
© 2003 American Association for Cancer Research

Experimental Therapeutics

ß-Catenin Regulates Vascular Endothelial Growth Factor Expression in Colon Cancer

Vijay Easwaran1, Sang H. Lee1, Landon Inge, Lida Guo, Cheryl Goldbeck, Evelyn Garrett, Marion Wiesmann, Pablo D. Garcia, John H. Fuller, Vivien Chan, Filippo Randazzo, Robert Gundel, Robert S. Warren, Jaime Escobedo, Sharon L. Aukerman, Robert N. Taylor and Wendy J. Fantl2

Chiron Corporation, Emeryville, California 94608 [V. E., S. H. L., L. I., L. G., C. G., E. G., M. W., P. D. G., J. H. F., V. C., F. R., R. G., J. E., S. L. A., W. J. F.], and Departments of Surgery [R. S. W.] and Obstetrics/Gynecology and Reproductive Sciences [R. N. T.], University of California San Francisco, California 94143-0556

To evaluate whether ß-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for ß-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for ß-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 ß-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 ß-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated ß-catenin up-regulated levels of VEGF-A mRNA and protein by 250–300%. When colon cancer cells with elevated ß-catenin levels were treated with ß-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between ß-catenin signaling and the regulation of VEGF-A expression in colon cancer.




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