beta-Catenin regulates vascular endothelial growth factor expression in colon cancer.
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.
Easwaran
Vijay
V
Chiron Corporation, Emeryville, California 94608, USA.
Lee
Sang H
SH
Inge
Landon
L
Guo
Lida
L
Goldbeck
Cheryl
C
Garrett
Evelyn
E
Wiesmann
Marion
M
Garcia
Pablo D
PD
Fuller
John H
JH
Chan
Vivien
V
Randazzo
Filippo
F
Gundel
Robert
R
Warren
Robert S
RS
Escobedo
Jaime
J
Aukerman
Sharon L
SL
Taylor
Robert N
RN
Fantl
Wendy J
WJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000098:blood supply / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D017491:Genes, APC; D011905:Genes, ras; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000737:chemistry; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D016222:Fibroblast Growth Factor 2