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[Cancer Research 63, 7799-7806, November 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Genetic Signatures of Differentiation Induced by 1{alpha},25-Dihydroxyvitamin D3 in Human Colon Cancer Cells

Héctor G. Pálmer1, Marta Sánchez-Carbayo2, Paloma Ordóñez-Morán1, María Jesús Larriba1, Carlos Cordón-Cardó2 and Alberto Muñoz1

1 Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain,
2 Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

Epidemiological and preclinical data indicate that vitamin D and its most active metabolite 1{alpha},25-dihydroxyvitamin D3 [1{alpha},25(OH)2D3] have anticancer activity. Accordingly, clinical trials are under way using several nonhypercalcemic 1{alpha},25(OH)2D3 analogues against various neoplasms including colon cancer. 1{alpha},25(OH)2D3 induces proliferation arrest and epithelial differentiation of human SW480-ADH colon cancer cells. We examined the gene expression profiles associated with 1{alpha},25(OH)2D3 exposure using oligonucleotide microarrays. 1{alpha},25(OH)2D3 changed the expression levels of numerous previously unreported genes, including many involved in transcription, cell adhesion, DNA synthesis, apoptosis, redox status, and intracellular signaling. Most genes were up-regulated, and only a small fraction were down-regulated. Fourteen of 17 candidate genes studied were validated as 1{alpha},25(OH)2D3 target genes by Northern and Western blotting or immunocytochemistry. They included c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, keratin-13, G0S2, and the putative tumor suppressors NES-1 and protease M. There was little overlap between genes regulated after short (4 h) or long (48 h) exposure. Gene regulatory effects of 1{alpha},25(OH)2D3 in SW480-ADH cells differed from those in LS-174T cells, which lack E-cadherin and do not differentiate in response to 1{alpha},25(OH)2D3. Data from this study reveal that 1{alpha},25(OH)2D3 causes a profound change in gene expression profiles and provide a mechanistic basis to the ongoing clinical studies using nonhypercalcemic vitamin D3 derivatives for colon cancer prevention and treatment.




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Copyright © 2003 by the American Association for Cancer Research.