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

Héctor G. Pálmer, Marta Sánchez-Carbayo, Paloma Ordóñez-Morán, María Jesús Larriba, Carlos Cordón-Cardó, Alberto Muñoz

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

Epidemiological and preclinical data indicate that vitamin D and its most active metabolite 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] have anticancer activity. Accordingly, clinical trials are under way using several nonhypercalcemic 1α,25(OH)2D3 analogues against various neoplasms including colon cancer. 1α,25(OH)2D3 induces proliferation arrest and epithelial differentiation of human SW480-ADH colon cancer cells. We examined the gene expression profiles associated with 1α,25(OH)2D3 exposure using oligonucleotide microarrays. 1α,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 1α,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 1α,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 1α,25(OH)2D3. Data from this study reveal that 1α,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.

Original languageEnglish
Pages (from-to)7799-7806
Number of pages8
JournalCancer Research
Volume63
Issue number22
StatePublished - 15 Nov 2003
Externally publishedYes

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