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Retinoids, vitamin A metabolites and synthetic analogs, have shown chemopreventive and therapeutic effects in animal models and clinical trials. It is thought that many of their effects are mediated by nuclear retinoid receptors of which there are two types: retinoic acid receptors (RARs) and retinoid X receptors, each of which has α, β, and γ subtypes. RARs form heterodimers with RXRs and bind to specific nucleotide sequences (response elements) in the promoter region of target genes. Binding of agonistic retinoids to the receptors triggers activation of the transcription of target genes. Carcinogenesis has been associated with decreased expression of specific retinoid receptors. The decreased expression of RARβ, primarily by DNA methylation, is one of the most frequently encountered changes occurring at early stages of carcinogenesis. Enforced expression of transfected RARβ suppresses cell growth and tumorigenicity. These and other findings have led to the hypothesis that RARβ acts as a tumor suppressor. To gain further insight into the involvement of RARβ in regulating the malignant phenotype, we transfected a retroviral vector harboring antisense RARβ sequences into non-small cell lung cancer H157 cells and isolated several clones expressing the antisense RARβ or vector control. Three clones of antisense RARβ transfectants with reduced level of RARβ exhibited rounded morphology and disorganized cytoskeleton structure typical of more malignant cells. These cells showed enhanced migration and altered cell-cell and cell-matrix adhesion. Antisense RARβ transfectants also showed resistance to anoikis in suspension culture and an increase in the level of genes such as galectin 3 known to protect cells from apoptosis. The antisense transfectants possessed a greatly increased ability to form colonies in semi-solid medium and to form rapidly growing subcutaneous tumors in nude mice relative to control vector transfectants. These results strongly support the conclusion that RARβ suppresses many properties associated with tumor progression and malignancy. Supported by a grant from the Department of the Army (DAMD 17-01-1-0689). C.C. and S-Y.S. contributed equally to this study.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]