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Review
. 2007 Aug 8;253(1):14-24.
doi: 10.1016/j.canlet.2006.11.019. Epub 2006 Dec 22.

Tumor-suppressive activity of retinoic acid receptor-beta in cancer

Xiao-Chun Xu  1
Affiliations
Review

Tumor-suppressive activity of retinoic acid receptor-beta in cancer

Xiao-Chun Xu. Cancer Lett. .

Abstract

Retinoids, a group of structural and functional analogs of vitamin A, are known to regulate a large number of essential biological processes and to suppress carcinogenesis. The effects of retinoids are mainly mediated by nuclear retinoid receptors, which include retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Each receptor has three subtypes (alpha, beta, and gamma) and each subtype has different isoforms. Retinoic acid receptor-beta (RAR-beta) has four isoforms that have different affinities to retinoids and different biological functions. Loss of expression of RAR-beta(2) during cancer development is associated with tumorigenesis and retinoid resistance; induction of its expression, on the other hand, can suppress carcinogenesis. Expression of another isoform, RAR-beta(4), is increased in various types of cancer. RAR-beta(4) transgenic mice develop hyperplasia and neoplasia in various tissues, and induction of RAR-beta(4) expression increases the growth of tumor cells that do not express RAR-beta(2). Future studies will focus on molecular pathways involving RAR-beta(2) and the role of RAR-beta(4) in cancer development.

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Figures

Fig. 1
Fig. 1
Comparison of RAR-β2 and RAR-β4 cDNA (modified from ref. 90). A. Organization of RAR cDNA is shown at the top and RAR-β isoforms at the bottom. The location of sequences that encode regions B to F and the 3’-untranslated region (UTR) common to all RAR-β isoforms is indicated, as well as those of the 5’-UTR and A region, which is isoform-specific. Numbers correspond to nucleotide positions in the human RAR-β2 cDNA sequence. The “A” regions of RAR-β2 and RAR-β4 are represented as a solid box. The region of RAR-β2 that is spliced to give RAR-β4 (between 266–619 bp) is indicated with a dashed line. B. Sequence and schematic representation of donor splice sites for RAR-β4 and RAR-β2 (positions 265 and 619, respectively).
Fig. 2
Fig. 2
A molecular pathway triggered by RAR-β2 for the suppression of human carcinogenesis. Benzo(a)pyrene diol epoxide (BPDE) exposure is a risk factor in the development of esophageal cancer. BPDE is thought to act by suppressing RAR-β2 expression and, in turn, upregulating EGFR expression and Erk1/2 phosphorylation, resulting in the induction of AP-1 and COX-2 expression. Further, BPDE can educe the expression of retinoid receptor-induced gene-1 (RRIG1), perhaps through reduction of RAR-β2. RRIG1 mediates RAR-β2 effects on the regulation of cancer cell growth and gene expression. RRIG1 protein binds to and inhibits RhoA activity and consequently suppresses Erk1/2 phosphorylation and expression of COX-2 and cyclin D1, resulting in reductions in tumor cell colony formation, invasion, and proliferation.
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