Retinoids and their receptors in modulation of differentiation, development, and prevention of head and neck cancers.
Retinoids suppress oral premalignant lesions (OPLs) and decrease the incidence of second primary tumors in head and neck (HN) cancer patients. The optimal clinical use of retinoids depends on the understanding of the mechanism by which they suppress carcinogenesis. It is thought that retinoids restore normal cell growth and differentiation by means of nuclear retinoic acid (RA) receptors (RAR alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma). We used cultured HNSCC cell lines and surgical specimens from normal oral mucosa and from premalignant oral lesions and HN squamous cell carcinomas (HNSCCs) to understand fundamental aspects of retinoids mode of action. RA inhibited the growth and suppressed the aberrant squamous cell differentiation in the majority of HNSCC cell lines examined. Four cell lines expressed mRNAs for RAR alpha, RAR beta, RAR gamma, and RXR alpha. RA treatment increased the levels of the three RAR mRNAs in most of the cell lines but had no effect on the RXR mRNAs. An inverse relationship has been established between the level of RAR beta and squamous differentiation markers. The expression of retrovirally transduced RAR beta in a HNSCC cell line, which did not express RAR beta constitutively, showed a 1,000-fold increase in sensitivity to the suppression of squamous cell differentiation by RA. The expression of retrovirally transduced RAR gamma sense rendered the cells more sensitive, and expression of retrovirally transduced RAR gamma anti-sense made them less sensitive to growth inhibition by RA than parental cells. These results indicate that RAR beta may mediate suppression of squamous differentiation, whereas RAR gamma may mediate the growth inhibition. RAR alpha, RAR beta, RAR gamma, RXR alpha, and RXR beta mRNAs were detected by in situ hybridization in specimens from normal oral mucosa, and all but RAR-beta were also expressed in most of the adjacent normal, hyperplastic, dysplastic, and malignant HN tissues. In contrast, RAR beta mRNA was detected in only 70% of adjacent normal and hyperplastic HN lesions, and its expression was decreased further to 56% of dysplastic lesions and to 35% of SCCs. Likewise, RAR beta was expressed in only 40% of OPLs. Treatment of OPLs with 13-cis-RA increased RAR beta expression from 40% to 90% of the cases. The increase in RAR beta level was associated with clinical response. These results show that selective loss of RAR beta mRNA expression occurs in the early stages of carcinogenesis and may be involved in HN cancer development; and demonstrate that RAR beta is induced by 13-cis-RA in humans.
Lotan
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Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
D002454:Cell Differentiation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018168:Receptors, Retinoic Acid; D014212:Tretinoin