Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis

Retinoids are essential for normal skin growth, differentiation, and apopto sis and are active pharmacologically in the prevention and treatment of ski n cancers and other lesions. Retinoid effects are mediated mainly by retino ic acid receptors (RARs) and retinoid X receptors (RXRs), which act as tran scription factors to alter gene expression. Using in situ hybridization, we analyzed the expression of RARs and RXRs in normal sun-exposed skin (n = 8 5), squamous cell carcinoma (SCC; n = 28), and actinic keratosis [AK (a pre cursor to SCC); n = 38], The expressions of five receptors (RAR-alpha and - gamma and RXR-alpha, -beta, and -gamma) were moderate to very strong in nor mal skin, with higher expressions in spinous and granular layers than in th e basal layer. RAR-beta expression was weak or absent in normal and lesion samples. All five receptors expressed in the skin were suppressed progressi vely from normal skin to premalignant skin (AK) to invasive skin SCC, Speci fic receptor decreases in lesions relative to normal skin ranged from 75% ( RXR-beta) to 96% (RAR-alpha) in SCC and from 37% (RAR-gamma) to 68% (RXR-be ta) in AK. The degree of suppression of RXR-alpha and RAR-gamma, the two pr edominant retinoid receptors in skin, was relatively less for RXR-alpha (58 % versus 868; P = 0.015) and relatively greater for RAR-gamma (37% versus 8 9%; P = 0.0001) between AK and SCC, suggesting that suppression of RXR-alph a may be an earlier event and expression of RAR-gamma may be a later event of multistep squamous skin carcinogenesis, Our results indicate that suppre ssed expression of retinoid receptors occurs early tin AK) and is associate d with progression of squamous skin carcinogenesis to SCC.