The role of vitamin A in differentiation and skin carcinogenesis

Abstract The field of vitamin A research has witnessed a remarkable surge in interest since the late 1980's, when the retinoid receptors were discovered and their genes cloned. Heterodimeric interactions between the retinoid X receptors (RXRs α, β, and γ), which bind 9-cis-retinoic acid, and other hormone receptors, including the retinoic acid receptors (RARs α, β, and γ), the thyroid hormone receptor (TR), the vitamin D receptor (VDR), the peroxisomal proliferator activated receptor (PPAR), and others make hormone action dependent on retinoid homeostasis. Retinoid response elements (RAREs) are present in the promoter and/or enhancer regions of several genes, including some of the homeobox genes, which control development and differentiation. The interaction between hormones and retinoids is added additional orders of complexity by the diversity of the RAREs including the spacer length, their 5′ or 3′ position, and their coexistence in composite sequences with other hormone response elements (e.g., an estrogen response element in the lactablbumin gene promoter, see Table 2). Control of normal epithelial differentiation is a fundamental function of retinoids. The histogenesis of squamous metaplasia caused by vitamin A deficiency is a stepwise process, which permits the gradual transition of phenotypes from simple-columnar, typical of the endocervical epithelium, to pseudostratified, to stratified-squamous and, eventually, to keratinizing. Conversely, the maintenance of the squamous keratinizing differentiation in the ectocervix and vagina requires estrogen. In the absence of this hormone, the squamous stratified ectocervical epithelium retrogrades to a simpler, two or three cell layer morphology, with the topmost layer expressing keratin K8, typical of the endocervical epithelium and mucous cells. Retinoid and estrogen receptor transcript expression is governed by dietary retinoid status and by estrogen availability, with squamous cells mostly expressing RARγ and estrogen receptor transcripts, and columnar cells mostly expressing RARβ. RXR transcripts appear mostly expressed in proliferating cells. The relevance of the retinoid receptors to carcinogenesis is highlighted in the work on acute promyelocytic leukemia. This work has demonstrated that the fusion gene PML-RARα, resulting from the t(15;17) chromosomal translocation, is etiologically connected with the disease and with complete remission after oral retinoid administration. Developments in retinoid metabolism, including the cloning of the cytochrome P450RAI and the connection between RA metabolism and cell growth inhibition, have recently taken place. Recent work has also shown that pharmacological dietary retinoic acid specifically inhibits malignant conversion in the mouse two-stage carcinogenesis system. Because RA upregulates retinoid receptor expression, it seems that retinoid receptors function as tumor suppressors. p]This field should serve as a paradigm for things to come for other essential nutrients, and spells out the notion that nutritional sciences are indeed fundamentally important, because they can contribute significantly to our understanding of different diseases and provide effective therapeutic approaches.