Darwiche N, Celli G, De Luca L M
Differentiation Control Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Endocrinology. 1994 May;134(5):2018-25. doi: 10.1210/endo.134.5.8156902.
Retinoids are powerful regulators of epithelial differentiation and are essential for its maintenance. Because retinoids are necessary for cervical epithelial differentiation, they have been used as chemopreventive agents of cervical dysplasia and neoplasia. We were interested in determining whether different cervical epithelial phenotypes express specific retinoid receptors. The cervical epithelium contains the two phenotypes, stratified squamous and simple columnar, which join at the squamocolumnar junction. In addition, the simple columnar epithelium undergoes squamous metaplasia in response to vitamin A deficiency. Therefore, the cervical epithelium is suitable to study the expression pattern of the retinoid receptors in the three phenotypes, simple columnar, stratified squamous, and squamous metaplastic, simultaneously. The distribution pattern of the major retinoic acid receptor (RAR) isoforms (alpha 1, alpha 2, beta 2, beta 3, gamma 1, and gamma 2) and retinoid-X receptors (RXR alpha, -beta, and -gamma) was studied by in situ hybridization. At the tissue level, RAR alpha (1 and 2) and RXR (alpha and beta) transcripts and, to a lesser extent, RAR gamma (1 and 2) transcripts were associated with the cervical stratified squamous subjunctional epithelium. The simple columnar epithelium, which is highly responsive to vitamin A status, expressed high levels of RAR alpha (1 and 2), RAR beta (2 and 3), and RXR (alpha and beta) transcripts. Only RAR beta (2 and 3) and RXR (alpha and beta) transcripts were down-modulated by the condition of vitamin A deficiency and expressed less in squamous metaplastic foci than the simple columnar epithelium. RXR gamma was undetectable in all three cervical epithelia. At the cellular level, basal and suprabasal expression was found for RARs, and preferential localization of RXRs was seen in basal cells. RXRs are auxiliary proteins for a variety of other nuclear receptors with which they form heterodimers, including RARs. The fact that RXRs are mainly localized in basal and columnar cells of the cervix suggests the need for the regulation and diversity generated by potential heterodimeric interactions in these rapidly proliferating cells in vivo. The unique pattern of expression and localization of the RARs and RXRs in different cervical epithelial tissues and cell types supports the hypothesis that they perform specific functions in cervical epithelial differentiation. This is in contrast to the major isoforms of each RAR, which have similar patterns of expression in the different cervical epithelial phenotypes and cell types, suggesting a redundancy in function.
维甲酸是上皮细胞分化的强大调节剂，对其维持至关重要。由于维甲酸是宫颈上皮细胞分化所必需的，它们已被用作宫颈发育异常和肿瘤形成的化学预防剂。我们感兴趣的是确定不同的宫颈上皮表型是否表达特定的维甲酸受体。宫颈上皮包含两种表型，即复层鳞状上皮和单层柱状上皮，它们在鳞柱交界相连。此外，单层柱状上皮在维生素A缺乏时会发生鳞状化生。因此，宫颈上皮适合同时研究维甲酸受体在三种表型（单层柱状、复层鳞状和鳞状化生）中的表达模式。通过原位杂交研究了主要视黄酸受体（RAR）亚型（α1、α2、β2、β3、γ1和γ2）和视黄酸X受体（RXRα、-β和-γ）的分布模式。在组织水平上，RARα（1和2）和RXR（α和β）转录本，以及程度较轻的RARγ（1和2）转录本，与宫颈复层鳞状交界下上皮相关。对维生素A状态高度敏感的单层柱状上皮表达高水平的RARα（1和2）、RARβ（2和3）和RXR（α和β）转录本。只有RARβ（2和3）和RXR（α和β）转录本在维生素A缺乏的情况下被下调，并且在鳞状化生灶中的表达低于单层柱状上皮。在所有三种宫颈上皮中均未检测到RXRγ。在细胞水平上，发现RARs在基底细胞和基底上层细胞中表达，并且RXRs在基底细胞中优先定位。RXRs是多种其他核受体的辅助蛋白，它们与这些核受体形成异二聚体，包括RARs。RXRs主要定位于宫颈的基底细胞和柱状细胞这一事实表明，在体内这些快速增殖的细胞中，潜在的异二聚体相互作用产生的调节和多样性是必要的。RARs和RXRs在不同宫颈上皮组织和细胞类型中的独特表达和定位模式支持了它们在宫颈上皮分化中发挥特定功能的假设。这与每个RAR的主要亚型形成对比，它们在不同宫颈上皮表型和细胞类型中的表达模式相似，表明功能上存在冗余。
