Sawey M J, Goldschmidt M H, Risek B, Gilula N B, Lo C W
Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104-6017, USA.
Mol Carcinog. 1996 Oct;17(2):49-61. doi: 10.1002/(SICI)1098-2744(199610)17:2<49::AID-MC1>3.0.CO;2-O.
To examine the possible role of gap junctions in mouse skin tumor progression, we generated a panel of mouse skin tissue samples exhibiting normal, hyperplastic, or neoplastic changes and characterized the expression of the gap-junction genes connexin 43 (Cx43) and connexin 26 (Cx26) by in situ hybridization and immunohistochemical analyses. In normal skin, these two gap junction genes were differentially expressed; Cx43 was found predominantly in the less differentiated lower spinous layers, whereas Cx26 was found in terminally differentiating upper spinous and granular layers. In hyperplastic epidermis exhibiting an expansion of the differentiated upper layer, i.e., epidermis with a thickened granular layer or in which the granular layer was replaced with keratinocytes exhibiting tricholemmal differentiation, expression of Cx43 and Cx26 remained segregated in the lower and upper spinous layers, respectively. However, in papillomas, Cx26 was localized in the lower but not upper spinous layer, an expression pattern identical to that of Cx43. In addition, the overall expression levels of both Cx43 and Cx26 appeared to be greatly elevated in the papillomas. It is interesting that such marked alteration in the pattern of Cx26 expression occurred within the context of hyperplastic changes histologically identical to those seen in the nonpapillomous hyperplasias. Interestingly, in neoplastic skin lesions containing a squamous cell carcinoma, Cx43 and Cx26 expression was extinguished. Moreover, expression of Cx43 was also significantly reduced in adjacent apparently nonneoplastic tissues. Overall, these observations show that perturbations in gap-junction gene expression are associated with skin hyperplasia and neoplasia. Such findings suggest a possible role for gap junctions in the malignant conversion of mouse epidermal cells.
为了研究间隙连接在小鼠皮肤肿瘤进展中的可能作用，我们制备了一组呈现正常、增生或肿瘤性变化的小鼠皮肤组织样本，并通过原位杂交和免疫组化分析对间隙连接基因连接蛋白43（Cx43）和连接蛋白26（Cx26）的表达进行了表征。在正常皮肤中，这两个间隙连接基因表达存在差异；Cx43主要在分化程度较低的棘层下层被发现，而Cx26则在终末分化的棘层上层和颗粒层被发现。在增生性表皮中，即分化上层扩张的表皮，也就是颗粒层增厚的表皮或颗粒层被表现为毛透明细胞分化的角质形成细胞所取代的表皮，Cx43和Cx26的表达仍分别隔离在棘层下层和上层。然而，在乳头状瘤中，Cx26定位于棘层下层而非上层，其表达模式与Cx43相同。此外，Cx43和Cx26的整体表达水平在乳头状瘤中似乎都大幅升高。有趣的是，Cx26表达模式的这种显著改变发生在组织学上与非乳头状瘤增生所见相同的增生性变化背景下。有趣的是，在含有鳞状细胞癌的肿瘤性皮肤病变中，Cx43和Cx26的表达消失。此外，在相邻的明显非肿瘤性组织中，Cx43的表达也显著降低。总体而言，这些观察结果表明间隙连接基因表达的扰动与皮肤增生和肿瘤形成有关。这些发现提示间隙连接在小鼠表皮细胞的恶性转化中可能发挥作用。
