rClca2 is associated with epidermal differentiation and is strongly downregulated by ultraviolet radiation
rClca2 is associated with epidermal differentiation and is strongly downregulated by ultraviolet radiation
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DOI：
10.1111/bjd.13038
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发表时间：
2014-08-01
影响因子：
10.3
通讯作者：
Tammi, R. H.
中科院分区：
文献类型：
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作者：
Bart, G.;Hamalainen, L.;Tammi, R. H.
目的寻找新的中波紫外线(UVB)靶基因，以了解UVB对皮肤有害作用的机制。方法用全基因组表达阵列、实时定量聚合酶链式反应和组织学方法对体外培养的大鼠角质形成细胞进行UVB照射。结果在大鼠角质形成细胞和小鼠皮肤模型中，最低表达的基因rClca2被进一步鉴定。结果单次30mJ cm-2的宽带UVB在器官表型表皮培养中有效。照射后24 h，627个基因的表达发生了变化。对数据的电子分析表明，DNA修复、代谢、细胞周期控制和氨基酸代谢处于激活状态，但仅限于在这些条件下的炎症。我们选择了先前被认为调节角质形成细胞分化和黏附的下调最多的基因rClca2进行进一步研究，发现UVB导致其表达长期下调。UVB可降低rClca2全长异构体(在分化细胞中表达)和截短型异构体(在基底层表达)。含有异构体特异性抗体的小鼠皮肤样本的免疫组织化学显示了类似的与表皮分化相关的模式。慢性紫外线辐射(UVR)诱导的小鼠皮肤增生区和癌变区的染色强度降低，分化相关亚型受到干扰。结论rClca2基因是一个新的UVB靶基因，可能在表皮分化和紫外线依赖性皮肤恶性肿瘤中起一定作用。
Background Excessive skin exposure to solar radiation damages proteins and DNA, ultimately leading to skin ageing and cancers.Objectives To identify new ultraviolet B (UVB) target genes to understand the mechanisms behind the detrimental effects of UVB.Methods Organotypic, stratified cultures of rat keratinocytes were exposed to UVB and analysed using a genome-wide expression array, quantitative real-time polymerase chain reaction and histology. The most downregulated gene, rClca2, was further characterized in rat keratinocytes and mouse skin models.Results A single, 30 mJ cm(-2) dose of broadband UVB proved effective in the organotypic epidermal culture. The expression of 627 genes was changed 24 h postirradiation. In silico analysis of the data indicated activation of DNA repair, metabolism, cell cycle control and amino acid metabolism, but only limited inflammation under these conditions. We selected for further investigation the most downregulated gene, rClca2, previously suggested to regulate keratinocyte differentiation and adhesion, and found that UVB caused a long-lasting downregulation in its expression. Both the rClca2 full-length isoform (expressed in the differentiating cells) and the truncated isoform (expressed in the basal layers) were reduced by UVB. Immunohistochemistry of mouse skin samples with isoform-specific antibodies showed a similar, epidermal differentiation-related pattern. In mouse specimens exposed to chronic ultraviolet radiation (UVR) the staining intensities were reduced and the differentiation-related isoform was disturbed in the hyperplastic and carcinomatous areas induced by UVR.Conclusions The data show that rClca2 is a novel UVB target gene and suggest that it might play a role in epidermal differentiation and UV-dependent skin malignancies.