Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
J Invest Dermatol. 2013 Nov;133(11):2609-2616. doi: 10.1038/jid.2013.213. Epub 2013 May 6.
Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown whether this loss increases UV-induced carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4(-/-)) and wild-type (WT) littermates were chronically UV-irradiated. Compared with WT, K14.Smad4(-/-) mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group 1 (Ercc1) messenger RNA was significantly reduced in UV-treated K14.Smad4(-/-) skin compared with WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4(-/-) keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4(-/-) keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses. Collectively, Smad4 loss-associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus, we identified a role for Snail in UV-induced DNA repair.
Smad4 缺失经常发生在人类皮肤鳞状细胞癌（SCC）中，但尚不清楚这种缺失是否会增加 UV 诱导的致癌作用，这是皮肤癌的主要病因。在本研究中，构建了角蛋白细胞特异性 Smad4 缺失（K14.Smad4(-/-)）和野生型（WT）同窝仔鼠，并对其进行慢性 UV 照射。与 WT 相比，K14.Smad4(-/-) 小鼠表现出更高的 DNA 损伤和对 UV 诱导皮肤癌的易感性。在参与修复 UV 诱导的 DNA 损伤的基因中，UV 处理的 K14.Smad4(-/-) 皮肤中的 Excision repair cross-complementation group 1 (Ercc1) mRNA 明显低于 WT 皮肤。进一步分析表明，Smad4 缺失导致 Snail 与 Ercc1 调控元件的结合减少，从而导致 Ercc1 转录减少。一致地，瞬时转染 Snai1 到 Smad4(-/-) 角质形成细胞中导致修复 UV 诱导的 DNA 损伤增加。将 Ercc1 转染到 Smad4(-/-) 角质形成细胞中可恢复对 UV 诱导的 DNA 损伤的修复。进一步的免疫染色显示，Smad4 蛋白的存在与人类皮肤 SCC 和光化性角化病中的 Snail 和 Ercc1 蛋白的存在相关。总之，Smad4 缺失相关的 Snail 减少会损害 Ercc1 介导的 DNA 修复，导致增加的 UV 诱导皮肤致癌作用。因此，我们确定了 Snail 在 UV 诱导的 DNA 修复中的作用。
