Department of Dermatology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York, United States of America.
PLoS One. 2013 Aug 19;8(8):e71887. doi: 10.1371/journal.pone.0071887. eCollection 2013.
Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin.
A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity.
The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata.
Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced.
先前的研究表明 NF-κB 信号通路参与了皮肤的发育和肿瘤发生。然而，这些研究受到可用的小鼠模型中 NF-κB 的过度或低表达所导致的致命性的限制。即使是 Cre 驱动的组织特异性转基因表达或 NF-κB 的靶向缺失也会导致细胞死亡。因此，本研究旨在评估一种新型的皮肤中 NF-κB 活性增强的小鼠模型。
利用同源重组技术开发了一种 NF-κB 活性增强的小鼠模型（称为 PD 小鼠）。
数据表明，NF-κB 活性的增加导致了小鼠表皮的过度增殖和发育不良。在 NF-κB 活性增强的背景下进行化学致癌作用促进了角化棘皮瘤的发展。
我们的发现支持 NF-κB 在角质细胞发育不良中的重要作用。我们发现，增强的 NF-κB 活性使角质细胞易发生过度增殖和角化棘皮瘤（KA）的发展，但不足以进行转化和 SCC 的发展。因此，我们提出在没有其他致癌事件的情况下，NF-κB 的激活可以促进 TNF 依赖性的、光化性角化病样的发育不良和 TNF 非依赖性的、KA 在化学致癌作用下的发展。这些研究表明，当 NF-κB 的激活被持续激活时，KA 无法得到解决。
