Impaired Notch signaling promotes de novo squamous cell carcinoma formation
Impaired Notch signaling promotes de novo squamous cell carcinoma formation
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DOI：
10.1158/0008-5472.can-06-0793
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Parmacek, Mchael S.
中科院分区：
文献类型：
--
作者：
Proweller, Aaron;Lili Tu;Parmacek, Mchael S.
通过皮肤中的Notch受体的信号传导与角质形成细胞的分化、增殖和存活以及基底细胞癌（BCC）的发病机制有关。为了确定皮肤中Notch受体介导的信号传导的复合功能并克服受体之间潜在的冗余，产生了表达泛Notch抑制剂、显性负性Mastermind Like I（DNMAML 1）的条件性转基因小鼠，以抑制所有典型的[CBF-1/无毛抑制因子/LAG-1（CSL）依赖性]表皮中的Notch信号传导。在这里，我们报告说，DNMAML 1小鼠显示增生的表皮和自发发展皮肤鳞状细胞癌（SCC）以及发育不良的前体病变，光化性角化病。表达表皮DNMAML 1的小鼠在基底上角质形成细胞和SCC的病变细胞中显示出核β-连环蛋白和细胞周期蛋白D1的增强的积累。这在人皮肤SCC中也观察到。这些结果提示了一种模型，其中CSL依赖性Notch信号传导赋予针对皮肤SCC的保护。在小鼠中抑制经典Notch信号传导导致SCC自发形成并重现人类疾病的证明产生了对SCC发病机制的基本见解，并提供了独特的体内动物模型来检查皮肤SCC的病理生物学和评估新的治疗方法。
Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor-mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like I (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)-dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear beta-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs. which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies.