IKKα enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas
IKKα enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas
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DOI：
10.4161/cc.7.13.6147
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发表时间：
2008-07-01
期刊：
影响因子：
4.3
通讯作者：
Casanova, M. Llanos
中科院分区：
文献类型：
--
作者：
Moreno-Maldonado, Rodolfo;Ramirez, Angel;Casanova, M. Llanos
皮肤鳞状细胞癌(SCCs)因其上皮细胞分化程度和组织学变异而表现出不同的临床特征。了解这些差异的原因可能会增加鳞状细胞的可治疗性。因此，研究角质形成细胞的分化机制具有重要意义。IKK(I Kappa B Kinase)α是一种重要的表皮形态发生蛋白，尽管其发挥功能的途径尚不清楚，其在癌症发生发展中的作用也存在争议。我们发现，增强的IKKα表达通过E-钙粘附素依赖的机制增加了人类角质形成细胞的早期和终末分化。在小鼠致瘤表皮细胞中，IKKα的表达增加导致所产生的SCC的分化模式发生变化，产生了一种独特的组织学变体，类似于人类棘层溶解SCC(ASCC)变体。尽管人类ASCC具有侵袭性的临床病程和高转移风险，但其病因尚不清楚。我们发现人类ASCC，就像在相应的IKKα小鼠肿瘤中观察到的那样，同时表达高水平的IKKα和E-钙粘素，但缺乏角蛋白K1和K10，通常与IKKα和E-钙粘素共表达。小鼠和人类ASCC变异体的特性之间的紧密相关性强烈地表明，ikkα与人类这种SCC变异体的发展有关。
Squamous cell carcinomas (SCCs) of the skin display different clinical features according to their epithelial differentiation grade and histological variant. Understanding the causes of these divergences might increase the curability of SCCs. Therefore, it is important to study the mechanisms of differentiation in keratinocytes. IKK (I kappa B kinase) alpha is an important protein for epidermal morphogenesis, although the pathways through which it exerts its function are unknown and controversy exists about its role in cancer development. We show that enhanced IKK alpha expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKK alpha in mouse tumorigenic epidermal cells leads to changes in the differentiation pattern of the resulting SCCs, originating a distinct histological variant that resembles the human acantholytic SCC (ASCC) variant. Although human ASCCs have an aggressive clinical course and high risk of metastasis, nothing is known about their etiology. We show that human ASCCs, as observed in the counterpart IKK alpha murine tumors, express high levels of both IKK alpha and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKK alpha and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKK alpha is responsible for the development of this human SCC variant.