MOLECULAR BASIS OF EPITHELIAL SKIN CANCER

上皮性皮肤癌的分子基础

• 批准号: 6190682
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6190682
• 关键词: basal cell carcinoma; biological signal transduction; gene mutation; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; transcription factor

The skin has served as an extremely useful model for studying factors regulating normal epithelial growth and development and the perturbation of these processes that occurs during neoplasia. Although much previous work has centered on squamous cell carcinoma, there has been increased interest in basal cell carcinoma (BCC) following the discovery that deregulated Sonic hedgehog (Shh) signaling is linked to the development of these tumors. Shh pathway activation may be the result of loss-of- function mutations (involving the Shh receptor PTCH1), or gain- of-function mutations (involving SMO, which is normally repressed by PTCH1). While uncontrolled Shh pathway activation is associated with tumor development, we and others have shown that targeted disruption of Shh results in severe impairment of hair follicle morphogenesis. Although it is clear that Shh signaling has important functions in normal skin and BCC, the pivotal nuclear target(s) mediating keratinocyte responses to this pathway have yet to be identified. Much of what is known about this pathway is based on genetic analysis in Drosophila, where the transcription factor Cubitus interruptus (Ci) mediates responses to the Shh homolog Hedgehog. We will explore the notion that one or more of the vertebrate Ci homologs (Gli1, Gli2, Gli3) plays a central role in Shh signaling in keratinocytes. We propose a series of comprehensive studies focusing on the biological, biochemical, and molecular consequences of Gli protein overexpression in keratinocytes. Although there is substantial evidence implicating deregulated Shh signaling in BCC, there is little insight into how activation of this pathway leads to tumor formation. The results of the proposed studies will provide new information to fill in this gap in our knowledge. In addition to BCCs, several other neoplasms have been linked to the Shh pathway, including medulloblastomas and rhabdomyosarcomas. Moreover, precisely-controlled Shh signaling is essential for embryonic patterning in multiple tissues, with deregulation of this pathway leading to a variety of developmental abnormalities. Thus, the knowledge gained during the course of the proposed studies is likely to have relevance to a variety of clinical disorders, and may ultimately lead to improved treatments for BCC and other tumors.

皮肤已成为研究调节正常上皮生长和发育的因素以及在肿瘤形成过程中这些过程的扰动的极其有用的模型。尽管以前的许多工作都集中在鳞状细胞癌上，但在发现去调控的Sonic hedgehog(Shh)信号与基底细胞癌(BCC)的发展有关后，人们对这些肿瘤的兴趣越来越大。Shh途径的激活可能是功能丧失突变(涉及Shh受体ptch1)或功能获得突变(涉及SMO，通常由ptch1抑制)的结果。虽然不受控制的Shh通路激活与肿瘤的发展有关，但我们和其他人已经证明，定向干扰Shh会导致毛囊形态发生的严重损害。虽然Shh信号在正常皮肤和基底细胞癌中具有重要的功能，但关键的核靶点(S)介导角质形成细胞对这一途径的反应尚不清楚。关于这一途径的大部分已知是基于对果蝇的遗传分析，在果蝇中，转录因子Cubitus interruptus(Ci)介导对Shh同源刺猬的反应。我们将探索一个或多个脊椎动物CI同源基因(Gli1、Gli2、Gli3)在角质形成细胞Shh信号中发挥核心作用的概念。我们提出了一系列全面的研究，重点是角质形成细胞中Gli蛋白过度表达的生物学、生化和分子后果。尽管有大量证据表明Shh信号失控与基底细胞癌有关，但对该通路的激活如何导致肿瘤的形成却知之甚少。拟议研究的结果将提供新的信息，以填补我们知识的这一空白。除了基底细胞癌，还有其他几种肿瘤与Shh通路有关，包括髓母细胞瘤和横纹肌肉瘤。此外，精确控制的Shh信号对于多个组织中的胚胎模式是必不可少的，这一途径的解除调控会导致各种发育异常。因此，在拟议的研究过程中获得的知识可能与各种临床疾病相关，并最终可能导致改善基底细胞癌和其他肿瘤的治疗。