MOLECULAR BASIS OF EPITHELIAL SKIN CANCER

皮肤已作为一个非常有用的模型，用于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发生的这些过程的扰动。虽然以前的工作主要集中在鳞状细胞癌，但在发现失调的Sonic hedgehog（Shh）信号传导与这些肿瘤的发展有关后，对基底细胞癌（BCC）的兴趣增加。 Shh途径活化可能是功能丧失突变（涉及Shh受体PTCH 1）或功能获得突变（涉及SMO，其通常被PTCH 1抑制）的结果。 虽然不受控制的Shh通路激活与肿瘤发展相关，但我们和其他人已经表明，Shh的靶向破坏导致毛囊形态发生严重受损。 虽然Shh信号传导在正常皮肤和BCC中具有重要功能，但介导角质形成细胞对该途径的反应的关键核靶点尚未确定。关于这一途径的大部分已知信息都是基于果蝇的遗传分析，其中转录因子Cubitus interruptus（Ci）介导了对Shh同源物Hedgehog的反应。我们将探讨的概念，一个或多个脊椎动物Ci同源物（Gli1，Gli2，Gli3）在角质形成细胞中的Shh信号中起着核心作用。 我们提出了一系列的综合研究集中在生物学，生物化学和分子后果的Gli蛋白过度表达角质形成细胞。尽管有大量证据表明BCC中Shh信号转导失调，但对该途径的激活如何导致肿瘤形成的了解甚少。 拟议研究的结果将提供新的信息，以填补我们知识中的这一空白。 除了基底细胞癌，其他几种肿瘤也与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信号传导对于多个组织中的胚胎图案化是必不可少的，该途径的失调导致各种发育异常。 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，并可能最终导致BCC和其他肿瘤的治疗改善。

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.