Role of CRD-BP in Basal Cell Carcinoma Development

描述（由申请人提供）：基底细胞癌（BCC）是最常见的皮肤癌，每年影响约100万美国人。在美国的医疗保险人群中，它的治疗费用是所有癌症中第五高的。尽管在过去的几十年里，BCC的新病例数量每年都在迅速增加，但其发病机制的分子基础尚不完全清楚。Hedgehog （Hh）信号通路的激活被证明是驱动BCC发展的关键因素。转基因小鼠模型提供了证据，证明转录因子GLI1的激活是导致BCC的致瘤程序启动的关键步骤。Wnt/¿-catenin信号通路在bcc中也被激活。典型的Wnt/¿-catenin信号可能通过调节Hh通路活性参与BCC的肿瘤发生。Wnt和Hh是在胚胎发育、干细胞维持和肿瘤发生中起关键作用的两个主要通路。这两种途径被认为在多个层面上相互作用或交叉调节，但这些相互作用的机制尚不清楚。在我们的初步研究中，我们确定了Wnt信号调节Hh信号通路转录结果的新机制。我们证明Wnt/¿-catenin信号传导诱导Hh转录激活因子GLI1的表达。我们发现，作为Wnt/¿-catenin信号传导的直接靶点，CRD-BP与GLI1 mRNA编码区片段结合并使其稳定。我们还发现Wnt/¿-catenin信号通路以依赖于CRD-BP的方式诱导GLI1的表达和转录活性。我们假设wnt诱导和CRD- bp依赖的GLI1表达和活性调控对bcc的发展很重要。我们建议描述CRD-BP在BCC肿瘤发生中的作用。根据这些目标，我们的具体目的是：(1)分析BCC中CRD-BP的表达以及Wnt和Hh信号通路的活性。(2)确定CRD-BP表达是否影响角质细胞增殖。(3)分析GLI1的CRD-BP依赖性调控是否涉及翻译暂停和/或microRNA。总之，这些研究的完成将是描述CRD-BP在BCC发展中的作用的第一步。该提案的结果将作为未来外部资助的关于CRD-BP在bcc成因中的作用的综合分析的基础。公共卫生相关性：这些研究可能会导致设计出能够抑制CRD-BP功能并有效治疗bcc的药物。这将显著降低基底细胞癌的护理成本，并成为重复手术治疗的有益替代方案，特别是对于患有遗传性疾病基底细胞痣综合征（BCNS）和免疫功能低下患者等多发性基底细胞肿瘤高风险患者。

DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting approximately one million Americans each year. Its cost of care represents the fifth highest for all cancers in the Medicare population in the United States. Although the number of new cases of BCC has increased rapidly each year in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of Hedgehog (Hh) signaling pathway was shown to be a key factor driving the development of BCC. Transgenic mouse models provided evidence that activation of the transcription factor GLI1 is a key step in the initiation of the tumorigenic program leading to BCC. The Wnt/¿-catenin signaling pathway was also shown to be activated in BCCs. Canonical Wnt/¿-catenin signaling is involved in the BCC tumorigenesis perhaps by modulating the Hh pathway activity. Wnt and Hh are two major pathways that are critical in embryonic development, stem cell maintenance, and tumorigenesis. These two pathways have been postulated to interact or cross regulate at multiple levels, yet the mechanisms of these interactions are not clear. In our preliminary studies, we identified a novel mechanism by which Wnt signaling regulates the transcriptional outcome of Hh signaling pathway. We demonstrated that Wnt/¿-catenin signaling induces expression of the Hh transcriptional activator GLI1. We showed that CRD-BP, a direct target of the Wnt/¿-catenin signaling, binds to the segment of the coding region of GLI1 mRNA and stabilizes it. We also showed that Wnt/¿-catenin signaling induces the expression and transcriptional activity of GLI1 in a CRD-BP dependent manner. We hypothesize that Wnt-induced and CRD- BP-dependent regulation of GLI1 expression and activities is important to the development of BCCs. We propose to delineate the role of CRD-BP in BCC tumorigenesis. Pursuant to these goals, the specific aims are: (1) To analyze the expression of CRD-BP and the activity of Wnt and Hh signaling pathways in BCC. (2) To determine whether CRD-BP expression affects keratinocyte proliferation. (3) To analyze whether CRD-BP- dependent regulation of GLI1 involves translational pausing and/or, microRNA. Overall, the completion of these studies will be the first step in delineating the role of CRD-BP in BCC development. The results of this proposal will be used as a basis for future extramurally funded comprehensive analysis on the role of CRD-BP in the genesis of BCCs. Public Health Relevance: These studies may potentially lead to design of the agents capable of inhibiting CRD-BP function and effective in the treatment of BCCs. This would significantly decrease the cost of care for BCCs and be a beneficial alternative to repeated surgical procedures especially for patients who are at high risk for multiple basal-cell tumors including people with heritable disorder basal cell nevus syndrome (BCNS) and immunocompromised patients. PUBLIC HEALTH RELEVANCE: Approximately one million Americans each year are affected by the skin cancer basal cell carcinoma. Its cost of care represents the fifth highest for all cancers in the Medicare population in the United States. The protein GLI1 is important for the development of basal cell carcinoma. We have identified a new mechanism leading to the stimulation of expression and activity of GLI1. We plan to study whether the newly-discovered mechanism is important for basal cell carcinoma development. This would be significant in developing new ways of treating basal cell carcinoma and reduce its cost of care.