Role of CRD-BP in Basal Cell Carcinoma Development

CRD-BP 在基底细胞癌发展中的作用

• 批准号: 7992898
• 负责人: Felicite K Noubissi
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992898
• 关键词: Affect; American; Apoptosis; Automobile Driving; Basal Cell Neoplasm; Basal Cell Nevus Syndrome; Basal cell carcinoma; Binding; Caring; Cell Aging; Cell Cycle; Cell Cycle Progression; Cell Maintenance; Code; Critical Pathways; Development; Disease; Ectopic Expression; Embryonic Development; Erinaceidae; Funding; Future; GLI Family Protein; GLI gene; Gene Targeting; Goals; Growth; Immunocompromised Host; Lead; Malignant Neoplasms; Medicare; Messenger RNA; MicroRNAs; Molecular; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Skin Cancer; Skin Tissue; Stem cells; Transcription Coactivator; Transgenic Mice; United States; base; c-myc Genes; cost; design; high risk; keratinocyte; mouse model; novel; programs; public health relevance; small hairpin RNA; smoothened signaling pathway; transcription factor; tumorigenesis; tumorigenic

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.

基底细胞癌（BCC）是最常见的皮肤癌，每年影响约一百万美国人。它的护理成本是美国医疗保险人群中所有癌症的第五高。虽然在过去的几十年中，BCC的新发病例数量每年都在迅速增加，但其发病机制的分子基础尚未完全了解。Hedgehog（Hh）信号通路的激活被证明是推动BCC发展的关键因素。转基因小鼠模型提供的证据表明，转录因子GLI 1的激活是导致BCC的致瘤程序启动的关键步骤。Wnt/β-连环蛋白信号通路也显示在BCC中被激活。典型的Wnt/β-catenin信号可能通过调节Hh通路的活性参与BCC肿瘤的发生。Wnt和Hh是胚胎发育、干细胞维持和肿瘤发生中至关重要的两个主要途径。这两种途径被认为在多个水平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，我们确定了一个新的机制，Wnt信号调节Hh信号通路的转录结果。我们证明了Wnt/β-连环蛋白信号转导诱导Hh转录激活因子GLI 1的表达。我们发现CRD-BP是Wnt/<$-catenin信号转导的直接靶点，它与GLI 1 mRNA的编码区片段结合并稳定它，我们还发现Wnt/<$-catenin信号转导以CRD-BP依赖的方式诱导GLI 1的表达和转录活性。我们假设Wnt诱导的和CRD-BP依赖的GLI 1表达和活性调节对BCC的发展是重要的。我们建议描绘CRD-BP在BCC肿瘤发生中的作用。（1）分析基底细胞癌中CRD-BP的表达及Wnt和Hh信号通路的活性。(2)确定CRD-BP表达是否影响角质形成细胞增殖。(3)分析CRD-BP依赖性GLI 1调节是否涉及翻译暂停和/或microRNA。总的来说，这些研究的完成将是确定CRD-BP在BCC发展中作用的第一步。这项建议的结果将被用作未来的壁外资助的CRD-BP在BCC的成因中的作用的综合分析的基础。公共卫生相关性：这些研究可能潜在地导致能够抑制CRD-BP功能并有效治疗BCC的药物的设计。这将显着降低BCC的护理成本，并成为重复手术的有益替代方案，特别是对于患有多种基底细胞肿瘤的高风险患者，包括患有遗传性疾病基底细胞痣综合征（BCNS）和免疫功能低下的患者。 公共卫生相关性：每年约有一百万美国人受到皮肤癌基底细胞癌的影响。它的护理成本是美国医疗保险人群中所有癌症的第五高。GLI 1蛋白在基底细胞癌的发生发展中起重要作用。我们已经确定了一种新的机制，导致刺激GLI 1的表达和活性。我们计划研究新发现的机制是否对基底细胞癌的发展很重要。这对于开发治疗基底细胞癌的新方法和降低其护理成本具有重要意义。