Role of CREB in Lung Cancer Development

CREB ​​在肺癌发展中的作用

• 批准号: 8423194
• 负责人: JA SEOK KOO
• 金额: $ 30.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423194
• 关键词: Role; CREB; Lung; Cancer; Development

DESCRIPTION (provided by applicant): Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States. Despite recent advances in understanding of aberrantly functioning signaling pathways involved in lung cancer development, the master regulator transcription factors affected by these altered signaling pathways that regulate the expression of critical genes involved in the growth and survival of lung cancer cells are still poorly understood. The transcription factor cyclic adenosine 3',5'- monophosphate-response element-binding protein (CREB) regulates the expression of numerous genes involved in cancer development and has been shown to play an important role in the proliferation, survival, and differentiation of several cell types. Recently, we found that CREB plays a role in the transdifferentiation and maintenance of the normal mucociliary phenotype of bronchial epithelial cells. In addition, CREB was expressed at significantly higher levels and more active in several non-small cell lung cancer (NSCLC) cell lines than in primary normal human tracheobronchial epithelial cells and in human lung squamous cell carcinoma and adenocarcinoma tissue than in paired adjacent normal lung tissue. Retrospective survival- duration analysis of patients with NSCLC showed that overexpression of the active form of CREB was a negative prognostic factor. Moreover, we observed that treatment with genetic and chemical inhibitors that blocked the expression and activation of CREB dramatically suppressed the growth and survival of NSCLC cells. In summary, our preliminary findings suggest that CREB is a critical molecule that controls both the normal differentiation of bronchial epithelial cells and the abnormal growth of lung cancer cells. Based on our findings, we hypothesize that aberrantly regulated CREB plays a critical role in the abnormal proliferation and survival of NSCLC cells. To test this hypothesis, we will pursue three specific aims: 1. To determine whether CREB promotes the pathogenesis of NSCLC by analyzing preneoplastic NSCLC lesions and modulating CREB expression and activity in an in vitro lung carcinogenesis model cell and in vivo animal models. 2. To identify the biologic and molecular consequences of modulating CREB activity using small molecule inhibitors in lung cancer development. 3. To establish the genetic role of CREB in the development of lung cancer. These studies will increase our understanding of the mechanisms of abnormal survival and proliferation of NSCLC cells, in particular, the role of CREB in lung cancer development. We are hopeful that this study will identify a novel target for preventive and/or therapeutic strategies in patients with NSCLC. PUBLIC HEALTH RELEVANCE: Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States, despite of the recent advances in development of new therapeutic targets and methods. The transcription factor cyclic adenosine 3',5'-monophosphate-response element-binding protein (CREB) regulates numerous genes involved in cancer development. In addition to our earlier studies demonstrated that CREB is a critical molecule that controls both the normal differentiation of bronchial epithelial cells and the abnormal growth of lung cancer cells, the proposed studies will substantially enhance our understanding of the mechanisms of abnormal survival and proliferation of lung cancer cells and facilitate to identify a novel target for preventive and/or therapeutic strategies in patients with lung cancer.

描述（由申请人提供）：肺癌是世界上最常见的癌症，也是美国男性和女性癌症相关死亡的主要原因。尽管最近对肺癌发展中功能异常的信号通路的理解取得了进展，但受这些改变的信号通路影响的主调节转录因子仍然知之甚少，这些转录因子调节参与肺癌细胞生长和存活的关键基因的表达。转录因子环腺苷 3',5'- 单磷酸反应元件结合蛋白 (CREB) 调节与癌症发展相关的众多基因的表达，并已被证明在多种癌症的增殖、存活和分化中发挥重要作用。细胞类型。最近，我们发现CREB在支气管上皮细胞的转分化和维持正常粘膜纤毛表型中发挥作用。此外，CREB在几种非小细胞肺癌（NSCLC）细胞系中的表达水平显着高于原代正常人气管支气管上皮细胞，并且在人肺鳞状细胞癌和腺癌组织中的表达水平显着高于配对的相邻正常肺。组织。 NSCLC 患者的回顾性生存时间分析表明，CREB ​​活性形式的过度表达是一个负面的预后因素。此外，我们观察到用基因和化学抑制剂阻断 CREB ​​表达和激活的治疗可显着抑制 NSCLC 细胞的生长和存活。总之，我们的初步研究结果表明，CREB是控制支气管上皮细胞正常分化和肺癌细胞异常生长的关键分子。根据我们的研究结果，我们假设异常调节的 CREB ​​在 NSCLC 细胞的异常增殖和存活中发挥着关键作用。为了检验这一假设，我们将追求三个具体目标： 1.通过分析NSCLC癌前病变并调节体外肺癌模型细胞和体内动物模型中的CREB表达和活性，确定CREB是否促进NSCLC的发病机制。 2. 确定使用小分子抑制剂调节 CREB ​​活性在肺癌发展中的生物学和分子后果。 3. 确定CREB在肺癌发生中的遗传作用。这些研究将增加我们对NSCLC细胞异常存活和增殖机制的理解，特别是CREB在肺癌发展中的作用。我们希望这项研究能够确定非小细胞肺癌患者预防和/或治疗策略的新靶点。 公共卫生相关性：尽管最近在开发新的治疗靶点和方法方面取得了进展，但肺癌是世界上最常见的癌症形式，也是美国男性和女性癌症相关死亡的主要原因。转录因子环腺苷 3',5'-单磷酸反应元件结合蛋白 (CREB) 调节许多与癌症发展有关的基因。除了我们早期的研究表明CREB是控制支气管上皮细胞正常分化和肺癌细胞异常生长的关键分子外，拟议的研究将大大增强我们对肺细胞异常存活和增殖机制的理解。癌细胞并有助于确定肺癌患者预防和/或治疗策略的新靶标。