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形式，也是美国男性和女性与癌症有关的主要原因。尽管最近了解与肺癌发育中涉及的异常运作的信号通路的进展，但受这些改变的信号传导途径影响的主要调节剂转录因子调节了与肺癌细胞生长和存活有关的关键基因表达的表达仍然很少了解。转录因子环状腺苷3'，5'-单磷酸反应元素结合蛋白（CREB）调节涉及癌症发展的许多基因的表达，并已被证明在几种细胞类型的增殖，生存和分化中起着重要作用。最近，我们发现CREB在支气管上皮细胞的正常粘膜外表型的转分化和维持中起作用。此外，比在原发性正常人类气管上皮细胞以及人肺鳞状细胞癌和腺癌组织中，在几个非小细胞肺癌（NSCLC）细胞系中，CREB的表达比在几个非小细胞肺癌（NSCLC）细胞系中更为活跃。 NSCLC患者的回顾性生存 - 持续时间分析表明，CREB活跃形式的过表达是一个负预后因素。此外，我们观察到用遗传和化学抑制剂的治疗阻断了CREB的表达和激活，从而极大地抑制了NSCLC细胞的生长和存活。总而言之，我们的初步发现表明，CREB是一个关键分子，可以控制支气管上皮细胞的正常分化和肺癌细胞异常生长。根据我们的发现，我们假设异常调节的CREB在NSCLC细胞的异常增殖和存活中起关键作用。为了检验这一假设，我们将追求三个特定的目的：1。确定CREB是否通过分析肿瘤前NSCLC病变来促进NSCLC的发病机理，并调节体外肺癌中的CREB表达和活性。 2。确定使用小分子抑制剂在肺癌发育中使用小分子抑制剂调节CREB活性的生物学和分子后果。 3。建立CREB在肺癌发展中的遗传作用。这些研究将增加我们对NSCLC细胞异常生存和增殖机制的理解，特别是CREB在肺癌发育中的作用。我们希望这项研究能够确定NSCLC患者的预防和/或治疗策略的新颖目标。 公共卫生相关性：肺癌是世界上最常见的癌症形式，也是美国男性和女性与癌症相关死亡的主要原因，尽管最近在新的治疗靶标和方法发展方面取得了进步。转录因子循环腺苷3'，5'-单磷酸反应元素结合蛋白（CREB）调节涉及癌症发展的许多基因。除了我们较早的研究还表明，CREB是一个关键分子，它可以控制支气管上皮细胞的正常分化和肺癌细胞的异常生长，拟议的研究将大大增强我们对肺癌生存异常和肺部癌细胞繁殖的机制的理解，并有助于确定针对癌症和癌症的新型患者。