Role of CREB in Lung Cancer Development

CREB ​​在肺癌发展中的作用

• 批准号: 8546983
• 负责人: JA SEOK KOO
• 金额: $ 31.94万
• 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/8546983
• 关键词: Abnormal Cell; Abnormal Epithelial Cell; Adenocarcinoma; Affect; Animal Model; Apoptosis; Basal Cell Hyperplasia; Binding Proteins; CREB1 gene; Cancer Etiology; Cancer Model; Cancer cell line; Carcinoma in Situ; Cell Cycle Arrest; Cell Differentiation process; Cell model; Cells; Cessation of life; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; Development; Distal; Dominant-Negative Mutation; Dysplasia; Epithelial; Epithelial Cells; Epithelium; Evaluation; Event; Freezing; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Goals; Growth; Human; Immunodeficient Mouse; In Vitro; Institution; Knockout Mice; Lesion; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Metaplasia; Methods; Modality; Modeling; Molecular; Molecular Abnormality; Mucous Membrane; Mucous body substance; Mus; Mutant Strains Mice; Mutation; Neoplasms; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nude Mice; Pathogenesis; Pathologic; Patients; Phenotype; Play; Premalignant; Premalignant Cell; Preventive; Prognostic Factor; Prognostic Marker; Research; Response Elements; Role; Signal Pathway; Slide; Small Interfering RNA; Specimen; Squamous Cell; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Structure of parenchyma of lung; Testing; Therapeutic; Tissue Banking; Tissue Banks; Tissues; Tracheobronchial; Transgenic Mice; United States; Woman; Work; Xenograft procedure; base; cancer cell; cell type; chemical genetics; in vivo; inhibitor/antagonist; lung carcinogenesis; malignant state; men; mouse model; neoplastic cell; never smoker; new therapeutic target; novel; overexpression; protein expression; protein function; small molecule; transcription factor; transdifferentiation; tumor; tumor progression; tumor xenograft; tumorigenic

ABSTRACT 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.

抽象的 肺癌是世界上最常见的癌症形式，也是癌症相关死亡的主要原因 在美国的男人和女人。尽管最近了解异常功能的进展 肺癌发育中涉及的信号通路，主调节转录因子受影响 这些改变的信号通路，调节与生长有关的关键基因的表达和 肺癌细胞的存活仍然很少了解。转录因子循环腺苷3'，5'-- 单磷酸反应元素结合蛋白（CREB）调节了许多基因的表达 参与癌症发展，已被证明在增殖，生存和 分化几种细胞类型。最近，我们发现Creb在转变和 维持支气管上皮细胞的正常粘膜纤毛表型。此外，克里布是 在几个非小细胞肺癌（NSCLC）细胞中以显着更高的水平表达，并且更活跃 线比在原发性正常人气管上皮细胞和人肺鳞状细胞中 癌和腺癌组织中的组织比在配对的邻近正常肺组织中。回顾性生存 - NSCLC患者的持续时间分析表明，CREB活性形式的过表达为 负预后因素。此外，我们观察到用遗传和化学抑制剂治疗 阻止CREB的表达和激活极大地抑制了NSCLC的生长和存活率 细胞。总而言之，我们的初步发现表明CREB是控制同时控制的关键分子 支气管上皮细胞的正常分化和肺癌细胞异常生长。基于我们 调查结果，我们假设异常调节的Creb在异常中起关键作用 NSCLC细胞的增殖和存活。为了检验这一假设，我们将追求三个具体目标： 1。确定CREB是否通过分析肿瘤性促进了NSCLC的发病机理 NSCLC病变并调节体外肺癌中的CREB表达和活性 模型细胞和体内动物模型。 2。使用小的生物学和分子后果调节CREB活性 肺癌发育中的分子抑制剂。 3。建立CREB在肺癌发展中的遗传作用。 这些研究将提高我们对异常生存机制的理解和 NSCLC细胞特别是CREB在肺癌发育中的作用。我们希望这项研究能 确定NSCLC患者的预防和/或治疗策略的新颖目标。