Role of Paxillin in Lung Cancer

桩蛋白在肺癌中的作用

• 批准号: 8064353
• 负责人: Ravi Salgia
• 金额: $ 31.81万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-02 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064353
• 关键词: Actins; Adenocarcinoma; Affect; African American; Apoptosis; Binding; Biochemical; Biological; Biological Markers; Biological Process; Caucasians; Caucasoid Race; Cell Line; Cell Survival; Cells; Chickens; Clinical; Clinical Markers; Complementary DNA; Complex; Cytoskeletal Proteins; Cytoskeleton; Data; Development; Disease; Focal Adhesions; Frequencies; Gene Mutation; Genes; Goals; Health; Hepatocyte Growth Factor; Histology; Human; Invaded; LIM Domain; Large Cell Carcinoma; Lead; Ligands; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metastatic Neoplasm to Lymph Nodes; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Organ; PTK2 gene; Patients; Phosphorylation; Play; Primary Neoplasm; Proteins; Race; Receptor Protein-Tyrosine Kinases; Role; Sampling; Signal Transduction; Site; Somatic Mutation; Squamous cell carcinoma; Staging; Subgroup; Therapeutic; Time; Tumor Tissue; Zinc Fingers; adapter protein; angiogenesis; base; bcr-abl Fusion Proteins; cancer cell; cell motility; gain of function mutation; in vivo; lung carcinogenesis; lung small cell carcinoma; lymph nodes; meetings; migration; mutant; novel; outcome forecast; overexpression; paxillin; prognostic; protein expression; response; tumor; tumor growth; two-dimensional

DESCRIPTION (provided by applicant): Lung cancer is a devastating illness with a poor overall survival. In order to dramatically impact on this disease, new targets and mechanisms have to be identified. One hallmark of lung cancer is enhanced cell motility, migration, invasion and early metastasis to lymph nodes and other organs. The cytoskeleton, especially actin-based, is intrinsically involved in these biological functions of lung cancer. We have previously shown that the focal adhesion is dramatically affected by transformation by various oncogenes, especially in lung cancer. In particular, the 68 kDa focal adhesion protein paxillin is dramatically altered (over-expressed and activated through phosphorylation) in non-small cell lung cancer (NSCLC). In preliminary data, we show for the first time that there are somatic mutations of the paxillin gene in NSCLC. In large cell carcinoma, for example, mutational frequency is up to 18%. There are differences in the mutational frequencies for the various histologies of lung cancer. The mutations were localized in between the LD domains (important for binding other molecules such as FAK) and in the LIM domains (zinc finger domains important in actin binding). Also, there were differences in paxillin gene mutations in lung cancer samples from African Americans, Caucasians, and Taiwanese. The most frequent mutation of paxillin, A127T, lead to enhanced lung cancer cell survival, tumor growth in vivo as well as enhanced angiogenesis. Using two-dimensional PAGE, the mutant A127T also led to differential protein expression in H522 NSCLC cells as compared to wild-type paxillin. We have also identified a subset of NSCLC that have amplification of the paxillin gene. Paxillin also was phosphorylated in response to activation of the receptor tyrosine kinase c-Met in lung cancer. Interestingly, in some cell lines with A127T mutation, there was a mutation of c-Met (R988C, juxtamembrane domain). Based on our most recent findings, we would propose the following aims: 1. Determine the expression, amplification, and mutations of paxillin in NSCLC and correlate with demographic and clinical factors, pertinent biological markers (such as c-Met) and patient survival; 2. Determine the biological functions of paxillin and mutated paxillin in NSCLC. Also, determine the potential for therapeutic inhibition in lung cancer; 3. Determine the combined role of paxillin and c-Met in NSCLC biological functions, angiogenesis and metastasis. In performing these studies, we will have arrived at novel mechanisms for transformation, metastasis and ultimately therapy against lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is a devastating illness with frequent metastases and poor response to therapy. We have determined that the cytoskeletal protein paxillin plays an important role in lung cancer, especially as related to cell motility/migration with ultimate metastasis. We have also identified that paxillin gene can be selectively mutated and/or amplified in lung cancer and thereby make them more aggressive. Our goal is to study the role of paxillin in lung cancer and ultimately arrive at novel therapy against this difficult disease.

描述（由申请人提供）：肺癌是一种破坏性疾病，总体生存率很低。为了显著影响这种疾病，必须确定新的靶点和机制。肺癌的一个标志是增强的细胞运动、迁移、侵袭和早期转移到淋巴结和其他器官。细胞骨架，特别是肌动蛋白为基础的细胞骨架，本质上参与了肺癌的这些生物学功能。我们以前已经表明，粘着斑受到各种癌基因转化的显著影响，特别是在肺癌中。特别是，68 kDa的粘着斑蛋白桩蛋白在非小细胞肺癌（NSCLC）中发生显著改变（过表达和通过磷酸化活化）。在初步的数据中，我们首次发现非小细胞肺癌中存在桩蛋白基因的体细胞突变。例如，在大细胞癌中，突变频率高达18%。不同组织学类型肺癌的突变频率存在差异。这些突变位于LD结构域（对结合其他分子如FAK很重要）和LIM结构域（对肌动蛋白结合很重要的锌指结构域）之间。此外，在非裔美国人、高加索人和台湾人的肺癌样本中，桩蛋白基因突变存在差异。桩蛋白最常见的突变A127 T导致增强的肺癌细胞存活、体内肿瘤生长以及增强的血管生成。使用二维PAGE，突变体A127 T也导致差异蛋白质表达在H522 NSCLC细胞相比，野生型桩蛋白。我们还发现了一个具有桩蛋白基因扩增的NSCLC亚组。在肺癌中，桩蛋白也被磷酸化以响应受体酪氨酸激酶c-Met的激活。有趣的是，在一些A127 T突变的细胞系中，存在c-Met的突变（R988 C，质膜结构域）。根据我们最近的研究结果，我们提出以下目标：1。确定桩蛋白在NSCLC中的表达、扩增和突变，并与人口统计学和临床因素、相关生物学标志物（如c-Met）和患者生存期相关; 2.确定桩蛋白和突变桩蛋白在NSCLC中的生物学功能。此外，确定肺癌治疗抑制的潜力; 3.确定桩蛋白和c-Met在NSCLC生物学功能、血管生成和转移中的联合作用。在进行这些研究时，我们将获得肺癌转化、转移和最终治疗的新机制。公共卫生相关性：肺癌是一种毁灭性的疾病，具有频繁的转移和对治疗的不良反应。我们已经确定，细胞骨架蛋白桩蛋白在肺癌中起着重要的作用，特别是与细胞运动/迁移与最终转移。我们还发现桩蛋白基因可以在肺癌中选择性突变和/或扩增，从而使其更具侵袭性。我们的目标是研究桩蛋白在肺癌中的作用，并最终找到治疗这一疑难疾病的新疗法。