Role of Paxillin in Lung Cancer

桩蛋白在肺癌中的作用

基本信息

批准号：
7473452
负责人：
Ravi Salgia
金额：
$ 32.68万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/7473452
关键词：
Actins Adenocarcinoma Affect African American Apoptosis Binding Biochemical Biological Biological Markers Biological Process Carcinoma Caucasians Caucasoid Race Cell Line Cell Survival Cells Chickens Clinical Complementary DNA Complex Cytoskeletal Proteins Cytoskeleton Data Development Disease Focal Adhesions Frequencies Gene Mutation Genes Goals Hepatocyte Growth Factor Histology Human Invaded LIM Domain Large Cell Carcinoma Lead Ligands Localized 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 Protein Overexpression Proteins Public Health Race Receptor Activation Receptor Protein-Tyrosine Kinases Role Sampling Signal Transduction Site Somatic Mutation Squamous cell carcinoma Staging Subgroup Therapeutic Time Tumor Cell Line 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 migration mutant novel outcome forecast paxillin prognostic protein expression response tumor tumor growth two-dimensional

项目摘要

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）：肺癌是一种毁灭性的疾病，总体生存率很低。为了对这种疾病产生显着影响，必须确定新的靶点和机制。肺癌的标志之一是细胞运动、迁移、侵袭和早期转移至淋巴结和其他器官的增强。细胞骨架，尤其是基于肌动蛋白的细胞骨架，本质上参与肺癌的这些生物学功能。我们之前已经表明，粘着斑受到各种癌基因转化的显着影响，尤其是在肺癌中。特别是，68 kDa 粘着斑蛋白桩蛋白在非小细胞肺癌 (NSCLC) 中发生显着改变（过度表达并通过磷酸化激活）。在初步数据中，我们首次表明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%。不同组织学的肺癌的突变频率存在差异。这些突变位于 LD 结构域（对于结合 FAK 等其他分子很重要）和 LIM 结构域（对于肌动蛋白结合很重要的锌指结构域）之间。此外，非裔美国人、白人和台湾人的肺癌样本中桩蛋白基因突变也存在差异。桩蛋白最常见的突变 A127T 可提高肺癌细胞存活率、体内肿瘤生长以及增强血管生成。使用二维 PAGE，与野生型桩蛋白相比，突变体 A127T 还导致 H522 NSCLC 细胞中蛋白质表达存在差异。我们还鉴定出了桩蛋白基因扩增的 NSCLC 子集。肺癌中桩蛋白也会因受体酪氨酸激酶 c-Met 的激活而被磷酸化。有趣的是，在一些具有A127T突变的细胞系中，存在c-Met突变（R988C，近膜结构域）。根据我们最新的研究结果，我们提出以下目标： 1. 确定 NSCLC 中桩蛋白的表达、扩增和突变，并将其与人口统计学和临床因素、相关生物标志物（如 c-Met）和患者生存相关联； 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paxillin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，我们将找到转化、转移和最终治疗肺癌的新机制。公共卫生相关性：肺癌是一种毁灭性的疾病，转移频繁且治疗反应不佳。我们已经确定细胞骨架蛋白桩蛋白在肺癌中发挥重要作用，特别是与细胞运动/迁移和最终转移相关。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，从而使它们更具侵袭性。我们的目标是研究桩蛋白在肺癌中的作用，并最终找到针对这种疑难疾病的新疗法。