Role of Paxillin in Lung Cancer

桩蛋白在肺癌中的作用

• 批准号: 8255362
• 负责人: Ravi Salgia
• 金额: $ 31.85万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255362
• 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）：肺癌是一种毁灭性的疾病，总生存率较差。为了对这种疾病产生巨大影响，必须确定新的目标和机制。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，尤其是基于肌动蛋白的细胞骨架，本质上参与了肺癌的这些生物学功能。我们以前已经表明，局灶性粘附受到各种癌基因的转化，尤其是在肺癌中的转化。特别是，在非小细胞肺癌（NSCLC）中，68 kDa局灶性粘附蛋白帕克西林在磷酸化（通过磷酸化中过表达和激活）发生了巨大变化。在初步数据中，我们首次显示了NSCLC中paxillin基因的体细胞突变。例如，在大细胞癌中，突变频率高达18％。肺癌各种组织学的突变频率存在差异。该突变位于LD结构域之间（对于结合其他分子（例如FAK）和LIM结构域（锌指结构域中对肌动蛋白结合很重要）的重要性。此外，非裔美国人，高加索人和台湾人的肺癌样本中的帕克西林基因突变存在差异。 Paxillin A127T最常见的突变导致肺癌细胞的存活增强，体内肿瘤生长以及增强的血管生成。使用二维页面，与野生型Paxillin相比，突变体A127T还导致H522 NSCLC细胞的差异蛋白表达。我们还确定了具有放大paxillin基因的NSCLC的子集。帕西林还响应于肺癌中受体酪氨酸激酶C-MET的激活而磷酸化。有趣的是，在某些具有A127T突变的细胞系中，有C-MET的突变（R988C，juxtammbrane域）。根据我们的最新发现，我们将提出以下目的：1。确定NSCLC中帕西林的表达，扩增和突变，并与人口统计学和临床​​因素，相关的生物学标记（例如C-MET）和患者生存相关； 2。确定NSCLC中帕克西林和突变的帕西林的生物学功能。另外，确定肺癌治疗抑制的潜力； 3。确定帕克西林和C-MET在NSCLC生物学功能，血管生成和转移中的综合作用。在进行这些研究时，我们将达到转化，转移和最终针对肺癌的治疗的新型机制。公共卫生相关性：肺癌是一种毁灭性疾病，经常发生转移和对治疗的反应不佳。我们已经确定细胞骨架蛋白帕西林在肺癌中起重要作用，尤其是与细胞运动/迁移有关的最终转移。我们还确定，可以选择性地突变和/或在肺癌中扩增帕西林基因，从而使其更具侵略性。我们的目标是研究帕西林在肺癌中的作用，并最终对这种困难疾病进行新的治疗。

项目成果

The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target.

• DOI: 10.1371/journal.pone.0067668
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ferguson BD;Liu R;Rolle CE;Tan YH;Krasnoperov V;Kanteti R;Tretiakova MS;Cervantes GM;Hasina R;Hseu RD;Iafrate AJ;Karrison T;Ferguson MK;Husain AN;Faoro L;Vokes EE;Gill PS;Salgia R
• 通讯作者: Salgia R

A new hope for precision medicine.

精准医疗的新希望。

• DOI: 10.1126/scitranslmed.3007622
• 发表时间: 2013
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Salgia,Ravi;Sattler,Martin
• 通讯作者: Sattler,Martin

FYN is overexpressed in human prostate cancer.

• DOI: 10.1111/j.1464-410x.2008.08009.x
• 发表时间: 2009-01
• 期刊: BJU international
• 影响因子: 4.5
• 作者: Posadas EM;Al-Ahmadie H;Robinson VL;Jagadeeswaran R;Otto K;Kasza KE;Tretiakov M;Siddiqui J;Pienta KJ;Stadler WM;Rinker-Schaeffer C;Salgia R
• 通讯作者: Salgia R