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Proteins as biomarkers for tobacco-induced lung cancer development and chemoprevention.

机译：蛋白质作为烟草诱导的肺癌发展和化学预防的生物标志物。

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Background: Lung cancer continues to be the most common cancer diagnosed in the world and is the leading cause of cancer-related death in both men and women in the United States. The non-small cell lung cancer (NSCLC) subtype adenocarcinoma is the leading histological type clinically diagnosed in the United States, accounting for over 30% of all cases. We embark upon two strategies with promising clinical implications: identification of (informative) molecular biomarkers related to the development of tobacco-induced lung cancer and the discovery of novel chemopreventive agents.;Hypotheses: Current clinical protein biomarkers for detection of lung cancer lack sensitivity and specificity. The proteomics field can contribute greatly to the understanding of mechanisms in cancer progression and treatment response. Therefore, in Chapter 2 we hypothesized that by using proteomic approaches in a well-defined preclinical mouse lung tumorigenesis model induced using the tobacco carcinogen NNK, protein biomarkers could be obtained to provide an accurate view of molecular alterations during lung cancer development. Such biomarkers can provide utility for early detection, but also in the validation of chemoprevention strategies. Smokers are at risk for a variety of health concerns including lung cancer. Non-invasive biological fluids such as blood plasma contains molecular profiles related to current health status. Therefore, in Chapter 3 taking advantage of proteomic techniques and proteins identified in Chapter 2, we hypothesized that dynamic changes in protein expression profiles in the blood plasma of smokers characterized by a proteomics approach would assist in identifying early molecular changes related to tobacco-induced diseases such as lung cancer. Selenium-containing compounds are promising chemopreventive agents against lung cancer development. Developments of agents that can target molecular pathways that are critical in lung carcinogenesis, such as nitric oxide synthase (iNOS) and nitric oxide production, known to be involved in the promotion/progression phases of lung carcinogenesis, are needed and may be beneficial in chemoprevention of lung cancer in both smokers and former smokers. Therefore, in Chapter 4 we hypothesized that substitution of sulfur for selenium in an inducible nitric oxide synthase inhibitor, S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), would enhance its chemopreventive activity.;Results: We discovered proteins, including the 14-3-3 protein isoforms (theta, epsilon, sigma, and zeta), annexin A5, Clara cell 10 kDa protein (CC10), high mobility group box 1, and carbonyl reductase 2 that were differentially expressed in the lungs of mice treated with the tobacco carcinogen NNK versus vehicle (control)-treated mice during the progression of adenocarcinoma development; some of these changes were further modulated by p-XSC. These proteins are involved in a variety of biological functions that are critical in lung carcinogenesis, as well as in its prevention. (Chapter 3) We identified differentially expressed plasma proteins in healthy chronic cigarette smokers compared to healthy non-smokers. Several of the proteins identified, including ITI-HC3 and VDBP, associated with immunity and inflammatory responses, and 14-3-3 sigma and zeta, identified in Chapter 2, have been shown to be associated with tobacco-related diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. (Chapter 4) We found Se-PBIT to be superior to both PBIT and p-XSC as an inducer of apoptosis and inhibitor of cell growth in NSCLC cells, as determined by analysis of its effects on important molecular targets involved in cell growth inhibition, induction of apoptosis, and cell cycle regulation.;Conclusions: Based on our results, we were able to demonstrate the utility of a well-defined animal model in developing candidate protein biomarkers for lung cancer. Such biomarkers may be useful in early detection of the disease, as well as in the efficacy of chemopreventive agents. (Chapter 3) Our clinical pilot study results demonstrated for the first time that chronic cigarette smoking can influence the expression profile of the human plasma proteome and these changes may be indicative of future health concerns. (Chapter 4) We demonstrated that selenium in the form of Se-PBIT is a promising candidate for chemoprevention of NSCLC and appears superior to PBIT and p-XSC. (Abstract shortened by UMI.)
机译：背景：肺癌仍然是世界上最常见的诊断出的癌症，并且是美国男女癌症相关死亡的主要原因。非小细胞肺癌（NSCLC）亚型腺癌是在美国临床诊断出的主要组织学类型，占所有病例的30％以上。我们采取了两种具有潜在临床意义的策略：鉴定与烟草诱导的肺癌发展相关的（信息性）分子生物标记物以及发现新型化学预防剂。假设：目前用于检测肺癌的临床蛋白质生物标记物缺乏敏感性和特异性。蛋白质组学领域可以极大地有助于理解癌症进展和治疗反应的机制。因此，在第2章中，我们假设通过蛋白质组学方法在由烟草致癌物NNK诱导的定义明确的临床前小鼠肺部肿瘤发生模型中，可以获得蛋白质生物标志物，以提供肺癌发展过程中分子变化的准确视图。这样的生物标记物可以提供用于早期检测的效用，而且还可以用于化学预防策略的验证。吸烟者面临多种健康问题，包括肺癌。非侵入性生物流体（例如血浆）包含与当前健康状况相关的分子特征。因此，在第3章中，利用蛋白质组学技术和第2章中鉴定的蛋白质，我们假设以蛋白质组学方法为特征的吸烟者血浆中蛋白质表达谱的动态变化将有助于鉴定与烟草诱发疾病有关的早期分子变化。如肺癌。含硒化合物是抗肺癌发展的有前途的化学预防剂。需要开发能够靶向于肺癌发生过程中至关重要的分子途径的药物，例如一氧化氮合酶（iNOS）和一氧化氮的生产，这些药物通路已知参与肺癌发生的促进/发展阶段，因此可能对化学预防有益吸烟者和前吸烟者的肺癌患病率。因此，在第4章中，我们假设在诱导型一氧化氮合酶抑制剂S，S'-（1,4-亚苯基双[1,2-乙二基]）双异硫脲（PBIT）中用硫取代硒会增强其化学预防活性。结果；我们发现了蛋白质，包括14-3-3蛋白质同工型（θ，ε，σ和zeta），膜联蛋白A5，Clara细胞10 kDa蛋白质（CC10），高迁移率族框1和羰基还原酶2在腺癌发生发展过程中，用烟草致癌物NNK处理的小鼠相对于用载体（对照）处理的小鼠的肺中差异表达；其中一些变化被p-XSC进一步调节。这些蛋白质参与了多种对肺癌发生及其预防至关重要的生物学功能。 （第3章）与健康的非吸烟者相比，我们确定了健康的慢性吸烟者中差异表达的血浆蛋白。已鉴定出与免疫和炎性反应相关的几种蛋白质，包括ITI-HC3和VDBP，以及在第2章中鉴定的14-3-3 sigma和zeta与烟草相关疾病，包括慢性阻塞性疾病有关肺部疾病（COPD）和肺癌。 （第4章）我们分析了Se-PBIT对非小细胞肺癌细胞凋亡的诱导作用和对细胞生长的抑制作用，它优于PBIT和p-XSC，这是通过分析其对参与细胞生长抑制的重要分子靶点的影响而确定的，结论：基于我们的研究结果，我们能够证明一种定义明确的动物模型在开发肺癌候选蛋白质生物标记物中的实用性。此类生物标志物可用于疾病的早期检测以及化学预防剂的功效。 （第3章）我们的临床试验研究结果首次证明，长期吸烟会影响人类血浆蛋白质组的表达谱，这些变化可能预示着未来的健康问题。 （第4章）我们证明了Se-PBIT形式的硒是非小细胞肺癌化学预防的有前途的候选物，并且似乎优于PBIT和p-XSC。 （摘要由UMI缩短。）

著录项

  • 作者

    Bortner, James D., Jr.;

  • 作者单位

    The Pennsylvania State University.;

  • 授予单位 The Pennsylvania State University.;
  • 学科 Biology Molecular.;Biology Histology.;Chemistry Biochemistry.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 226 p.
  • 总页数 226
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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