蛋白质组学及其在肿瘤标志物研究中的应用

2001年2月人类基因组图谱基本绘制完成,但对基因调节与功能等问题仍未能解读,被赋予研究基因表达调节及其产物功能任务的"后基因组学"即应运而生[1].     

蛋白质组学在肿瘤标志物研究中的进展

随着人类基因组计划的完成，功能基因组学研究日益深入，蛋白质组学就成为人们研究的热点。广义上讲，蛋白质组（proteome）是指“一个细胞或一个组织基因组在一定条件下所表达的全部蛋白质”。蛋白质组学（proteomics）是指以蛋白质组为研究对象，从整体的角度，分析细胞内动态变化的蛋白质组成与活动规律。     

蛋白质组学在肿瘤标志物研究中的进展

随着人类基因组计划的完成,功能基因组学研究日益深入,蛋白质组学就成为人们研究的热点。广义上讲,蛋白质组(proteome)是指“一个细胞或一个组织基因组在一定条件下所表达的全部蛋白质”。蛋白质组学(proteomics)是指以蛋白质组为研究对象,从整体的角度,分析细胞内动态变化的蛋白质组成与活动规律[1]。肿瘤发生过程中,细胞恶变前后的表达蛋白质组发生了变化。应用蛋白质组学研究技术比较肿瘤发生过程中蛋白质的变化,可以发现肿瘤相关的特异蛋白质,不仅为肿瘤诊断提供分子标志,也可能为肿瘤的治疗和药物开发提供靶标。本文就比较蛋白质组学技…     

蛋白质组学在结直肠癌生物标志物研究中的应用

蛋白质组学是以蛋白质组为研究对象的一门崭新的生命科学,其技术主要包括样品的制备技术、双向凝胶电泳、差异凝胶电泳、多维蛋白质鉴定技术和表面增强激光解析电离飞行时间质谱等。结直肠癌是人类最常见的恶性肿瘤之一,近几年蛋白质组学在结直肠癌生物标志物的研究中取得了很大进展。本文对此作一综述。     

蛋白质组学在肝癌标志物研究中的应用

近年来蛋白质组学被广泛地应用于各种疾病研究，已由原来单一的比较蛋白质组学研究拓展到如今涉及功能蛋白质、蛋白质间相互作用等多方面的研究；有关蛋白质组学在肝癌标志物研究中的应用对于肝癌的诊断有重要的意义。     

蛋白质组学及其在甲状腺肿瘤研究中的应用

甲状腺肿瘤根据其分化程度和生物学特征可分为良性和恶性两大类,良性者多为腺瘤,恶性者多为腺癌。WHO把甲状腺腺瘤划分为:普遍型腺瘤,不典型腺瘤和Hiirthle细胞型腺瘤[1]。甲状腺癌根据其组织类型、生物学行为及恶性程度不同的病变,临床病理分为:乳头状甲状腺癌(papillary thyr     

蛋白质组学研究在确定新的肿瘤标志物中的意义

随着蛋白质组学技术、高通量技术及生物信息学技术的发展，越来越多的肿瘤标志物被发现，并将逐步应用于临床，这些进展必将为肿瘤的早期检测和风险评价提供可靠的依据。现综述蛋白质组学研究策略在肿瘤标志物的筛选和鉴定中的应用。     

蛋白质组学在实体瘤肿瘤标志物研究中的应用

在后基因组时代,生物学的中心任务是认识基因组的功能。由于基因功能主要是通过其表达蛋白质来实现的,要了解基因的全部信息,必须深入研究不同基因编码的蛋白质,因此蛋白质组学在生命科学研究中已具有重要的地位。肿瘤细胞或组织蛋白质样本通常经过双向电泳等技术可以按不同大小、等电点或类型得以分离(profiling),然后通过质谱技术和蛋白质数据库比较,进一步将特殊的感兴趣的蛋白质鉴定出来。肿瘤蛋白质组学是整个蛋白质组学研究中的一项重要内容,通过蛋白质组分析技术将能够从细胞整体水平上认识在肿瘤的发生、发展过程中蛋白表达谱的变化,为寻找特异的肿瘤标志物这一研究领域带来了新的希望。近几年来,使用蛋白质组学和激光捕获显微切割技术(laser capture microdissection,LCM)已在多种肿瘤中发现了许多有研究前景的肿瘤标志物侯选蛋白,尽管目前被肯定的肿瘤特异性标志物尚为数不多,但和以往相比已经有了十分显著的进步,本文对此做了简要综述。     

基于质谱的尿蛋白质组学在肿瘤生物标志物发现中的研究进展

基于质谱（mass spectrometry,MS）的蛋白质组学技术的快速发展,应用蛋白质组学方法寻找新的肿瘤生物标志物成为肿瘤研究的热点。尿液以各种形式收集血液在稳态机制控制下排出的废物,其积累了人体生物系统的变化,能够很好地反映机体疾病的状态。相较于目前临床检测常用的血液样本,尿液样本具有成分简单稳定、可连续收集、更易检测感兴趣的低丰度蛋白等诸多优势,这使其成为肿瘤生物标志物研究的理想来源。尿液蛋白大多为分泌蛋白,因此在尿液中发现的潜在蛋白也可能是血液中很好的生物标志物。本文总结了基于MS的尿蛋白质组学在肿瘤生物标志物发现中的研究进展,并对常见肿瘤中筛选的尿蛋白标志物候选分子进行了系统归纳和分析。      

蛋白质组学在肺癌研究中的应用

人类基因组计划全基因组测序已完成，绘制了基因框架图，掌握了大量的基因组序列的信息并全面了解了基因组和基因表达变化的方法。由于基因的功能除了由排序决定外，还受多种因素的影响，而蛋白质代表了基因的信息，其功能一旦出现异常即可直接引发疾病，因而研究蛋白质的改变对全面了解肿瘤的发生发展有重要意义。     

肺癌相关血清学肿瘤标志物研究进展

肿瘤生物标志物近年来一直是肿瘤基础和临床研究的一个十分活跃的领域.尽管迄今尚未找到肺癌特异性抗原,国内外研究人员已发现多种有潜力用于肺癌早期诊断、临床分型和分期、预后判断和疗效观察等的肿瘤生物标志.本文以癌胚抗原、神经元特异性烯醇化酶、细胞角蛋白19片段抗原、碳水化合物抗原242、粘蛋白1抗原、神经细胞粘附分子、组织多肽特异性抗原、干细胞因子、血管内皮生长因子、肝细胞生长因子、肺癌相关抗原和磷脂酰肌醇蛋白聚糖等为例,对肺癌相关血清学肿瘤生物标志物的研究进展作一综述.     

Identification of serum biomarkers for colon cancer by proteomic analysis

Colorectal cancer (CRC) is often diagnosed at a late stage with concomitant poor prognosis. Early detection greatly improves prognosis; however, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their applicability. No serum-based test is currently of sufficient sensitivity or specificity for widespread use. In the best currently available blood test, carcinoembryonic antigen exhibits low sensitivity and specificity particularly in the setting of early disease. Hence, there is great need for new biomarkers for early detection of CRC. We have used surface-enhanced laser desorbtion/ionisation (SELDI) to investigate the serum proteome of 62 CRC patients and 31 noncancer subjects. We have identified proteins (complement C3a des-arg, alpha1-antitrypsin and transferrin) with diagnostic potential. Artificial neural networks trained using only the intensities of the SELDI peaks corresponding to identified proteins were able to classify the patients used in this study with 95% sensitivity and 91% specificity.     

SELDI-TOF-MS技术在非小细胞肺癌中的应用

表面增强激光解析离子化飞行时间质谱（SELDI-TOF-MS）技术是一种使用特殊的增强表面直接捕获待测样本中的蛋白质分子,然后经激光解析离子化．飞行时间质谱测定被捕获的蛋白质的相对分子量、丰度的新兴技术。目前该项技术已经成功应用于前列腺癌的诊断、子宫良恶性肿瘤的鉴别等方面。SELDI-TOF-MS技术通过寻找肿瘤病人相关的特异性蛋白用于对非小细胞肺癌的早期诊断,指导治疗及预测预后等方面具有很好的应用前景。     

肺癌的表观遗传研究进展

肺癌分子生物标志物早期检测是一种有效发现并且影响治疗癌症的有效分子工具。表观遗传在肺癌的发生、发展过程中起着重要的作用。表观遗传机制的研究从根本上改变了我们传统对于肺癌的发现,诊断及治疗的观点。表观遗传为肺癌的生物标记发展,早期发现和治疗风险评估提供新的见解。     

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide

Background:

Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients.

Methods:

Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS).

Results:

Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide.

Conclusion:

Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.     

肺癌骨转移相关分子的比较蛋白质组学研究

目的:分析比较人肺癌不同骨转移潜能细胞株的差异表达蛋白质图谱,筛选在肺癌骨转移中起重要作用的关键蛋白质分子。方法:利用双向凝胶电泳(2-DE)和基质辅助激光解析离子化-飞行时间-质谱技术,分析人肺癌骨转移细胞株SBC-5和非骨转移细胞株SBC-3/DOX蛋白质图谱的差异表达,查询数据库筛选肺癌骨转移相关蛋白质。结果:PDQuest 8.0软件分析3次相同条件下的2-DE图谱,结果显示重复性、匹配性较好。SBC-5检测到(1116±64)个蛋白点,平均匹配率为84%;SBC-3/DOX检测到(1132±72)个蛋白点,平均匹配率为82%;蛋白质点分布以PI 4-7、相对分子质量20 000-80 000范围内最多。两种细胞株16个差异蛋白质点胰酶胶内酶解,质谱分析获得14张肽质量指纹谱,鉴定出Annexin A1,CaN,IGFBP-1,ADAM32等8种胶内差异蛋白质。结论:人肺癌不同骨转移潜能细胞株SBC-5和SBC-3/DOX的2-DE蛋白质图谱具有明显的差异表达,多种差异表达蛋白可能与肺癌骨转移相关。     

Multiple serological biomarkers for colorectal cancer detection

The aim of this study was to initiate a survey of human autoantibody responses to a panel of select colorectal tumor‐associated antigens identified by previous serological analysis of a cDNA expression library and to subsequently identify multiple serological biomarkers for the detection of colorectal cancer. For screening of autoantibodies against colorectal tumor‐associated antigens, sera from 94 colorectal cancer patients and 54 normal controls were analyzed by enzyme‐linked immunosorbent assay using recombinant rCCCAP, rHDAC5, rP53, rNMDAR and rNY‐CO‐16 proteins as coating antigens. Seropositivity among colorectal cancer patients to the 5 individual coating antigens varied from 18.1% to 35.1%. Seropositivity to any of the 5 coating antigens was 58.5% and combining this analysis with evaluation of serum carcinoembryonic antigen (≥5 ng/ml) significantly increased the seropositivity to 77.6%. Seropositivity of early‐stage (Dukes' Stages A and B) colorectal cancer patients to CEA was 21.9%, and seropositivity to any of the 5 colorectal cancer‐associated antigens was 53.7%, and the combination of these 2 measurements resulted in a higher diagnostic capacity (65.9%) than either marker alone. In conclusion, these results collectively indicated that combined detection of serum autoantibody profiles against our panel of colorectal tumor‐associated antigens and the analysis of carcinoembryonic antigen provides a promising diagnostic biomarker for colorectal cancer, particularly among early‐stage patients.     

Toward an early diagnosis of lung cancer: an autoantibody signature for squamous cell lung carcinoma

Serum‐based diagnosis offers the prospect of early lung carcinoma detection and of differentiation between benign and malignant nodules identified by CT. One major challenge toward a future blood‐based diagnostic consists in showing that seroreactivity patterns allow for discriminating lung cancer patients not only from normal controls but also from patients with non‐tumor lung pathologies. We addressed this question for squamous cell lung cancer, one of the most common lung tumor types. Using a panel of 82 phage‐peptide clones, which express potential autoantigens, we performed serological spot assay. We screened 108 sera, including 39 sera from squamous cell lung cancer patients, 29 sera from patients with other non‐tumor lung pathologies, and 40 sera from volunteers without known disease. To classify the serum groups, we employed the standard Naïve Bayesian method combined with a subset selection approach. We were able to separate squamous cell lung carcinoma and normal sera with an accuracy of 93%. Low‐grade squamous cell lung carcinoma were separated from normal sera with an accuracy of 92.9%. We were able to distinguish squamous cell lung carcinoma from non‐tumor lung pathologies with an accuracy of 83%. Three phage‐peptide clones with sequence homology to ROCK1, PRKCB1 and KIAA0376 reacted with more than 15% of the cancer sera, but neither with normal nor with non‐tumor lung pathology sera. Our study demonstrates that seroreactivity profiles combined with statistical classification methods have great potential for discriminating patients with squamous cell lung carcinoma not only from normal controls but also from patients with non‐tumor lung pathologies. © 2008 Wiley‐Liss, Inc.     

MicroRNAs as lung cancer biomarkers

Lung cancer is the leading cause of cancer mortality worldwide. Its high mortality is due to the poor prognosis of the disease caused by a late disease presentation, tumor heterogeneities within histological subtypes, and the relatively limited understanding of tumor biology. Importantly, lung cancer histological subgroups respond differently to some chemotherapeutic substances and side effects of some therapies appear to vary between subgroups. Biomarkers able to stratify for the subtype of lung cancer, prognosticate the course of disease, or predict the response to treatment are in high demand. In the last decade, microRNAs (miRNAs), measured in resected tumor samples or in fine needle aspirate samples have emerged as biomarkers for tumor diagnosis, prognosis and prediction of response to treatment, due to the ease of their detection and in their extreme specificity. Moreover, miRNAs present in sputum, in plasma, in serum or in whole blood have increasingly been explored in the last five years as less invasive biomarkers for the early detection of cancers. In this review we cover the increasing amounts of data that have accumulated in the last ten years on the use of miRNAs as lung cancer biomarkers.     

血清三种肿瘤标志物检测在肺癌诊断中的应用

目的:探讨血清肿瘤标志物癌胚抗原(CEA)、神经元特异性烯醇化酶(NSE)、鳞癌相关抗原(SCC-Ag)检测对肺癌诊断的临床应用价值。方法:采用电化学发光法检测91例肺癌患者(肺癌组)、42例肺部良性病变患者(良性对照组)和40例健康体检者(正常对照组)血清中的3种肿瘤标志物。结果:肺癌患者血清3种肿瘤标志物水平明显高于良性对照组和正常对照组(P<0.01)。CEA敏感性为47.78%,特异性为90.11%;NSE敏感性为46.41%,特异性为91.01%;SCC-Ag敏感性为45.89%,特异性为94.98%;3项联合检测敏感性高达95.21%,特异性为82.12%。结论:联合检测血清中的CEA、NSE、SCC-Ag可显著提高肺癌诊断的敏感性,对肺癌的早期诊断有重要临床应用价值。