摘要
本文完善了甲基化同位素标记定量技术,并将其应用在人类大肠癌早期诊断、淋巴转移相关蛋白质以及蛋白质翻译后修饰的研究中,以解释早期大肠癌、大肠癌转移中的分子事件,筛选可以作为诊断标准的分子标志物。
论文首次将甲基化同位素标记定量引入凝胶电泳色谱质谱联用(GeLC-MS)技术路线中,并标准化了甲基化标记定量的实验流程,丌发相应甲基化定量软件,实现了高重现性和准确性的相对定量。另外,甲基化辅助的凝胶电泳色谱质谱联用技术,不仅仅可以定量在两样品中蛋白质表达的差异,也可以定量定性它们在降解水平的差异,这对于癌症研究尤为重要。在早期大肠癌的研究中,相对于正常组织,我们发现了501个蛋白质在早期大肠癌组织中表现出了两倍以上差异表达(P<0.05)。在前80个差异表达蛋白质中,20个存在降解水平的差异。通过生物信息学的功能分析,在泛素化-蛋白酶体通路巾起着重要作用的两个糖蛋白质A1AT和CTSD被筛选出来进行后续验证。血清：学水平,组织芯片水平和基因水平的实验验证了A1AT和CTSD在早期大肠癌中的关键作用,并且通过联用这两个指标,96.77%的大肠癌病人可以特异性的被检测出来。
基于质谱的蛋白质组定量技术首次被应用于大肠癌淋巴转移研究中,并全面揭示了转移潜力相关的蛋白质水平上的表达差异。在此基础上利用了生物信息学的手段对差异蛋白质谱数据进行判读,获得用以进一步功能分析的备选分子,并用定量PCR进行验证。癌症中蛋白质翻译后修饰的变化也是促进肿瘤生长、转移的重要分子事件,因此我们还对早期大肠癌和正常大肠组织的蛋白质糖基化和磷酸化后修饰进行了鉴定和比较分析,为大肠癌分子标志物的临床应用奠定了理论基础。
第一部分基于甲基化同位素标记的蛋白质组定量方法研究
在基于质谱的定量蛋白质组学领域,同位素标记色谱质谱联用相对其他技术有着高效、高精度和高序列覆盖度的特点。但是昂贵的同位素标记试剂以及复杂的同位素标记方法限制了这些同位素标记技术在蛋白质定量领域的应用。为了规避这些影响因素,我们引入了一个相对廉价的酯化反应,并对整个实验流程进行优化使其适用于定量研究。我们将标准蛋白质的酶解肽段混合物分别进行甲基化和氘代甲基化标记,按照不同比率混合之后送入色谱分离和质谱鉴定,用以评价甲基化反应在LC-LTQ-Orbitrap路线中的表现。标准肽段的谱图表明,甲基化反应快速完全而且基本没有副产物。观测值和理论定量值在10倍差异之内保持了优良的线性。同一蛋白质各个肽段的定量差异(标准偏差)小于10%,具有良好的重现性。另外在数据处理过程中,我们发现标记位点大于6以及大于3电荷肽段的定量结果与理论结果的差异相对较大。基于这些实验现象,我们总结了一些规则以指导蛋白质定量候选肽段的选择,并将其写入了编写的软件中。良好的线性和实验重复性说明甲基化标记能很好的胜任基于质谱的定量研究。
第二部分蛋白质组学方法研究大肠癌早期诊断生物标志物
大肠癌是世界上致死几率位列第二、中国位列第四的癌症,随着人民生活水平的提高,这个几率还在不断的上升。人的一生中患上大肠癌的几率在6%左右,并且如果在早期发现,90%的大肠癌病患可以手术治愈。不幸的是,大肠癌被诊断出来的时候常常就已经是晚期了。而且现在常用的一些生物标志物例如癌胚抗原(CEA)缺乏必要的灵敏度和特异性：更可靠的生物标志物以及新型诊断手段的发掘是大肠癌诊疗发展的必由之路。
鉴于大肠癌早诊的严峻形势,我们建立并标准化了一套甲基化同位素标记色谱质谱联用的蛋白质组学方法,将其应用于早期大肠癌和正常组织的差异蛋白质组学研究。我们引入了经典的甲基化反应,在这个反应中乙酰氯催化d0或者d3甲醇和肽段的酸性基团反应,生成具有3 Da差异的成对标记位点。我们使用了一维凝胶电泳分离(SDS-PAGE)后接一维色谱分离联用LTQ-Orbitrap的技术用于提高蛋白质的鑒定率。我们选择了13例Ⅰ期大肠癌,24例Ⅱ期大肠癌以及相应的正常组织进行差异谱的验证。在Ⅰ期样本中我们总共鉴定了1003个蛋白质,Ⅱ期样品中鉴定了1086个,其中837个蛋白质被同时鑒定到。另外,相对于正常组织,501个蛋白质在癌组织中表现出了差异表达的趋势。与前人的研究一致,这些蛋白质中的三分之一是众所周知的肿瘤相关因子。有趣的是,许多差异表达蛋白质都是首次在大肠癌中被鉴定到,这或许得益于GeLC-MS路线对于蛋白质鉴定的贡献。和我们的预想一致,在GO功能分析中这些蛋白质中很多都与调亡、钙离子调节以及细胞周期调控相关。我们使用了IPA分析定量数据进行功能分析以构建相互作用的网络,发现糖酵解/糖异生通路和泛素化通路是大肠癌中变化最大的两条通路。另外,通过PROTOMAP分析,我们还发现了一些在后修饰和降解水平上的有差异的蛋白质。
为了规避单一方法带来的假阴性和假阳性,我们选择了在肿瘤发生发展中可能起到重要调控作用的差异表达蛋白质,进行进一步的免疫印迹以及组织芯片分析。首先,对于12个差异表达蛋白质的组织免疫印迹实验验证了我们的GeLCMS实验数据。其次,鉴于AlAT和CTSD两个糖蛋白质在泛素化蛋白酶体通路中的重要作用,我们用免疫印迹方法对14例早期大肠癌病人的肿瘤组织和正常大肠组织中的表达差异进行了评估。在大多数的肿瘤组织中AlAT的表达降低,CTSD的表达升高,更有趣的是在AlAT的肿瘤组织免疫印迹图中我们还观察到了高分子量端的额外条带,这极有可能是AlAT失活后形成的多聚体。我们还采用了372孔的组织芯片去检测AlAT和CTSD这两个蛋白质的原位表达,发现这两个蛋白质分别具有了56.99%和83.97%的特异性。最后,为了能更方便的应用于临床诊断,我们采取了42例早期大肠癌病人的血清以及42例健康志愿者的血清进行免疫学分析。综上,血清和组织水平的实验都验证了我们前期的观察,也进一步说明AlAT和CTSD可以作为可靠的大肠癌早期诊断生物标志物候选分子用于临床研究。
第三部分定量蛋白质组方法筛选大肠癌淋巴转移相关分子标志物
尽管恶性肿瘤治疗已取得很大进展,但许多癌症病人仍由于肿瘤的转移而死亡。有鉴于此,肿瘤的侵润和转移成为了成功治疗肿瘤的最大障碍。淋巴转移是大肠癌转移的主要途径,目前还未见基于质谱的蛋白质组学应用于大肠癌淋巴转移相关分子标志物筛选的报道。本论文采用甲基化同位素标记辅助两维色谱质谱联用的技术路线,分析淋巴转移大肠癌和未转移早期大肠癌组织样品的蛋白质水平表达差异。共鉴定到了651种非冗余的差异表达蛋白质,取0.95的差异表达置信度进行分析我们总共筛选出了65个蛋白质作为候选的生物标志物。因为癌细胞与淋巴管内皮细胞的相互作用是淋巴转移的前提,通过GO功能分析,LGALS3BP, SAFB, CAV1, HIN1, S100A4, EIF3F, ERH, TPM1这几个与粘附、侵袭、运动相关的蛋白质因子被挑选出来进行其他水平的验证。考虑到测试的假阳性,我们另取了16例淋巴转移大肠癌和16例非淋巴转移的大肠癌组织进行免疫印迹和基因水平的定量PCR实验。在淋巴转移前后的蛋白质组学研究中发现并验证了与淋巴转移有关的差异表达蛋白质,印证了大肠癌淋巴转移的分子机制。
第四部分高通量大肠癌蛋白质组后修饰的研究
本部分主要研究了早期大肠癌和正常大肠组织中的磷酸化和糖基化后修饰差异。蛋白质的翻译后修饰如磷酸化、糖基化和泛素化等,能够调节细胞的增殖、发育和分化、细胞骨架调控、细胞凋亡、神经活动、肌肉收缩、新陈代谢,肿瘤发生等多种生命活动过程。当细胞中的翻译后修饰状念发生变化时,可能引起-系列的疾病,因此鉴定后修饰的位点、定量不同生理病理状态下的相对量的变化对于更好的理解生物体内的疾病发生发展机制是十分必要的。定量蛋白质组学的技术原则上都能适用于翻译后修饰肽段的分析,但是翻译后修饰的含量都比较低,需要经过预富集才能方便的应用与质谱检测。本部分的主要内容是检测大肠癌发生发展中磷酸化水平的变化,大肠癌组织和正常组织的酶解肽段在经过甲基化同位素标记之后,采用固相金属离子亲和色谱(IMAC)和二氧化钛填料富集磷酸化的肽段。甲基化标记反应封闭了肽段中原有的酸性位点从而能富集过程的效率,在前期的试验中磷酸化富集的特异性达到了98.28%。另外我们还发现,IMAC相对二氧化肽有着更好的富集特异性,而基于二氧化钛的富集有更高的回收率。此外,新型的纳米核壳材料被合成出来用于大肠癌组织样品的糖基化后修饰富集,鉴定到了属于155个糖蛋白质的194个糖肽。大肠癌中后修饰形式的改变可以作为大肠癌发生、发展以及疗效评价的表征手段。
第五部分中国人健康肝脏蛋白质表达谱的免疫学定量研究
人肝蛋白质组计划是人类蛋白质组组织(HUPO)发起的首个关于人类特定器官的蛋白质组研究项目,旨在建立中国人健康肝脏的表达潜,获得与人类肝脏蛋白质表达、分类、功能网络相关的最全面的信息。规模化高通量蛋白质组的定量分析一直是科技界的难题,人肝蛋白质组计划采用了优化肽段计数的质潜半定量方法,通过三种分离鉴定技术路线,鉴定到了分布在6个浓度数量级上的6788个95%置信度的非冗余蛋白质。为了验证以上技术路线中质谱定量的准确性,我们在丰度从低到高的6个数量级上各选择了一定数量的蛋白质进行免疫分析。在抗原抗体选择时我们首先将已有的蛋白质蛋白质列表和商用抗体列表进行比对,剔除极端分子量(>150 kD和<30 kD)的抗原,订购成对的抗原抗体。在酶联免疫分析(ELISA)和免疫印迹(WB)试验中,抗原(标准蛋白质)和肝脏蛋白质提取液各自取一个相应的浓度梯度上样,并不断的重复实验直到所有肝脏蛋白质样品的灰度都落在标准蛋白质的浓度梯度之间,与此同时通过作标准曲线获得肝脏中该蛋白质的绝对含量。对于少数缺失免疫学数据的浓度数量级,采用标准加入法的色谱分析,用紫外吸收的强度来评估肝脏样品中该蛋白质的含量。除了2个偏差较大的数据,免疫学方法得到的蛋白质绝对含量在总体上验证了肽段计数的质谱半定量数据,为中国人健康肝脏组织蛋白质数据库的建立提供了重要依据。
第六部分增加电荷数提高电子转移解离碎裂效率在定量蛋白质组中的应用研究
用于肽段测序的串级质谱是蛋白质组大规模鉴定中的核心技术。碰撞诱导解离(CID)作为最常用的肽段碎裂质谱技术主要适用于双电荷的中短肽段分析,但是由于CID的能量较高,常常会在碰撞过程中丢失肽段后修饰的信息。相对于CID,2004年发展的新型电子转移解离(ETD)技术更为温和,适于分析多电荷的长肽段,并能够保持肽段上的后修饰信息。受限制于能量传递的效率,ETD对双电荷离子的碎裂效率和产生离子碎片的序列覆盖度较为有限。由于70%以上胰蛋白酶酶解肽段在电喷雾中都为2电荷,致使ETD在常规的蛋白质组学分析中碎裂效率不高。目前,研究者主要通过提高肽段的电荷数来增强ETD的碎裂效率。这些方法包括：1.提高鞘气的温度；2.增加色谱流动相的表面张力；3.采用AspN、LysC等能产生大肽段的酶；4.对肽段进行化学修饰使其更适于带上高电荷。为了对比这些方法在提高ETD鉴定效率方面的效能,我们分别采用了能产生大肽段的LysC酶,对trypsin酶解肽段进行胍基化和双甲基修饰以及在色谱流动相中添加高表面张力低挥发性的间硝基甲苯(m-NBA)的方法,去评估SILAC标记的amj2细胞株在LC-ETDMS试验中的鉴定效率。本论文首次将mNBA和双甲基化胍基化反应运用到复杂生物样品的分析测试中,并在所有LC-ETD试验中都观察到了增强电荷数的作用,给基于ETDMS的生物样品定量分析带来了便利。
We developed and improved the methylation isotope labeling methods in quantitative proteome, and applied it in colorectal cancer (CRC) early diagnosis, lymphatic metastasis and protein post-translational modification research. The aim of our study is to interpret molecules events in the early stage of CRC and metastasis in CRC that may bring about new biomarkers for early diagnosis.
For the first time, we combined methylation isotope labeling with methylation isotope labeling assisted gel enhanced liquid chromatography mass spectrometry (GeLC-MS) methods in quantitative proteome analysis, established standard methylation quantification pipeline and developed in house methylation quantification software that achieved high reproductive and precise relative methylation quantification. Furthermore, by introducing GeLC-MS strategy, we can not only quantify the protein expression difference between two samples, but also qualify and quantify their difference in degradation level which is rather important in cancer research. In our research, altogether 501 differentially expressed proteins between early stage CRC and normal tissues were discovered (P<0.05). In the most regulated 80 proteins, we found degradation in 20 of them. By functional annotation analysis, two glycoproteins, Al AT and CTSD which are playing important role in ubiquitination proteasome pathway were chosen as candidate biomarkers. On serum level, we confirmed the key role AlAT and CTSD playing in early CRC by tissue microarray and genetic experiments. By combed applying the two biomarkers,96.77%CRC patients were specifically detected.
Quantitative proteomics based on Mass Spectrometry was introduced to CRC lymphatic metastasis research for the first time, and revealed the different expression level of metastatic potential related proteins. By using bioinformatics tools, we interpreted the differential proteome data to get candidate biomarkers for future functional analysis and validated them by Q-PCR. Change in protein post-translational modification in cancer is also an important molecule event in promoting tumor growth and cancer metastasis. We identified and compared the differential expressed glycosylated and phosphorylated proteins in normal and early CRC tissue, and thus established theory foundation for future CRC biomarker in clinical application.
Part 1. Quantification Proteomics Research Based on Methylation Isotopic Labeling
In the field of mass spectrometry based proteome quantification, isotopic labeling has an advantage over other quantification methods for its high efficiency, high accuracy and high sequence coverage, but expansive isotope labeling reagents and complex isotope labeling methods restrict their application in quantification proteomics. To eliminate such constraint, we introduced a relatively cheap esterification reaction to isotopic labeling and optimized its performance in proteome quantification research. We d0-or d3-methylated the tryptic peptides of standard proteins, mixed them by different ratios, separated by LC and identified by mass spectrometry in order to evaluate the application of methylation reaction in LC-LTQ-Orbitrap pipeline. The spectrum of standard peptides showed that the methylation reaction was fast and completed without any detectable byproducts. High coefficient of determination under ratio 10 indicates good fidelity between theoretical and observed heavy/light ratio. Taking spectrum complexity and labeling efficiency into account, peptides with more than 6 reaction sites or charge state≥4+(5%of total spectrums) were not used. Based on above, we summarized a set of standards for selecting the candidate peptide for quantification by our quantification software. Good linearity and reproducibility indicate well qualified methylation labeling for quantification study.
Part 2. Clinical diagnosis biomarker for Early Stage of CRC by Proteomics Method
CRC is the second highest probability of cancer death in the world and the forth in China while the probability keeps increasing with the improvement of people's life. In human life, chance of suffering from CRC is about 6%, and if diagnosed at early stage, 90%of the patients can be cured by surgery. Unfortunately, most CRC are diagnosed at advanced stage. Common biomarkers, such as carcinoembryonic antigen (CEA) lack enough sensitivity and specificity. Exploring more reliable biomarkers and new diagnostic tools is the only way for the development of CRC treatment.
Given the grim situation CRC early diagnosis, we established and standardized proteomics techniques can be applied to post-translational modification peptide analysis, but the content of the PTM proteins are relatively low which requires the enrichment step before MS detection. The enzymatic peptides were methylation isotopic labeled before using immobilized metal ion affinity chromatography (IMAC) and titanium dioxide to enrich the phosphorylated peptides. Methylation labeling reaction enclosed the acide sites of the peptides that can increase the efficiency of the enrichment, and the specificity of the phosphorylation enrichment went up to 83.33%. In addition, we also found that, IMAC had better enrichment specificity than titanium dioxide while the latter could enrich more phosphorylated peptides. Further, the new core-shell nano-material was introduced to the glycolpeptide enrichment which identified 194 glycopeptide of 155 glycoproteins. The PTM change of CRC cancer can evaluate the development and treatment of the cancer.
Part 5. Profiling Protein Expression in Chinese Healthy Liver by Quantitative Immunology Research
Human Liver Proteome Project (HLPP) is initiated by the Human Proteome Organization (HUPO) which is the first human organ-specific proteome research project aiming at establishing expression profile of Chinese healthy liver in order to obtain human liver protein expression, classification, network-related functions. The most comprehensive obstacle in science community is the large-scale high-throughput quantitative analysis of proteins, and HLPP used optimized peptide mass spectra counting method for MS semi-quantitation, and by three isolation and identification techniques,6788 non-redundant proteins were identified 7 orders of abundance magnitude on 95%confidence level. To demonstrate the accuracy of our quantitative mass spectrometry method, we did protein immunoassay on selected proteins from every abundance magnitude. For the choice of the antigen-antibodies, we first compared a list of commercial antibodies with our selected proteins and deleted antigens with extreme molecular weight (> 150Da and<20Da), and bought paried antigen-antibody. In the enzyme-linked immunoassay (ELISA) and immunoblotting (WB) test, the antigen (standard protein) and liver protein extracts each were taken a corresponding concentration gradient, and repeated until the intensity of liver protein fell between the standard protein concentration gradient, while the absolute amount of the protein was obtained by making standard curve. Meanwhile, for a small number of concentration magnitude which lacked immunology data, we used additional standard chromatographic analysis which the content of the protein in the liver samples was assessed by the intensity of the UV absorption. Despite of two set of large-deviation data, absolute amount of proteins obtained by immunological methods, in general, validated peptide mass spectra of semi-quantitative count data, and provided important reference to the protein database of Chinese healthy liver.
Part 6. Application of Increasing the Number of Charge State to Improve the Efficiency of Electron Transfer Dissociation in Protein Quantitative Proteomics Research
Tandem Mass Spectrometry for peptide sequencing is the core technology in large-scale identification of proteins. Collision induced dissociation (CID) is the most commonly used technology for peptide fragmentation mass spectrometry which mainly used in the identification of double charged short peptides. However, due to high energy transfer, the peptide PTM information is often lost in the collision. Relative to CID, in 2004 year, the new electron transfer dissociation (ETD) technology is a gentler and more suitable technology for identifying multi-charged long peptides and keeps peptides PTM information. Restricted to energy transfer efficiency, production of doubly charged ion fragments and the sequence coverage is limited. Since over 70%of trypsin digestion peptides are doubly charged in ESI, the efficiency of ETD fragmentation is quite low. Currently, the researchers mainly increase the efficiency of ETD fragmentation by raising the charge state of peptides including 1. Increase the temperature of sheath gas; 2.increase the surface tension of water mobile phase; 3. Digest with AspN, LysC to produce large peptides; 4. Chemically modify the peptide to make it more suitable to carry more charges. To compare these methods in improving the efficiency of the performance of ETD identification, we used to LysC to produce larger peptides, guanidylation of the tryptic peptides with dual-methylation modification and adding low-volatile-nitrotoluene (m-NBA) which has high surface tension to the mobile phase of chromatography to assess the identification of SILAC labeled AMJ2 cell line in LC-ETD-MS experiment. This thesis for the first time applied mNBA. dual-methylation and guanidine reaction to the analysis of complex biological samples, and observed increased charge state in all ETD-MS based quantitative analysis which facilitated the quantification analysis based on ETD-MS.
引文
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