肝细胞癌N-糖链的结构改变及其机制研究
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摘要
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一，其病情进展快、预后差，因早期诊断困难、治疗手段有限而死亡率高。因此，研究其发生发展的分子基础，寻找HCC早期诊断生物标志物和潜在治疗靶点，对HCC的诊断和治疗具有重要意义。
糖蛋白糖链参与细胞识别、信号传导、免疫监视，维持着多细胞生物体各项有序性生命活动。糖链的异常改变通常与多种疾病包括肿瘤的发生发展密切相关。对恶性肿瘤特异性糖链结构与功能的研究不仅可以揭示糖链的生物学功能，还能为肿瘤生物标志物的筛选和新药靶点的开发奠定基础。DSA-FACE技术是本世纪初新兴的糖生物学检测技术，因其高通量、高灵敏度的特点，目前已在肿瘤血清生物标志物研究中得到足够认识，但利用该技术对非血清样本的研究则少有报道。
本文从糖生物学角度、利用DSA-FACE技术对HCC特异性N-糖链结构及其发生异常改变的分子机理进行研究，以期为HCC的早期诊断、恶性演进和转移预测提供生物标志物，为HCC靶向治疗靶点选择及基于糖链结构改变的恶性转化机制研究奠定基础。在研究中，首先优化了血清糖蛋白N-糖组DSA-FACE检测技术，有效提高了其检测效率。在此基础上，建立了可用于体外培养细胞系及临床组织样本细胞表面N-糖组分析技术，通过分析膜蛋白不同制备方法（去污剂法和超速离心法），并引入石墨化炭黑（GC）树脂纯化技术、优化研究体系，使得该技术对于细胞表面N-糖组的检测更加灵敏、可靠，并具有良好的可重复性，从而拓展了DSA-FACE技术的应用范围，突破了以往只用于检测血清样本N-糖组的局限性。
在优化N-糖链检测技术的基础上，本文分析了北方地区190例HCC患者血清样本，以110例乙肝病毒感染者及179例健康人血清样本作为对照。结果发现，由血清中三个发生异常变化的N-糖链NGA2F、NGA2FB和NA3联合获得的Log[(NGA2F+NGA2FB)/NA3]指标对于HCC的诊断准确性可达85%，诊断灵敏度和特异性分别可达到71.1%和86.0%，且该指标的诊断准确性不受患者性别、年龄、肿瘤病理分期、癌细胞分化程度等因素影响。深入分析本研究中40例AFP处于正常值范围（AFP <20ng/mL）的HCC患者血清，结果显示有23例血清中Log[(NGA2F+NGA2FB)/NA3]指标明显高于阈值（0.1045），证明该指标可有效降低AFP对于HCC的漏诊率。进一步利用Logistic回归分析法建立基于血清特异性糖链（NGA2F、NGA2FB、NA3）与AFP的联合诊断模型，ROC曲线分析表明，联合诊断模型对于HCC的诊断准确性可达到94.8%。该结果证实，以血清N-糖链生物标志物为基础的联合诊断模型可作为我国北方地区HCC特异性的普查生物标志物。
利用本文建立的细胞表面N-糖组DSA-FACE技术完成88对临床HCC组织样本细胞表面N-糖组分析。结果表明，与癌旁对照组相比，峰L10（NA3FB）在HCC细胞表面显著性增加（p<0.0001），而峰L6（M8）在HCC细胞表面显著性降低（p<0.0001）。这两个N-糖链在不同性别、年龄及癌细胞分化程度的患者中均表现出显著性改变，并于HCC发病早期就具有明显改变的趋势。此外，通过与具有不同组织来源及性别差异的100对乳腺癌组织细胞表面N-糖组的比较，NA3FB在两种不同的肿瘤细胞表面均具有显著性增高趋势，而NA2和M8的差异表达则具有明显的组织特异性。进一步通过分析61例HCC患者的临床组织样本及相应的血清样本N-糖组，发现，NA3FB不仅在HCC细胞表面显著性增高（p<0.0001），而且在相应患者血清中的含量也显著增高（p<0.0001）。这表明， HCC驻留型及分泌型糖蛋白NA3FB糖链修饰异常增多可能与HCC的发病机制具有相关性。
为探讨NA3FB显著增加的分子机理，本文对能够合成NA3FB的五种糖基转移酶（Fut8、GalT-1、GnT-V、GnT-IVa、GnT-IVb）在HCC临床组织中的表达进行了分析。结果表明，与相应癌旁组织相比，肿瘤组织中只有GnT-IVamRNA及蛋白的表达水平具有增高趋势。利用RNAi技术减低mgat4a表达48h后，检测HCC细胞系HepG2细胞表面NA3FB的表达水平。结果表明，与阴性对照相比，基因沉默组细胞表面NA3FB显著减少。这说明NA3FB的减少与糖基转移酶GnT-IVa的基因沉默直接相关。因此，该结果证实HCC细胞中GnT-IVa的异常高表达与细胞表面及血清中NA3FB异常增加密切相关。
综上所述，本文通过分析膜蛋白制备方法及引入GC树脂纯化方法，建立了适合于不同临床样本N-糖链的DSA-FACE检测技术，获得了适用于中国北方地区HCC早期诊断的血清糖链生物标志物，发现了HCC细胞表面异常增加的糖链NA3FB与GnT-IVa的异常高表达密切相关。由此，这种糖基化异常机理的初步分析为深入研究糖基转移酶与糖链结构异常、与HCC发生发展的关系提供了新的思路，对HCC早期诊断和潜在靶向治疗的靶点选择奠定了基础。
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand has a high mortality rate due to the difficulty of early diagnosis and limitedtherapeutic methods. Therefore, it becomes critical to reveal the underlyingmolecular mechanisms of HCC development and to look for early diagnosticbiomarkers and treatment targets for HCC.
The glycans of glycoproteins play pivotal roles in cell recognition, signaltransduction, immune surveillance and maintenance of ordered life activities ofmutilcellular organisms. Glycan alternations are closely associated with theinitiation and progression of many diseases including cancer. Research onstructures and functions of tumor-specific glycans will not only reveal thebiofunctions of glycans, but also enable the identification of new cancer biomarkersand drug targets. DSA-FACE (DNA sequencer-assisted fluorophore-assistedcarbohydrate electrophoresis) is an emerging glycobiological technique in thiscentury and has been widely used in the research of serum biomarkers for cancer.However, the application of this technique in non-serum specimens has rarely beenreported.
This thesis studied the structure of HCC-specific N-glycans and associatedmolecular mechanisms using DSA-FACE technique. First of all, DSA-FACEtechnique used to detect N-glycans in serum was optimized and the detectivequantum efficiency has been remarkably promoted. Based on this, a DSA-FACEtechnique that can detect N-glycans in the in-vitro cultured cell lines and humanclinical tissues was developed. Compared to the conventional DSA-FACE, thisnewly developed technique has much higher stability, sensitivity and repeatability,which has been achieved by optimizing membrane protein extraction methods andintroducing GC resin purification procedure. This technique expands theapplication field of DSA-FACE and eliminates the limitation of conventionalDSA-FACE technique that only can be used for the glycan detection in serumsamples.
Using the optimized serum DSA-FACE technique,190serum samples of HCCpatients were detected along with179serum samples of healthy humans and110serum samples of HBV-infected patients as controls. The results indicated thatLog[(NGA2F+NGA2FB)/NA3] which composed of3abnormal N-glycans, NGA2F,NGA2FB and NA3, in HCC patients are potential early diagnostic serumbiomarkers for HCC. The diagnostic efficiency of this biomarker is as high as85%with71.1%sensitivity and86.0%specificity. The diagnostic efficiency of this biomarker is independent of sex, age, tumor stage and differentiation degree ofHCC patients. Furthermore, the serum samples from23out of40HCC patientswhose AFP values are within normal range (AFP <20ng/ml) showed distinctlyhigher Log[(NGA2F+NGA2FB)/NA3] value above the threshod (0.1045), whichindicated that Log[(NGA2F+NGA2FB)/NA3] can effectively reduce the falsenegative rate of AFP detection. Thus, a HCC-specific glycans (NGA2F, NGA2FBand NA3)-AFP combined diagnosis model was further established using Logisticregression. The diagnostic efficiency of the combined diagnosis model for HCCreached94.8%as shown in ROC curve. This result supports the idea that the serumN-glycan biomarker-based combined diagnosis model can serve as a HCC-specificscreening biomarker in the north of P. R. China.
Then, the cell surface N-glycan profiles of88pairs of HCC clinical tissues wereexamined by the newly established DSA-FACE technique which was suit for celllines and clinical tissues. The results indicated that the N-glycan peak L10(corresponding to NA3FB) was significantly increased (p<0.0001) on the cellsurface of HCC tissues compared to the paired adjacent normal tissues, while peakL6was significantly decreased (p<0.0001) on the cell surface of HCC tissues. Sametrend of alternations on both N-glycans were observed in all sex, age and celldifferentiation degree groups. In fact, these alterations have been found to presentat early stage of HCC. In addition, by comparison with the N-glycan profiles of100pairs breast cancer tissues we found that NA3FB was significant increased on thecell surface in a tissue and sex independent manner, while NA2and M8showeddistinct tissue specificity. The further comparative analysis of the clinical tissuesand corresponding serum samples in61HCC patients showed that NA3FB was notonly increased on the cell surface of HCC cells (p<0.0001), but also increased inthe corresponding serum samples (p<0.0001). This indicated that the abnormalincreased resident and excreted NA3FB glycoprotein was likely related to thetumorogenesis mechanisms of HCC.
In order to investigate the molecular mechanisms of the significant enhancedNA3FB, both resident and excreted glycoproteins, in HCC patients, the expressionlevel of5glycosyltransferases (Fut8, GalT-1, GnT-V, GnT-IVa, GnT-IVb) whichcan produce NA3FB in HCC were analyzed. The results indicated that onlyGnT-Iva on both mRNA and protein levels were significantly increased in HCCtissues compared with paired adjacent tissues. The cell surface NA3FB in HepG2cells was detected48hours later after mgat4a (the gene of GnT-IVa) knockdown byusing RNAi technique. NA3FB was significantly decreased in response to mgat4aknockdown, suggesting that the decrease of NA3FB was related to the gene silence of GnT-IVa. Therefore, the enhanced GnT-IVa in HCC was closely related to theincreased levels of NA3FB both on HCC cell surface and in serum.
To sum up, this study successfully established a N-glycan DSA-FACE techniquewhich was suit for the analysis of different clinical tissue specimens. The obtainedN-glycan serum biomarker can be used for the early diagnosis of HCC in the northarea of China. HCC-cell-surface-specific biomarker NA3FB was closely associatedwith the increased GnT-Iva in HCC. Therefore, the preliminary study on this alertedglycosylation mechanisms in HCC provides a new path for further research on therelationship of glycosyltransferases and glycan structure with the carcinogenesisand malignant progression of HCC. It also advanced the study on the earlydiagnosis and targeting therapy of HCC.
糖蛋白糖链参与细胞识别、信号传导、免疫监视，维持着多细胞生物体各项有序性生命活动。糖链的异常改变通常与多种疾病包括肿瘤的发生发展密切相关。对恶性肿瘤特异性糖链结构与功能的研究不仅可以揭示糖链的生物学功能，还能为肿瘤生物标志物的筛选和新药靶点的开发奠定基础。DSA-FACE技术是本世纪初新兴的糖生物学检测技术，因其高通量、高灵敏度的特点，目前已在肿瘤血清生物标志物研究中得到足够认识，但利用该技术对非血清样本的研究则少有报道。
本文从糖生物学角度、利用DSA-FACE技术对HCC特异性N-糖链结构及其发生异常改变的分子机理进行研究，以期为HCC的早期诊断、恶性演进和转移预测提供生物标志物，为HCC靶向治疗靶点选择及基于糖链结构改变的恶性转化机制研究奠定基础。在研究中，首先优化了血清糖蛋白N-糖组DSA-FACE检测技术，有效提高了其检测效率。在此基础上，建立了可用于体外培养细胞系及临床组织样本细胞表面N-糖组分析技术，通过分析膜蛋白不同制备方法（去污剂法和超速离心法），并引入石墨化炭黑（GC）树脂纯化技术、优化研究体系，使得该技术对于细胞表面N-糖组的检测更加灵敏、可靠，并具有良好的可重复性，从而拓展了DSA-FACE技术的应用范围，突破了以往只用于检测血清样本N-糖组的局限性。
在优化N-糖链检测技术的基础上，本文分析了北方地区190例HCC患者血清样本，以110例乙肝病毒感染者及179例健康人血清样本作为对照。结果发现，由血清中三个发生异常变化的N-糖链NGA2F、NGA2FB和NA3联合获得的Log[(NGA2F+NGA2FB)/NA3]指标对于HCC的诊断准确性可达85%，诊断灵敏度和特异性分别可达到71.1%和86.0%，且该指标的诊断准确性不受患者性别、年龄、肿瘤病理分期、癌细胞分化程度等因素影响。深入分析本研究中40例AFP处于正常值范围（AFP <20ng/mL）的HCC患者血清，结果显示有23例血清中Log[(NGA2F+NGA2FB)/NA3]指标明显高于阈值（0.1045），证明该指标可有效降低AFP对于HCC的漏诊率。进一步利用Logistic回归分析法建立基于血清特异性糖链（NGA2F、NGA2FB、NA3）与AFP的联合诊断模型，ROC曲线分析表明，联合诊断模型对于HCC的诊断准确性可达到94.8%。该结果证实，以血清N-糖链生物标志物为基础的联合诊断模型可作为我国北方地区HCC特异性的普查生物标志物。
利用本文建立的细胞表面N-糖组DSA-FACE技术完成88对临床HCC组织样本细胞表面N-糖组分析。结果表明，与癌旁对照组相比，峰L10（NA3FB）在HCC细胞表面显著性增加（p<0.0001），而峰L6（M8）在HCC细胞表面显著性降低（p<0.0001）。这两个N-糖链在不同性别、年龄及癌细胞分化程度的患者中均表现出显著性改变，并于HCC发病早期就具有明显改变的趋势。此外，通过与具有不同组织来源及性别差异的100对乳腺癌组织细胞表面N-糖组的比较，NA3FB在两种不同的肿瘤细胞表面均具有显著性增高趋势，而NA2和M8的差异表达则具有明显的组织特异性。进一步通过分析61例HCC患者的临床组织样本及相应的血清样本N-糖组，发现，NA3FB不仅在HCC细胞表面显著性增高（p<0.0001），而且在相应患者血清中的含量也显著增高（p<0.0001）。这表明， HCC驻留型及分泌型糖蛋白NA3FB糖链修饰异常增多可能与HCC的发病机制具有相关性。
为探讨NA3FB显著增加的分子机理，本文对能够合成NA3FB的五种糖基转移酶（Fut8、GalT-1、GnT-V、GnT-IVa、GnT-IVb）在HCC临床组织中的表达进行了分析。结果表明，与相应癌旁组织相比，肿瘤组织中只有GnT-IVamRNA及蛋白的表达水平具有增高趋势。利用RNAi技术减低mgat4a表达48h后，检测HCC细胞系HepG2细胞表面NA3FB的表达水平。结果表明，与阴性对照相比，基因沉默组细胞表面NA3FB显著减少。这说明NA3FB的减少与糖基转移酶GnT-IVa的基因沉默直接相关。因此，该结果证实HCC细胞中GnT-IVa的异常高表达与细胞表面及血清中NA3FB异常增加密切相关。
综上所述，本文通过分析膜蛋白制备方法及引入GC树脂纯化方法，建立了适合于不同临床样本N-糖链的DSA-FACE检测技术，获得了适用于中国北方地区HCC早期诊断的血清糖链生物标志物，发现了HCC细胞表面异常增加的糖链NA3FB与GnT-IVa的异常高表达密切相关。由此，这种糖基化异常机理的初步分析为深入研究糖基转移酶与糖链结构异常、与HCC发生发展的关系提供了新的思路，对HCC早期诊断和潜在靶向治疗的靶点选择奠定了基础。
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand has a high mortality rate due to the difficulty of early diagnosis and limitedtherapeutic methods. Therefore, it becomes critical to reveal the underlyingmolecular mechanisms of HCC development and to look for early diagnosticbiomarkers and treatment targets for HCC.
The glycans of glycoproteins play pivotal roles in cell recognition, signaltransduction, immune surveillance and maintenance of ordered life activities ofmutilcellular organisms. Glycan alternations are closely associated with theinitiation and progression of many diseases including cancer. Research onstructures and functions of tumor-specific glycans will not only reveal thebiofunctions of glycans, but also enable the identification of new cancer biomarkersand drug targets. DSA-FACE (DNA sequencer-assisted fluorophore-assistedcarbohydrate electrophoresis) is an emerging glycobiological technique in thiscentury and has been widely used in the research of serum biomarkers for cancer.However, the application of this technique in non-serum specimens has rarely beenreported.
This thesis studied the structure of HCC-specific N-glycans and associatedmolecular mechanisms using DSA-FACE technique. First of all, DSA-FACEtechnique used to detect N-glycans in serum was optimized and the detectivequantum efficiency has been remarkably promoted. Based on this, a DSA-FACEtechnique that can detect N-glycans in the in-vitro cultured cell lines and humanclinical tissues was developed. Compared to the conventional DSA-FACE, thisnewly developed technique has much higher stability, sensitivity and repeatability,which has been achieved by optimizing membrane protein extraction methods andintroducing GC resin purification procedure. This technique expands theapplication field of DSA-FACE and eliminates the limitation of conventionalDSA-FACE technique that only can be used for the glycan detection in serumsamples.
Using the optimized serum DSA-FACE technique,190serum samples of HCCpatients were detected along with179serum samples of healthy humans and110serum samples of HBV-infected patients as controls. The results indicated thatLog[(NGA2F+NGA2FB)/NA3] which composed of3abnormal N-glycans, NGA2F,NGA2FB and NA3, in HCC patients are potential early diagnostic serumbiomarkers for HCC. The diagnostic efficiency of this biomarker is as high as85%with71.1%sensitivity and86.0%specificity. The diagnostic efficiency of this biomarker is independent of sex, age, tumor stage and differentiation degree ofHCC patients. Furthermore, the serum samples from23out of40HCC patientswhose AFP values are within normal range (AFP <20ng/ml) showed distinctlyhigher Log[(NGA2F+NGA2FB)/NA3] value above the threshod (0.1045), whichindicated that Log[(NGA2F+NGA2FB)/NA3] can effectively reduce the falsenegative rate of AFP detection. Thus, a HCC-specific glycans (NGA2F, NGA2FBand NA3)-AFP combined diagnosis model was further established using Logisticregression. The diagnostic efficiency of the combined diagnosis model for HCCreached94.8%as shown in ROC curve. This result supports the idea that the serumN-glycan biomarker-based combined diagnosis model can serve as a HCC-specificscreening biomarker in the north of P. R. China.
Then, the cell surface N-glycan profiles of88pairs of HCC clinical tissues wereexamined by the newly established DSA-FACE technique which was suit for celllines and clinical tissues. The results indicated that the N-glycan peak L10(corresponding to NA3FB) was significantly increased (p<0.0001) on the cellsurface of HCC tissues compared to the paired adjacent normal tissues, while peakL6was significantly decreased (p<0.0001) on the cell surface of HCC tissues. Sametrend of alternations on both N-glycans were observed in all sex, age and celldifferentiation degree groups. In fact, these alterations have been found to presentat early stage of HCC. In addition, by comparison with the N-glycan profiles of100pairs breast cancer tissues we found that NA3FB was significant increased on thecell surface in a tissue and sex independent manner, while NA2and M8showeddistinct tissue specificity. The further comparative analysis of the clinical tissuesand corresponding serum samples in61HCC patients showed that NA3FB was notonly increased on the cell surface of HCC cells (p<0.0001), but also increased inthe corresponding serum samples (p<0.0001). This indicated that the abnormalincreased resident and excreted NA3FB glycoprotein was likely related to thetumorogenesis mechanisms of HCC.
In order to investigate the molecular mechanisms of the significant enhancedNA3FB, both resident and excreted glycoproteins, in HCC patients, the expressionlevel of5glycosyltransferases (Fut8, GalT-1, GnT-V, GnT-IVa, GnT-IVb) whichcan produce NA3FB in HCC were analyzed. The results indicated that onlyGnT-Iva on both mRNA and protein levels were significantly increased in HCCtissues compared with paired adjacent tissues. The cell surface NA3FB in HepG2cells was detected48hours later after mgat4a (the gene of GnT-IVa) knockdown byusing RNAi technique. NA3FB was significantly decreased in response to mgat4aknockdown, suggesting that the decrease of NA3FB was related to the gene silence of GnT-IVa. Therefore, the enhanced GnT-IVa in HCC was closely related to theincreased levels of NA3FB both on HCC cell surface and in serum.
To sum up, this study successfully established a N-glycan DSA-FACE techniquewhich was suit for the analysis of different clinical tissue specimens. The obtainedN-glycan serum biomarker can be used for the early diagnosis of HCC in the northarea of China. HCC-cell-surface-specific biomarker NA3FB was closely associatedwith the increased GnT-Iva in HCC. Therefore, the preliminary study on this alertedglycosylation mechanisms in HCC provides a new path for further research on therelationship of glycosyltransferases and glycan structure with the carcinogenesisand malignant progression of HCC. It also advanced the study on the earlydiagnosis and targeting therapy of HCC.
引文
[1] El-Serag H B, Rudolph K L. Hepatocellular carcinoma: epidemiology andmolecular carcinogenesis[J]. Gastroenterology,2007,132(7):2557-2576.
[2] Tang Z Y, Yu Y Q, Zhou X D, et al. Subclinical hepatocellular carcinoma: ananalysis of391patients[J]. Journal of surgical oncology,1993,3:55-58.
[3]王维林，白屠红.肝癌血清标志物研究的新进展[J].肿瘤，2009，4(29)：389-393.
[4] Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to earlyand late phase intrahepatic recurrence of hepatocellular carcinoma afterhepatectomy[J]. Journal of hepatology，2003，38(2)：200-207.
[5] Nagasue N, Ono T, Yamanoi A, et al. Prognostic factors and survival afterhepatic resection for hepatocellular carcinoma without cirrhosis[J]. Brit J Surg,2001,88(4):515-522.
[6]陈明慧，李雪川，唐伟等.脱-γ-羧基凝血酶原与原发性肝癌[J].生命的化学，2008，1(28)：69-71.
[7] Nanashima A O K, Tobinaga S, et al. Comparative strdy of survival of patientswith hepatocellular carcinoma predicted by different staging systems usingmultivariate analysis[J]. Eur J Surg Oncol,2005,31(8)：882-890.
[8]袁联文，唐伟，李永国等.脱-γ-羧基凝血酶原：一种有用的血清肝癌标志物[J].中华普通外科杂志，2004，19(8)：506-506.
[9] Nakatsura T Y Y, Senju S, et al. Glypican-3, overexpressed specifically inhuman hepatocellular carcinoma, is a novel tumormarker[J]. BiochemBiophys Res Commun,2003,306(1):16-25.
[10] Capurro M, Wanless I R, Sherman M, et al. Glypican-3: a novel serum andhistochemical marker for hepatocellular carcinoma[J]. Gastroenterology,2003,125(1):89-97.
[11] Marrero JA R P, Nikolaevao, et al. GP73, a residerGolgi glycoprotein, is anovel serum marker for hepatocellular carcimon[J]. Journal of hepatology,2005,43(6):1007-1012.
[12]曹晶.肝癌细胞分泌蛋白和糖蛋白的蛋白质组学研究[D].上海：复旦大学博士学位论文，2009：45-48..
[13] Hamilton S R. Targeted therapy of cancer: new roles for pathologists incolorectal cancer[J]. Mod Pathol,2008,21Suppl2: S23-30.
[14]刘宝瑞，钱晓萍.原发性肝癌分子靶向治疗研究进展[J].世界华人消化杂志，2009，17(10)：993-997.
[15] Daveau M, Scotte M, Francois A, et al. Hepatocyte growth factor,transforming growth factor alpha, and their receptors as combined markers ofprognosis in hepatocellular carcinoma[J]. Mol Carcinogen,2003,36(3):130-141.
[16] Tommasi S, Pinto R, Pilato B, et al. Molecular pathways and related targettherapies in liver carcinoma[J]. Current pharmaceutical design,2007,13(32):3279-3287.
[17] Gollob J A, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer:therapeutic potential of targeting the Raf/MEK/ERK signal transductionpathway[J]. Seminars in oncology,2006,33(4):392-406.
[18] Yang Z F, Poon R T. Vascular changes in hepatocellular carcinoma[J]. AnatRec (Hoboken),2008,291(6):721-734.
[19]吴健民.加强肿瘤标志物临床应用的质量管理[J].华中医学杂志，2007，31(1)：1-3.
[20] Apweiler R H H, Sharon N. On the frequency of protein glycosylation, asdeduced from analysis of the SWISS-PROTdatabase[J]. J. Biochim BiophysActa,1999,1473(1):4-8.
[21] Feizi T. Progress in deciphering the information content of the 'glycome'-acrescendo in the closing years of the millennium[J]. Glycoconjugate J,2000,17(7-9):553-565.
[22]孙兴权，李静，耿美玉等.糖组学研究中糖蛋白糖链结构分析技术[J].化学进展，2007，19(1)：130-135.
[23] RA L. A calculation of all possible oligosaccharide isomers both branched andlinear yields1.05×1012structures for a reducing hexasaccharide: the IsomerBarrier to development of single-method saccharide sequencingor synthesissystem[J]. J. Glycobiology,1994,4(6):759-767.
[24] Bertozzi C R, Kiessling L L. Chemical glycobiology[J]. Science (New York,N.Y),2001,291(5512):2357-2364.
[25] Helenius A, Aebi M. Intracellular functions of N-linked glycans[J]. Science(New York, N.Y),2001,291(5512):2364-2369.
[26] Dube D H, Bertozzi C R. Glycans in cancer and inflammation. Potential fortherapeutics and diagnostics[J]. Nat Rev Drug Discov,2005,4(6):477-488.
[27] Dennis JW G M, Warren CE. Glyeoprotein glycosylation and cancerprogression[J]. Bioehim Biophys Acta,1999,1473(1):21-34.
[28] Dwek M V, Ross H A, Leathem A J. Proteome and glycosylation mappingidentifies post-translational modifications associated with aggressive breastcancer[J]. Proteomics,2001,1(6):756-762.
[29] James W, Dennis S L, Carol Waghorne, et al. β1-6Branching of Asn-LinkedOligosaccharides Is Directly Associated with Metastasis[J]. Science (NewYork, N.Y),1987,236:582-585.
[30] Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth andmetastasis in Mgat5-deficient mice[J]. Nat Med,2000,6(3):306-312.
[31] Demetriou M, Nabi I R, Coppolino M, et al. Reduced contact-inhibition andsubstratum adhesion in epithelial cells expressing GlcNAc-transferase V[J].The Journal of cell biology,1995,130(2):383-392.
[32] J. L. Magnani B N, M. Brockhaus, D. Zopf, Z.Steplewski, et al. Ginsburgantibody-defined antigen associated with gastrointestinal cancer is aganglioside containing sialylated lacto-N-fucopentaose II[J]. J Biol Chem,1982,257:14365-14369.
[33] D. Jordon J J, M. Kaneko. Blood group antigens, Lewisx and Lewisy in thediagnostic discrimination of malignant mesothelioma versusadenocarcinoma[J]. Am J Pathol,1989,135:931-937.
[34] H. S. Cooper M J M, C. Bass, P. L. Fagel, et al. Expression of blood groupantigens H-2, Ley, and sialylated-Lea in human colorectal carcinoma. Animmunohistochemical study using double-labeling techniques[J]. Am J Pathol,1991,138:103-110.
[35] F. G. Hanisch C H, A. Hasegawa. Sialyl Lewisx antigen as defined bymonoclonal antibody AM-3is a marker of dysplasia in the colonicadenoma-carcinoma sequence[J]. Cancer Res,1992,52:3138-3144.
[36] S. Sakamoto T W, T. Tokumaru, H. Takagi, et al. Expression of Lewisa,Lewisb, Lewisx, Lewisy, siayl-Lewisa, and sialyl-Lewisx blood groupantigens in human gastric carcinoma and in normal gastric tissue[J]. CancerRes,1989,49:745-752.
[37] C. Cordon-Cardo V E R, C. L. Finstad, J. Sheinfeld, et al. Blood group-relatedantigens in human kidney: modulation of Lewis determinants in renal cellcarcinoma[J]. Cancer Res,1989,49:212-218.
[38] Matsuura N, Narita T, Mitsuoka C, et al. Increased level of circulatingadhesion molecules in the sera of breast cancer patients with distantmetastases[J]. Japanese journal of clinical oncology,1997,27(3):135-139.
[39] Wei J, Cui L, Liu F, et al. E-selectin and Sialyl Lewis X expression isassociated with lymph node metastasis of invasive micropapillary carcinomaof the breast[J]. Int J Surg Pathol,2011,18(3):193-200.
[40] Ichikawa D, Kitamura K, Tani N, et al. Molecular detection of disseminatedcancer cells in the peripheral blood and expression of sialylated antigens incolon cancers[J]. J Surg Oncol,2000,75(2):98-102.
[41] Nakamori S, Kameyama M, Imaoka S, et al. Increased expression of sialylLewisx antigen correlates with poor survival in patients with colorectalcarcinoma: clinicopathological and immunohistochemical study[J]. CancerRes,1993,53(15):3632-3637.
[42] Nakamori S, Kameyama M, Imaoka S, et al. Involvement of carbohydrateantigen sialyl Lewis(x) in colorectal cancer metastasis[J]. Diseases of thecolon and rectum,1997,40(4):420-431.
[43] Yamada N, Chung Y S, Maeda K, et al. Increased expression of sialyl Lewis Aand sialyl Lewis X in liver metastases of human colorectal carcinoma[J].Invasion&metastasis,1995,15(3-4):95-102.
[44] Dall'Olio F, Malagolini N, Trinchera M, et al. Mechanisms ofcancer-associated glycosylation changes[J]. Front Biosci,2012,17:670-699.
[45] Mathieu S, Gerolami R, Luis J, et al. Introducing alpha (1,2)-linked fucoseinto hepatocarcinoma cells inhibits vasculogenesis and tumor growth[J].International journal of cancer,2007,121(8):1680-1689.
[46] Litynska A, Przybylo M, Pochec E, et al. Comparison of the lectin-bindingpattern in different human melanoma cell lines[J]. Melanoma research,2001,11(3):205-212.
[47] Chan F L, Choi H L, Ho S M. Analysis of glycoconjugate patterns of normaland hormone-induced dysplastic Noble rat prostates, and anandrogen-independent Noble rat prostate tumor, by lectin histochemistry andprotein blotting[J]. The Prostate,2001,46(1):21-32.
[48] Dawsey S M, Fleischer D E, Wang G Q, et al. Mucosal iodine stainingimproves endoscopic visualization of squamous dysplasia and squamous cellcarcinoma of the esophagus in Linxian, China[J]. Cancer,1998,83(2):220-231.
[49] Sugimachi K, Ohno S, Matsuda H, et al. Lugol-combined endoscopicdetection of minute malignant lesions of the thoracic esophagus[J]. Annals ofsurgery,1988,208(2):179-183.
[50] Freire T, Osinaga E. The sweet side of tumor immunotherapy[J].Immunotherapy,2013,4(7):719-734.
[51] Newton K, Dixit V M. Signaling in innate immunity and inflammation[J].Cold Spring Harbor perspectives in biology,2012,4(3):56-72.
[52] Petersen J, Purcell A W, Rossjohn J. Post-translationally modified T cellepitopes: immune recognition and immunotherapy[J]. Journal of molecularmedicine (Berlin, Germany),2009,87(11):1045-1051.
[53] Freire T, Bay S, Vichier-Guerre S, et al. Carbohydrate antigens: synthesisaspects and immunological applications in cancer[J]. Mini reviews inmedicinal chemistry,2006,6(12):1357-1373.
[54] Itzkowitz S H, Bloom E J, Kokal W A, et al. Sialosyl-Tn. A novel mucinantigen associated with prognosis in colorectal cancer patients[J]. Cancer,1990,66(9):1960-1966.
[55] Itzkowitz S H, Yuan M, Montgomery C K, et al. Expression of Tn, sialosyl-Tn,and T antigens in human colon cancer[J]. Cancer Res,1989,49(1):197-204.
[56] Langkilde N C, Wolf H, Clausen H, et al. Nuclear volume and expression ofT-antigen, sialosyl-Tn-antigen, and Tn-antigen in carcinoma of the humanbladder. Relation to tumor recurrence and progression[J]. Cancer,1992,69(1):219-227.
[57] Langkilde N C, Wolf H, Clausen H, et al. Localization and identification ofT-(Gal beta1-3GalNAc alpha1-O-R) and T-like antigens in experimental ratbladder cancer[J]. The Journal of urology,1992,148(4):1279-1284.
[58] Muramatsu T. Carbohydrate signals in metastasis and prognosis of humancarcinomas[J]. Glycobiology,1993,3(4):291-296.
[59] Cao Y, Stosiek P, Springer G F, et al. Thomsen-Friedenreich-relatedcarbohydrate antigens in normal adult human tissues: a systematic andcomparative study[J]. Histochemistry and cell biology,1996,106(2):197-207.
[60] Springer G F. T and Tn, general carcinoma autoantigens[J]. Science (NewYork, N.Y),1984,224(4654):1198-1206.
[61] Brezicka F T, Olling S, Nilsson O, et al. Immunohistological detection offucosyl-GM1ganglioside in human lung cancer and normal tissues withmonoclonal antibodies[J]. Cancer Res,1989,49(5):1300-1305.
[62] Nilsson O, Brezicka F T, Holmgren J, et al. Detection of a ganglioside antigenassociated with small cell lung carcinomas using monoclonal antibodiesdirected against fucosyl-GM1[J]. Cancer Res,1986,46(3):1403-1407.
[63] Vangsted A J, Clausen H, Kjeldsen T B, et al. Immunochemical detection of asmall cell lung cancer-associated ganglioside (FucGM1) antigen in serum[J].Cancer Res,1991,51(11):2879-2884.
[64] Brockhausen I. Glycodynamics of mucin biosynthesis in gastrointestinaltumor cells[J]. Advances in experimental medicine and biology,2003,535:163-188.
[65] Zhang S, Zhang H S, Reuter V E, et al. Expression of potential target antigensfor immunotherapy on primary and metastatic prostate cancers[J]. Clin CancerRes,1998,4(2):295-302.
[66] Rabinovich G A, van Kooyk Y, Cobb B A. Glycobiology of immuneresponses[J]. Annals of the New York Academy of Sciences,2011,1253:1-15.
[67] Cormier J N, Panelli M C, Hackett J A, et al. Natural variation of theexpression of HLA and endogenous antigen modulates CTL recognition in anin vitro melanoma model[J]. International journal of cancer,1999,80(5):781-790.
[68] Saeland E, van Kooyk Y. Highly glycosylated tumour antigens: interactionswith the immune system[J]. Biochemical Society transactions,2012,39(1):388-392.
[69] Narimatsu H. Human glycogene cloning: focus on beta3-glycosyltransferaseand beta4-glycosyltransferase families[J]. Current opinion in structuralbiology,2006,16(5):567-575.
[70] Taniguchi N, Korekane H. Branched N-glycans and their implications for celladhesion, signaling and clinical applications for cancer biomarkers and intherapeutics[J]. BMB reports,2011,44(12):772-781.
[71] Narasimhan S. Control of glycoprotein synthesis. UDP-GlcNAc:glycopeptidebeta4-N-acetylglucosaminyltransferase III, an enzyme in hen oviduct whichadds GlcNAc in beta1-4linkage to the beta-linked mannose of thetrimannosyl core of N-glycosyl oligosaccharides[J]. J Biol Chem,1982,257(17):10235-10242.
[72] Schachter H, Narasimhan S, Gleeson P, et al. Oligosaccharide branching ofglycoproteins: biosynthetic mechanisms and possible biological functions[J].Philosophical transactions of the Royal Society of London,1982,300(1099):145-159.
[73] Stanley. P S H, Taniguchi. N. N-Glycans; In Essentials of Glycobiology[J].Cold Spring Harbor Laboratory Press,2009,(2nd ed):101-114.
[74] Shoreibah M, Perng G S, Adler B, et al. Isolation, characterization, andexpression of a cDNA encoding N-acetylglucosaminyltransferase V[J]. J BiolChem,1993,268(21):15381-15385.
[75] Gu J, Nishikawa A, Tsuruoka N, et al. Purification and characterization ofUDP-N-acetylglucosamine:alpha-6-D-mannosidebeta1,6N-acetylglucosaminyltransferase V from a human lung cancer cell line[J]. Journal of biochemistry,1993,113(5):614-619.
[76] Oguri S, Minowa M T, Ihara Y, et al. Purification and characterization ofUDP-N-acetylglucosamine:alpha1,3-D-mannosidebeta1,4-N-acetylglucosaminyltransferase (N-acetylglucosaminyltransferase-IV) from bovine smallintestine[J]. J Biol Chem,1997,272(36):22721-22727.
[77] Minowa M T, Oguri S, Yoshida A, et al. cDNA cloning and expression ofbovine UDP-N-acetylglucosamine: alpha1,3-D-mannoside beta1,4-N-acetylglucosaminyltransferase IV[J]. J Biol Chem,1998,273(19):11556-11562.
[78] Yanagidani S, Uozumi N, Ihara Y, et al. Purification and cDNA cloning ofGDP-L-Fuc: N-acetyl-beta-D-glucosaminide: alpha1-6fucosyltransferase(alpha1-6FucT) from human gastric cancer MKN45cells[J]. Journal ofbiochemistry,1997,121(3):626-632.
[79] Guo H B, Johnson H, Randolph M, et al. Specific posttranslationalmodification regulates early events in mammary carcinoma formation[J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2012,107(49):21116-21121.
[80] Partridge E A, Le Roy C, Di Guglielmo G M, et al. Regulation of cytokinereceptors by Golgi N-glycan processing and endocytosis[J]. Science (NewYork, N.Y),2004,306(5693):120-124.
[81] H S. Biosynthetic controls that determine the branching andmicroheterogeneity of protein-bound oligosaccharides[J]. Advances inexperimental medicine and biology,1986,205:53-85.
[82] Yoshimura M, Nishikawa A, Ihara Y, et al. Suppression of lung metastasis ofB16mouse melanoma by N-acetylglucosaminyltransferase III genetransfection[J]. Proceedings of the National Academy of Sciences of theUnited States of America,1995,92(19):8754-8758.
[83] Nishikawa A, Gu J, Fujii S, et al. Determination ofN-acetylglucosaminyltransferases III, IV and V in normal and hepatomatissues of rats[J]. Biochimica et biophysica acta,1990,1035(3):313-318.
[84] Yamashita K, Totani K, Iwaki Y, et al. Comparative study of the sugar chainsof gamma-glutamyltranspeptidases purified from human hepatocellularcarcinoma and from human liver[J]. Journal of biochemistry,1989,105(5):728-735.
[85] Endo T, Nishimura R, Kawano T, et al. Structural differences found in theasparagine-linked sugar chains of human chorionic gonadotropins purifiedfrom the urine of patients with invasive mole and with choriocarcinoma[J].Cancer Res,1987,47(19):5242-5245.
[86] Ide Y, Miyoshi E, Nakagawa T, et al. Aberrant expression ofN-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreaticcancer[J]. Biochem Biophys Res Commun,2006,341(2):478-482.
[87] Ohtsubo K. Targeted genetic inactivation of GnT-IVa impairs insulin secretionfrom pancreatic beta cells and evokes type2diabetes[J]. Methods inenzymology,2013,479:205-222.
[88] Ohtsubo K, Chen M Z, Olefsky J M, et al. Pathway to diabetes throughattenuation of pancreatic beta cell glycosylation and glucose transport[J]. NatMed,2012,17(9):1067-1075.
[89] Okuyama N, Ide Y, Nakano M, et al. Fucosylated haptoglobin is a novelmarker for pancreatic cancer: a detailed analysis of the oligosaccharidestructure and a possible mechanism for fucosylation[J]. International journalof cancer,2006,118(11):2803-2808.
[90] Takeda Y, Shinzaki S, Okudo K, et al. Fucosylated haptoglobin is a novel typeof cancer biomarker linked to the prognosis after an operation in colorectalcancer[J]. Cancer,2012,118(12):3036-3043.
[91] Nakagawa T, Uozumi N, Nakano M, et al. Fucosylation of N-glycansregulates the secretion of hepatic glycoproteins into bile ducts[J]. J Biol Chem,2006,281(40):29797-29806.
[92] Kam R K, Poon T C, Chan H L, et al. High-throughput quantitative profilingof serum N-glycome by MALDI-TOF mass spectrometry and N-glycomicfingerprint of liver fibrosis[J]. Clinical chemistry,2007,53(7):1254-1263.
[93] Nakagawa T, Miyoshi E, Yakushijin T, et al. Glycomic analysis ofalpha-fetoprotein L3in hepatoma cell lines and hepatocellular carcinomapatients[J]. Journal of proteome research,2008,7(6):2222-2233.
[94] Goldman R, Ressom H W, Varghese R S, et al. Detection of HepatocellularCarcinoma Using Glycomic Analysis[J]. Clin Cancer Res,2009,15(5):1808-1813.
[95] Tang Z Q, Varghese R S, Bekesova S, et al. Identification of N-Glycan SerumMarkers Associated with Hepatocellular Carcinoma from Mass SpectrometryData[J]. Journal of proteome research,2010,9(1):104-112.
[96] Chen P, Liu Y, Kang X, et al. Identification of N-glycan of alpha-fetoproteinby lectin affinity microarray[J]. Journal of cancer research and clinicaloncology,2008,134(8):851-860.
[97] Dai Z, Zhou J, Qiu S J, et al. Lectin-based glycoproteomics to explore andanalyze hepatocellular carcinoma-related glycoprotein markers[J].Electrophoresis,2009,30(17):2957-2966.
[98]李春辉.应用凝集素芯片检测肝癌细胞表面糖链变化[J].生物化学与生物物理进展，2010，37(7)：269-277.
[99] Liu X E, Desmyter L, Gao C F, et al. N-glycomic changes in hepatocellularcarcinoma patients with liver cirrhosis induced by hepatitis B virus[J].Hepatology,2007,46(5):1426-1435.
[100] Liu X E, Dewaele S, Vanhooren V, et al. Alteration of N-glycome indiethylnitrosamine-induced hepatocellular carcinoma mice: a non-invasivemonitoring tool for liver cancer[J]. Liver Int,2011,30(8):1221-1228.
[101] Higai K, Shibukawa K, Muto S, et al. Targeted proteo-glycomics analysis ofSialyl Lewis X antigen expressing glycoproteins secreted by human hepatomacell line[J]. Anal Sci,2003,19(1):85-92.
[102] Tanabe K, Deguchi A, Higashi M, et al. Outer arm fucosylation of N-glycansincreases in sera of hepatocellular carcinoma patients[J]. Biochem BiophysRes Commun,2008,374(2):219-225.
[103] Mehta A, Block T M. Fucosylated glycoproteins as markers of liver disease[J].Dis Markers,2008,25(4-5):259-265.
[104] Breton C, Snajdrova L, Jeanneau C, et al. Structures and mechanisms ofglycosyltransferases[J]. Glycobiology,2006,16(2):29r-37r.
[105] Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth andmetastasis in Mgat5-deficient mice[J]. Nat Med,2000,6(3):306-312.
[106] Marrero JA R P, Nikolaeva O, et al. GP73, a resident Golgi glycoprotein, is anovel serum marker for hepatocellular careinorna[J]. J. Hepatol,2005,43:2007-2012.
[107] Spangenberg HC T R,.Blum HE. Serum markers of hepatoeellularcareinoma[J]. Semin Liver Dis,2006,26:385-390.
[108] Deugnier Y, David V, Brissot P, et al. Serum alpha-L-fucosidase: a newmarker for the diagnosis of primary hepatic carcinoma?[J]. Hepatology,1984,4(5):889-892.
[109]马艳平，张波，祝臣栋等. α-L-岩藻糖苷酶、甲胎蛋白及其异质体在原发性肝癌诊断中的意义[J].中国综合临床，2003，19：83-84.
[110] Man XB T L, Zhang BH, et al. Upregulation of Glypcan-3expression inhepatoeellular carcinoma but downregulation in cholangiocarcinoma indicatesits differential diagnosis value in primary liver cancers[J]. Liver Int,2005,25:962-966.
[111] Wang L, Ku X M, Li Y, et al. Regulation of matrix metalloproteinaseproduction and tumor cell invasion by four monoclonal antibodies againstdifferent epitopes of HAb18G/CD147extracellular domain[J]. Hybridoma,2006,25(2):60-67.
[112] Ormandy LA F A, Cantz T, et al. Dircect ex vivo analysis of dendritic cells inpatients with hepatoce!lular carcinoma[J]. World J Gastroenterol,2006,12:3275-3282.
[113] Qoronfleh M W, Benton B, Ignacio R, et al. Selective Enrichment ofMembrane Proteins by Partition Phase Separation for Proteomic Studies[J].Journal of biomedicine&biotechnology,2003(4):249-255.
[114] Naka R, Kamoda S, Ishizuka A, et al. Analysis of total N-glycans in cellmembrane fractions of cancer cells using a combination of serotonin affinitychromatography and normal phase chromatography[J]. Journal of proteomeresearch,2006,5(1):88-97.
[115] Rakus J F, Mahal L K. New technologies for glycomic analysis: toward asystematic understanding of the glycome[J]. Annual review of analyticalchemistry (Palo Alto, Calif),2011,4:367-392.
[116] N T. Three-dimensinal mapping of N-linked oligosaccharides usinganion-exchange, hydrophobic and hydrophilic interaction modes ofhigh-performance liquid chromatography[J]. J Chromatogr A,1996,720(1-2):217-255.
[117] Tateno H, Nakamura-Tsuruta S, Hirabayashi J. Frontal affinitychromatography: sugar-protein interactions[J]. Nature protocols,2007,2(10):2529-2537.
[118] Westerlund-Wikstrom B, Korhonen T K. Molecular structure of adhesindomains in Escherichia coli fimbriae[J]. Int J Med Microbiol,2005,295(6-7):479-486.
[119]陈国千.糖蛋白糖链结构分析与恶性肿瘤的诊断[J].国外医学临床生物化学与检脸学分册，2000，22(9)：171-174.
[120] Wang LJ L F, Sun W, et al. Concanavaion A-captured glycoproteins in healthyhuman urine[J]. Mol Cell Proteomics,2006,5:560-562.
[121] Dai Z F J, Liu YK, et al. Identification and analysis of α1,6-fucosylatedglycoproteins associated with hepatocellular carcinoma metastasis[J].Proteomics,2006,6:5857-5867.
[122] Zhao J, Simeone D M, Heidt D, et al. Comparative serum glycoproteomicsusing lectin selected sialic acid glycoproteins with mass spectrometricanalysis: Application to pancreatic cancer serum[J]. Journal of proteomeresearch,2006,5(7):1792-1802.
[123] Harvey D J. Matrix-assisted laser desorption/ionization mass spectrometry ofcarbohydrates[J]. Mass spectrometry reviews,1999,18(6):349-450.
[124] Harvey D J. Identification of protein-bound carbohydrates by massspectrometry[J]. Proteomics,2001,1(2):311-328.
[125] Froesch M, Bindila L M, Baykut G, et al. Coupling of fully automated chipelectrospray to Fourier transform ion cyclotron resonance mass spectrometryfor high-performance glycoscreening and sequencing[J]. Rapid CommunMass Spectrom,2004,18(24):3084-3092.
[126] Kameyama A, Kikuchi N, Nakaya S, et al. A strategy for identification ofoligosaccharide structures using observational multistage mass spectrallibrary[J]. Anal Chem,2005,77(15):4719-4725.
[127] Shaw G S, Sun Y, Barber K R, et al. Sequence specific analysis of theheterogeneous glycan chain from peanut peroxidase by1H-NMRspectroscopy[J]. Phytochemistry,2000,53(1):135-144.
[128] Kogelberg H, Piskarev V E, Zhang Y, et al. Determination by electrospraymass spectrometry and1H-NMR spectroscopy of primary structures ofvariously fucosylated neutral oligosaccharides based on theiso-lacto-N-octaose core[J]. European journal of biochemistry/FEBS,2004,271(6):1172-1186.
[129] Nimrichter L, Gargir A, Gortler M, et al. Intact cell adhesion to glycanmicroarrays[J]. Glycobiology,2004,14(2):197-203.
[130] Zheng T, Peelen D, Smith L M. Lectin arrays for profiling cell surfacecarbohydrate expression[J]. Journal of the American Chemical Society,2005,127(28):9982-9983.
[131] Mao X, Luo Y, Dai Z, et al. Integrated lectin affinity microfluidic chip forglycoform separation[J]. Anal Chem,2004,76(23):6941-6947.
[132] Raman R, Raguram S, Venkataraman G, et al. Glycomics: an integratedsystems approach to structure-function relationships of glycans[J]. Naturemethods,2005,2(11):817-824.
[133] Callewaert N, Geysens S, Molemans F, et al. Ultrasensitive profiling andsequencing of N-linked oligosaccharides using standard DNA-sequencingequipment[J]. Glycobiology,2001,11(4):275-281.
[134] Chen C, Schmilovitz-Weiss H, Liu X E, et al. Serum protein N-glycansprofiling for the discovery of potential biomarkers for nonalcoholicsteatohepatitis[J]. Journal of proteome research,2009,8(2):463-470.
[135]刘波，宋淼，巩新等.一种利用DSA-FACE分析寡糖链的方法[J].生物技术通讯，2008，6(19)：885-889.
[136] Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosisof liver cirrhosis using DNA sequencer-based total serum protein glycomics[J].Nat Med,2004,10(4):429-434.
[137]赵云鹏，高春芳，房萌等.原发性肝细胞癌患者血清N-糖组的表达分析[J].第二军医大学学报，2007，28(12)：1280-1283.
[138] Vanderschaeghe D, Laroy W, Sablon E, et al. GlycoFibroTest is a highlyperformant liver fibrosis biomarker derived from DNA sequencer-based serumprotein glycomics[J]. Mol Cell Proteomics,2009,8(5):986-994.
[139] Fang M, Dewaele S, Zhao Y P, et al. Serum N-glycome biomarker formonitoring development of DENA-induced hepatocellular carcinoma in rat[J].Molecular cancer,2011,9:215.
[140] Blomme B, Van Steenkiste C, Vanhuysse J, et al. Impact of elevation of totalbilirubin level and etiology of the liver disease on serum N-glycosylationpatterns in mice and humans[J]. American journal of physiology,2012,298(5):G615-624.
[141] Debruyne E N, Vanderschaeghe D, Van Vlierberghe H, et al. Diagnostic valueof the hemopexin N-glycan profile in hepatocellular carcinoma patients[J].Clinical chemistry,2011,56(5):823-831.
[142] Zhao Y P, Ruan C P, Wang H, et al. Identification and assessment of newbiomarkers for colorectal cancer with serum N-glycan profiling[J]. Cancer,2012,118(3):639-650.
[143] Gui H L, Gao C F, Wang H, et al. Altered serum N-glycomics in chronichepatitis B patients[J]. Liver Int,2012,30(2):259-267.
[144] Fang M, Zhao Y P, Zhou F G, et al. N-glycan based models improvediagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma[J].International journal of cancer,2012,127(1):148-159.
[145] Vanhooren V, Desmyter L, Liu X E, et al. N-glycomic changes in serumproteins during human aging[J]. Rejuvenation research,2007,10(4):521-531a.
[146] Vanhooren V, Dewaele S, Libert C, et al. Serum N-glycan profile shift duringhuman ageing[J]. Experimental gerontology,2011,45(10):738-743.
[147] Vanhooren V, Laroy W, Libert C, et al. N-glycan profiling in the study ofhuman aging[J]. Biogerontology,2008,9(5):351-356.
[148] Vanhooren V, Liu X E, Franceschi C, et al. N-glycan profiles as tools indiagnosis of hepatocellular carcinoma and prediction of healthy humanageing[J]. Mech Ageing Dev,2009,130(1-2):92-97.
[149] Chen C C, Engelborghs S, Dewaele S, et al. Altered serum glycomics inAlzheimer disease: a potential blood biomarker?[J]. Rejuvenation research,2012,13(4):439-444.
[150] Ding N, Nie H, Sun X, et al. Human serum N-glycan profiles are age and sexdependent[J]. Age and ageing,2012,40(5):568-575.
[151] Lee K J, Jung J H, Lee J M, et al. High-throughput quantitative analysis ofplant N-glycan using a DNA sequencer[J]. Biochem Bioph Res Co,2009,380(2):223-229.
[152] Holland N B, Qiu Y, Ruegsegger M, et al. Biomimetic engineering ofnon-adhesive glycocalyx-like surfaces using oligosaccharide surfactantpolymers[J]. Nature,1998,392(6678):799-801.
[153] Hirabayashi J, Kasai K. Separation technologies for glycomics[J]. Journal ofchromatography,2002,771(1-2):67-87.
[154] Morelle W, Michalski J C. Glycomics and mass spectrometry[J]. Currentpharmaceutical design,2005,11(20):2615-2645.
[155] Bordier C. Phase separation of integral membrane proteins in Triton X-114solution[J]. J Biol Chem,1981,256(4):1604-1607.
[156] Baik Y S, Cheong W J. Development of SPE for recovery of polysaccharidesand its application to the determination of monosaccharides composition ofthe polysaccharide sample of a lactobacillus KLB58[J]. Journal of separationscience,2007,30(10):1509-1515.
[157] Packer N H, Lawson M A, Jardine D R, et al. Analyzing glycoproteinsseparated by two-dimensional gel electrophoresis[J]. Electrophoresis,1998,19(6):981-988.
[158] Gil G C, Kim Y G, Kim B G. A relative and absolute quantification of neutralN-linked oligosaccharides using modification with carboxymethyltrimethylammonium hydrazide and matrix-assisted laser desorption/ionizationtime-of-flight mass spectrometry[J]. Analytical biochemistry,2008,379(1):45-59.
[159] Wilson J J, Brodbelt J S. Ultraviolet photodissociation at355nm offluorescently labeled oligosaccharides[J]. Anal Chem,2008,80(13):5186-5196.
[160] Schulz B L, Packer N H, Karlsson N G. Small-scale analysis of O-linkedoligosaccharides from glycoproteins and mucins separated by gelelectrophoresis[J]. Anal Chem,2002,74(23):6088-6097.
[161] Zhao J, Qiu W, Simeone D M, et al. N-linked glycosylation profiling ofpancreatic cancer serum using capillary liquid phase separation coupled withmass spectrometric analysis[J]. Journal of proteome research,2007,6(3):1126-1138.
[162] Lee K J, Jung J H, Lee J M, et al. High-throughput quantitative analysis ofplant N-glycan using a DNA sequencer[J]. Biochem Biophys Res Commun,2009,380(2):223-229.
[163] Bruix J, Boix L, Sala M, et al. Focus on hepatocellular carcinoma[J]. Cancercell,2004,5(3):215-219.
[164] Liaw Y F. Prevention and surveillance of hepatitis B virus-relatedhepatocellular carcinoma[J]. Semin Liver Dis,2005,25Suppl1:40-47.
[165] Koike K. Molecular basis of hepatitis C virus-associated hepatocarcinogenesis:lessons from animal model studies[J]. Clin Gastroenterol Hepatol,2005,3(10Suppl2): S132-135.
[166] Merican I, Guan R, Amarapuka D, et al. Chronic hepatitis B virus infection inAsian countries[J]. J Gastroenterol Hepatol,2000,15(12):1356-1361.
[167] Yuen M F, Wong D K, Fung J, et al. HBsAg Seroclearance in chronic hepatitisB in Asian patients: replicative level and risk of hepatocellular carcinoma[J].Gastroenterology,2008,135(4):1192-1199.
[168] Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosisof liver cirrhosis using DNA sequencer-based total serum protein glycomics[J].Nat Med,2004,10(4):429-434.
[169] Qu Y, Gao C F, Zhou K, et al. Serum N-glycomic markers in combination withpanels improves the diagnosis of chronic hepatitis B[J]. Annals of hepatology,2013,11(2):202-212.
[170] Laroy W, Contreras R, Callewaert N. Glycome mapping on DNA sequencingequipment[J]. Nature protocols,2006,1(1):397-405.
[171] Bram Blomme C V S, Paola Grassi, Stuart M. Haslam, et al. Alterations ofserum protein N-glycosylation in two mouse models of chronic liver diseaseare hepatocyte and not B cell driven[J]. American journal of physiology,2011,300:833-842.
[172] Vlad A M, Finn O J. Glycoprotein tumor antigens for immunotherapy ofbreast cancer[J]. Breast disease,2004,20:73-79.
[173] Banerjee A, Lang J Y, Hung M C, et al. Unfolded protein response is requiredin nu/nu mice microvasculature for treating breast tumor with tunicamycin[J].J Biol Chem,2011,286(33):29127-29138.
[174] Yamaguchi H, Uchida M. A chaperone-like function of intramolecularhigh-mannose chains in the oxidative refolding of bovine pancreatic RNaseB[J]. Journal of biochemistry,1996,120(3):474-477.
[175] Morishima S, Morita I, Tokushima T, et al. Expression and role of mannosereceptor/terminal high-mannose type oligosaccharide on osteoclast precursorsduring osteoclast formation[J]. The Journal of endocrinology,2003,176(2):285-292.
[176] Driouich A, Gonnet, P., Makkie, M., et al. The role of high-mannose andcomplex asparagine-linked glycans in the secretion and stability ofglycoproteins[J]. Planta,1989,180:96-104.
[177] Vagin O, Kraut J A, Sachs G. Role of N-glycosylation in trafficking of apicalmembrane proteins in epithelia[J]. Am J Physiol Renal Physiol,2009,296(3):F459-469.
[178] Vervecken W, Kaigorodov V, Callewaert N, et al. In vivo synthesis ofmammalian-like, hybrid-type N-glycans in Pichia pastoris[J]. Applied andenvironmental microbiology,2004,70(5):2639-2646.
[179] Lee S J, Evers S, Roeder D, et al. Mannose receptor-mediated regulation ofserum glycoprotein homeostasis[J]. Science (New York, N.Y),2002,295(5561):1898-1901.
[180] Weigel P H. Galactosyl and N-acetylgalactosaminyl homeostasis: a functionfor mammalian asialoglycoprotein receptors[J]. Bioessays,1994,16(7):519-524.
[181] Kronewitter S R, An H J, de Leoz M L, et al. The development ofretrosynthetic glycan libraries to profile and classify the human serumN-linked glycome[J]. Proteomics,2009,9(11):2986-2994.
[182] Ling Wang, Xue-en Liu, Claude Libert, et al. Alteration of liver N-glycome inpatients with hepatocellular carcinoma[J]. OJGas,2012:113-125.
[183] Handerson T, Camp R, Harigopal M, et al. Beta1,6-branched oligosaccharidesare increased in lymph node metastases and predict poor outcome in breastcarcinoma[J]. Clin Cancer Res,2005,11(8):2969-2973.
[184] Lubke T, Marquardt T, Etzioni A, et al. Complementation cloning identifiesCDG-IIc, a new type of congenital disorders of glycosylation, as aGDP-fucose transporter deficiency[J]. Nature genetics,2001,28(1):73-76.
[185] Luhn K, Wild M K, Eckhardt M, et al. The gene defective in leukocyteadhesion deficiency II encodes a putative GDP-fucose transporter[J]. Naturegenetics,2001,28(1):69-72.
[186] Wang X, Inoue S, Gu J, et al. Dysregulation of TGF-beta1receptor activationleads to abnormal lung development and emphysema-like phenotype in corefucose-deficient mice[J]. Proceedings of the National Academy of Sciences ofthe United States of America,2005,102(44):15791-15796.
[187] Wang X, Gu J, Ihara H, et al. Core fucosylation regulates epidermal growthfactor receptor-mediated intracellular signaling[J]. J Biol Chem,2006,281(5):2572-2577.
[2] Tang Z Y, Yu Y Q, Zhou X D, et al. Subclinical hepatocellular carcinoma: ananalysis of391patients[J]. Journal of surgical oncology,1993,3:55-58.
[3]王维林，白屠红.肝癌血清标志物研究的新进展[J].肿瘤，2009，4(29)：389-393.
[4] Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to earlyand late phase intrahepatic recurrence of hepatocellular carcinoma afterhepatectomy[J]. Journal of hepatology，2003，38(2)：200-207.
[5] Nagasue N, Ono T, Yamanoi A, et al. Prognostic factors and survival afterhepatic resection for hepatocellular carcinoma without cirrhosis[J]. Brit J Surg,2001,88(4):515-522.
[6]陈明慧，李雪川，唐伟等.脱-γ-羧基凝血酶原与原发性肝癌[J].生命的化学，2008，1(28)：69-71.
[7] Nanashima A O K, Tobinaga S, et al. Comparative strdy of survival of patientswith hepatocellular carcinoma predicted by different staging systems usingmultivariate analysis[J]. Eur J Surg Oncol,2005,31(8)：882-890.
[8]袁联文，唐伟，李永国等.脱-γ-羧基凝血酶原：一种有用的血清肝癌标志物[J].中华普通外科杂志，2004，19(8)：506-506.
[9] Nakatsura T Y Y, Senju S, et al. Glypican-3, overexpressed specifically inhuman hepatocellular carcinoma, is a novel tumormarker[J]. BiochemBiophys Res Commun,2003,306(1):16-25.
[10] Capurro M, Wanless I R, Sherman M, et al. Glypican-3: a novel serum andhistochemical marker for hepatocellular carcinoma[J]. Gastroenterology,2003,125(1):89-97.
[11] Marrero JA R P, Nikolaevao, et al. GP73, a residerGolgi glycoprotein, is anovel serum marker for hepatocellular carcimon[J]. Journal of hepatology,2005,43(6):1007-1012.
[12]曹晶.肝癌细胞分泌蛋白和糖蛋白的蛋白质组学研究[D].上海：复旦大学博士学位论文，2009：45-48..
[13] Hamilton S R. Targeted therapy of cancer: new roles for pathologists incolorectal cancer[J]. Mod Pathol,2008,21Suppl2: S23-30.
[14]刘宝瑞，钱晓萍.原发性肝癌分子靶向治疗研究进展[J].世界华人消化杂志，2009，17(10)：993-997.
[15] Daveau M, Scotte M, Francois A, et al. Hepatocyte growth factor,transforming growth factor alpha, and their receptors as combined markers ofprognosis in hepatocellular carcinoma[J]. Mol Carcinogen,2003,36(3):130-141.
[16] Tommasi S, Pinto R, Pilato B, et al. Molecular pathways and related targettherapies in liver carcinoma[J]. Current pharmaceutical design,2007,13(32):3279-3287.
[17] Gollob J A, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer:therapeutic potential of targeting the Raf/MEK/ERK signal transductionpathway[J]. Seminars in oncology,2006,33(4):392-406.
[18] Yang Z F, Poon R T. Vascular changes in hepatocellular carcinoma[J]. AnatRec (Hoboken),2008,291(6):721-734.
[19]吴健民.加强肿瘤标志物临床应用的质量管理[J].华中医学杂志，2007，31(1)：1-3.
[20] Apweiler R H H, Sharon N. On the frequency of protein glycosylation, asdeduced from analysis of the SWISS-PROTdatabase[J]. J. Biochim BiophysActa,1999,1473(1):4-8.
[21] Feizi T. Progress in deciphering the information content of the 'glycome'-acrescendo in the closing years of the millennium[J]. Glycoconjugate J,2000,17(7-9):553-565.
[22]孙兴权，李静，耿美玉等.糖组学研究中糖蛋白糖链结构分析技术[J].化学进展，2007，19(1)：130-135.
[23] RA L. A calculation of all possible oligosaccharide isomers both branched andlinear yields1.05×1012structures for a reducing hexasaccharide: the IsomerBarrier to development of single-method saccharide sequencingor synthesissystem[J]. J. Glycobiology,1994,4(6):759-767.
[24] Bertozzi C R, Kiessling L L. Chemical glycobiology[J]. Science (New York,N.Y),2001,291(5512):2357-2364.
[25] Helenius A, Aebi M. Intracellular functions of N-linked glycans[J]. Science(New York, N.Y),2001,291(5512):2364-2369.
[26] Dube D H, Bertozzi C R. Glycans in cancer and inflammation. Potential fortherapeutics and diagnostics[J]. Nat Rev Drug Discov,2005,4(6):477-488.
[27] Dennis JW G M, Warren CE. Glyeoprotein glycosylation and cancerprogression[J]. Bioehim Biophys Acta,1999,1473(1):21-34.
[28] Dwek M V, Ross H A, Leathem A J. Proteome and glycosylation mappingidentifies post-translational modifications associated with aggressive breastcancer[J]. Proteomics,2001,1(6):756-762.
[29] James W, Dennis S L, Carol Waghorne, et al. β1-6Branching of Asn-LinkedOligosaccharides Is Directly Associated with Metastasis[J]. Science (NewYork, N.Y),1987,236:582-585.
[30] Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth andmetastasis in Mgat5-deficient mice[J]. Nat Med,2000,6(3):306-312.
[31] Demetriou M, Nabi I R, Coppolino M, et al. Reduced contact-inhibition andsubstratum adhesion in epithelial cells expressing GlcNAc-transferase V[J].The Journal of cell biology,1995,130(2):383-392.
[32] J. L. Magnani B N, M. Brockhaus, D. Zopf, Z.Steplewski, et al. Ginsburgantibody-defined antigen associated with gastrointestinal cancer is aganglioside containing sialylated lacto-N-fucopentaose II[J]. J Biol Chem,1982,257:14365-14369.
[33] D. Jordon J J, M. Kaneko. Blood group antigens, Lewisx and Lewisy in thediagnostic discrimination of malignant mesothelioma versusadenocarcinoma[J]. Am J Pathol,1989,135:931-937.
[34] H. S. Cooper M J M, C. Bass, P. L. Fagel, et al. Expression of blood groupantigens H-2, Ley, and sialylated-Lea in human colorectal carcinoma. Animmunohistochemical study using double-labeling techniques[J]. Am J Pathol,1991,138:103-110.
[35] F. G. Hanisch C H, A. Hasegawa. Sialyl Lewisx antigen as defined bymonoclonal antibody AM-3is a marker of dysplasia in the colonicadenoma-carcinoma sequence[J]. Cancer Res,1992,52:3138-3144.
[36] S. Sakamoto T W, T. Tokumaru, H. Takagi, et al. Expression of Lewisa,Lewisb, Lewisx, Lewisy, siayl-Lewisa, and sialyl-Lewisx blood groupantigens in human gastric carcinoma and in normal gastric tissue[J]. CancerRes,1989,49:745-752.
[37] C. Cordon-Cardo V E R, C. L. Finstad, J. Sheinfeld, et al. Blood group-relatedantigens in human kidney: modulation of Lewis determinants in renal cellcarcinoma[J]. Cancer Res,1989,49:212-218.
[38] Matsuura N, Narita T, Mitsuoka C, et al. Increased level of circulatingadhesion molecules in the sera of breast cancer patients with distantmetastases[J]. Japanese journal of clinical oncology,1997,27(3):135-139.
[39] Wei J, Cui L, Liu F, et al. E-selectin and Sialyl Lewis X expression isassociated with lymph node metastasis of invasive micropapillary carcinomaof the breast[J]. Int J Surg Pathol,2011,18(3):193-200.
[40] Ichikawa D, Kitamura K, Tani N, et al. Molecular detection of disseminatedcancer cells in the peripheral blood and expression of sialylated antigens incolon cancers[J]. J Surg Oncol,2000,75(2):98-102.
[41] Nakamori S, Kameyama M, Imaoka S, et al. Increased expression of sialylLewisx antigen correlates with poor survival in patients with colorectalcarcinoma: clinicopathological and immunohistochemical study[J]. CancerRes,1993,53(15):3632-3637.
[42] Nakamori S, Kameyama M, Imaoka S, et al. Involvement of carbohydrateantigen sialyl Lewis(x) in colorectal cancer metastasis[J]. Diseases of thecolon and rectum,1997,40(4):420-431.
[43] Yamada N, Chung Y S, Maeda K, et al. Increased expression of sialyl Lewis Aand sialyl Lewis X in liver metastases of human colorectal carcinoma[J].Invasion&metastasis,1995,15(3-4):95-102.
[44] Dall'Olio F, Malagolini N, Trinchera M, et al. Mechanisms ofcancer-associated glycosylation changes[J]. Front Biosci,2012,17:670-699.
[45] Mathieu S, Gerolami R, Luis J, et al. Introducing alpha (1,2)-linked fucoseinto hepatocarcinoma cells inhibits vasculogenesis and tumor growth[J].International journal of cancer,2007,121(8):1680-1689.
[46] Litynska A, Przybylo M, Pochec E, et al. Comparison of the lectin-bindingpattern in different human melanoma cell lines[J]. Melanoma research,2001,11(3):205-212.
[47] Chan F L, Choi H L, Ho S M. Analysis of glycoconjugate patterns of normaland hormone-induced dysplastic Noble rat prostates, and anandrogen-independent Noble rat prostate tumor, by lectin histochemistry andprotein blotting[J]. The Prostate,2001,46(1):21-32.
[48] Dawsey S M, Fleischer D E, Wang G Q, et al. Mucosal iodine stainingimproves endoscopic visualization of squamous dysplasia and squamous cellcarcinoma of the esophagus in Linxian, China[J]. Cancer,1998,83(2):220-231.
[49] Sugimachi K, Ohno S, Matsuda H, et al. Lugol-combined endoscopicdetection of minute malignant lesions of the thoracic esophagus[J]. Annals ofsurgery,1988,208(2):179-183.
[50] Freire T, Osinaga E. The sweet side of tumor immunotherapy[J].Immunotherapy,2013,4(7):719-734.
[51] Newton K, Dixit V M. Signaling in innate immunity and inflammation[J].Cold Spring Harbor perspectives in biology,2012,4(3):56-72.
[52] Petersen J, Purcell A W, Rossjohn J. Post-translationally modified T cellepitopes: immune recognition and immunotherapy[J]. Journal of molecularmedicine (Berlin, Germany),2009,87(11):1045-1051.
[53] Freire T, Bay S, Vichier-Guerre S, et al. Carbohydrate antigens: synthesisaspects and immunological applications in cancer[J]. Mini reviews inmedicinal chemistry,2006,6(12):1357-1373.
[54] Itzkowitz S H, Bloom E J, Kokal W A, et al. Sialosyl-Tn. A novel mucinantigen associated with prognosis in colorectal cancer patients[J]. Cancer,1990,66(9):1960-1966.
[55] Itzkowitz S H, Yuan M, Montgomery C K, et al. Expression of Tn, sialosyl-Tn,and T antigens in human colon cancer[J]. Cancer Res,1989,49(1):197-204.
[56] Langkilde N C, Wolf H, Clausen H, et al. Nuclear volume and expression ofT-antigen, sialosyl-Tn-antigen, and Tn-antigen in carcinoma of the humanbladder. Relation to tumor recurrence and progression[J]. Cancer,1992,69(1):219-227.
[57] Langkilde N C, Wolf H, Clausen H, et al. Localization and identification ofT-(Gal beta1-3GalNAc alpha1-O-R) and T-like antigens in experimental ratbladder cancer[J]. The Journal of urology,1992,148(4):1279-1284.
[58] Muramatsu T. Carbohydrate signals in metastasis and prognosis of humancarcinomas[J]. Glycobiology,1993,3(4):291-296.
[59] Cao Y, Stosiek P, Springer G F, et al. Thomsen-Friedenreich-relatedcarbohydrate antigens in normal adult human tissues: a systematic andcomparative study[J]. Histochemistry and cell biology,1996,106(2):197-207.
[60] Springer G F. T and Tn, general carcinoma autoantigens[J]. Science (NewYork, N.Y),1984,224(4654):1198-1206.
[61] Brezicka F T, Olling S, Nilsson O, et al. Immunohistological detection offucosyl-GM1ganglioside in human lung cancer and normal tissues withmonoclonal antibodies[J]. Cancer Res,1989,49(5):1300-1305.
[62] Nilsson O, Brezicka F T, Holmgren J, et al. Detection of a ganglioside antigenassociated with small cell lung carcinomas using monoclonal antibodiesdirected against fucosyl-GM1[J]. Cancer Res,1986,46(3):1403-1407.
[63] Vangsted A J, Clausen H, Kjeldsen T B, et al. Immunochemical detection of asmall cell lung cancer-associated ganglioside (FucGM1) antigen in serum[J].Cancer Res,1991,51(11):2879-2884.
[64] Brockhausen I. Glycodynamics of mucin biosynthesis in gastrointestinaltumor cells[J]. Advances in experimental medicine and biology,2003,535:163-188.
[65] Zhang S, Zhang H S, Reuter V E, et al. Expression of potential target antigensfor immunotherapy on primary and metastatic prostate cancers[J]. Clin CancerRes,1998,4(2):295-302.
[66] Rabinovich G A, van Kooyk Y, Cobb B A. Glycobiology of immuneresponses[J]. Annals of the New York Academy of Sciences,2011,1253:1-15.
[67] Cormier J N, Panelli M C, Hackett J A, et al. Natural variation of theexpression of HLA and endogenous antigen modulates CTL recognition in anin vitro melanoma model[J]. International journal of cancer,1999,80(5):781-790.
[68] Saeland E, van Kooyk Y. Highly glycosylated tumour antigens: interactionswith the immune system[J]. Biochemical Society transactions,2012,39(1):388-392.
[69] Narimatsu H. Human glycogene cloning: focus on beta3-glycosyltransferaseand beta4-glycosyltransferase families[J]. Current opinion in structuralbiology,2006,16(5):567-575.
[70] Taniguchi N, Korekane H. Branched N-glycans and their implications for celladhesion, signaling and clinical applications for cancer biomarkers and intherapeutics[J]. BMB reports,2011,44(12):772-781.
[71] Narasimhan S. Control of glycoprotein synthesis. UDP-GlcNAc:glycopeptidebeta4-N-acetylglucosaminyltransferase III, an enzyme in hen oviduct whichadds GlcNAc in beta1-4linkage to the beta-linked mannose of thetrimannosyl core of N-glycosyl oligosaccharides[J]. J Biol Chem,1982,257(17):10235-10242.
[72] Schachter H, Narasimhan S, Gleeson P, et al. Oligosaccharide branching ofglycoproteins: biosynthetic mechanisms and possible biological functions[J].Philosophical transactions of the Royal Society of London,1982,300(1099):145-159.
[73] Stanley. P S H, Taniguchi. N. N-Glycans; In Essentials of Glycobiology[J].Cold Spring Harbor Laboratory Press,2009,(2nd ed):101-114.
[74] Shoreibah M, Perng G S, Adler B, et al. Isolation, characterization, andexpression of a cDNA encoding N-acetylglucosaminyltransferase V[J]. J BiolChem,1993,268(21):15381-15385.
[75] Gu J, Nishikawa A, Tsuruoka N, et al. Purification and characterization ofUDP-N-acetylglucosamine:alpha-6-D-mannosidebeta1,6N-acetylglucosaminyltransferase V from a human lung cancer cell line[J]. Journal of biochemistry,1993,113(5):614-619.
[76] Oguri S, Minowa M T, Ihara Y, et al. Purification and characterization ofUDP-N-acetylglucosamine:alpha1,3-D-mannosidebeta1,4-N-acetylglucosaminyltransferase (N-acetylglucosaminyltransferase-IV) from bovine smallintestine[J]. J Biol Chem,1997,272(36):22721-22727.
[77] Minowa M T, Oguri S, Yoshida A, et al. cDNA cloning and expression ofbovine UDP-N-acetylglucosamine: alpha1,3-D-mannoside beta1,4-N-acetylglucosaminyltransferase IV[J]. J Biol Chem,1998,273(19):11556-11562.
[78] Yanagidani S, Uozumi N, Ihara Y, et al. Purification and cDNA cloning ofGDP-L-Fuc: N-acetyl-beta-D-glucosaminide: alpha1-6fucosyltransferase(alpha1-6FucT) from human gastric cancer MKN45cells[J]. Journal ofbiochemistry,1997,121(3):626-632.
[79] Guo H B, Johnson H, Randolph M, et al. Specific posttranslationalmodification regulates early events in mammary carcinoma formation[J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2012,107(49):21116-21121.
[80] Partridge E A, Le Roy C, Di Guglielmo G M, et al. Regulation of cytokinereceptors by Golgi N-glycan processing and endocytosis[J]. Science (NewYork, N.Y),2004,306(5693):120-124.
[81] H S. Biosynthetic controls that determine the branching andmicroheterogeneity of protein-bound oligosaccharides[J]. Advances inexperimental medicine and biology,1986,205:53-85.
[82] Yoshimura M, Nishikawa A, Ihara Y, et al. Suppression of lung metastasis ofB16mouse melanoma by N-acetylglucosaminyltransferase III genetransfection[J]. Proceedings of the National Academy of Sciences of theUnited States of America,1995,92(19):8754-8758.
[83] Nishikawa A, Gu J, Fujii S, et al. Determination ofN-acetylglucosaminyltransferases III, IV and V in normal and hepatomatissues of rats[J]. Biochimica et biophysica acta,1990,1035(3):313-318.
[84] Yamashita K, Totani K, Iwaki Y, et al. Comparative study of the sugar chainsof gamma-glutamyltranspeptidases purified from human hepatocellularcarcinoma and from human liver[J]. Journal of biochemistry,1989,105(5):728-735.
[85] Endo T, Nishimura R, Kawano T, et al. Structural differences found in theasparagine-linked sugar chains of human chorionic gonadotropins purifiedfrom the urine of patients with invasive mole and with choriocarcinoma[J].Cancer Res,1987,47(19):5242-5245.
[86] Ide Y, Miyoshi E, Nakagawa T, et al. Aberrant expression ofN-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreaticcancer[J]. Biochem Biophys Res Commun,2006,341(2):478-482.
[87] Ohtsubo K. Targeted genetic inactivation of GnT-IVa impairs insulin secretionfrom pancreatic beta cells and evokes type2diabetes[J]. Methods inenzymology,2013,479:205-222.
[88] Ohtsubo K, Chen M Z, Olefsky J M, et al. Pathway to diabetes throughattenuation of pancreatic beta cell glycosylation and glucose transport[J]. NatMed,2012,17(9):1067-1075.
[89] Okuyama N, Ide Y, Nakano M, et al. Fucosylated haptoglobin is a novelmarker for pancreatic cancer: a detailed analysis of the oligosaccharidestructure and a possible mechanism for fucosylation[J]. International journalof cancer,2006,118(11):2803-2808.
[90] Takeda Y, Shinzaki S, Okudo K, et al. Fucosylated haptoglobin is a novel typeof cancer biomarker linked to the prognosis after an operation in colorectalcancer[J]. Cancer,2012,118(12):3036-3043.
[91] Nakagawa T, Uozumi N, Nakano M, et al. Fucosylation of N-glycansregulates the secretion of hepatic glycoproteins into bile ducts[J]. J Biol Chem,2006,281(40):29797-29806.
[92] Kam R K, Poon T C, Chan H L, et al. High-throughput quantitative profilingof serum N-glycome by MALDI-TOF mass spectrometry and N-glycomicfingerprint of liver fibrosis[J]. Clinical chemistry,2007,53(7):1254-1263.
[93] Nakagawa T, Miyoshi E, Yakushijin T, et al. Glycomic analysis ofalpha-fetoprotein L3in hepatoma cell lines and hepatocellular carcinomapatients[J]. Journal of proteome research,2008,7(6):2222-2233.
[94] Goldman R, Ressom H W, Varghese R S, et al. Detection of HepatocellularCarcinoma Using Glycomic Analysis[J]. Clin Cancer Res,2009,15(5):1808-1813.
[95] Tang Z Q, Varghese R S, Bekesova S, et al. Identification of N-Glycan SerumMarkers Associated with Hepatocellular Carcinoma from Mass SpectrometryData[J]. Journal of proteome research,2010,9(1):104-112.
[96] Chen P, Liu Y, Kang X, et al. Identification of N-glycan of alpha-fetoproteinby lectin affinity microarray[J]. Journal of cancer research and clinicaloncology,2008,134(8):851-860.
[97] Dai Z, Zhou J, Qiu S J, et al. Lectin-based glycoproteomics to explore andanalyze hepatocellular carcinoma-related glycoprotein markers[J].Electrophoresis,2009,30(17):2957-2966.
[98]李春辉.应用凝集素芯片检测肝癌细胞表面糖链变化[J].生物化学与生物物理进展，2010，37(7)：269-277.
[99] Liu X E, Desmyter L, Gao C F, et al. N-glycomic changes in hepatocellularcarcinoma patients with liver cirrhosis induced by hepatitis B virus[J].Hepatology,2007,46(5):1426-1435.
[100] Liu X E, Dewaele S, Vanhooren V, et al. Alteration of N-glycome indiethylnitrosamine-induced hepatocellular carcinoma mice: a non-invasivemonitoring tool for liver cancer[J]. Liver Int,2011,30(8):1221-1228.
[101] Higai K, Shibukawa K, Muto S, et al. Targeted proteo-glycomics analysis ofSialyl Lewis X antigen expressing glycoproteins secreted by human hepatomacell line[J]. Anal Sci,2003,19(1):85-92.
[102] Tanabe K, Deguchi A, Higashi M, et al. Outer arm fucosylation of N-glycansincreases in sera of hepatocellular carcinoma patients[J]. Biochem BiophysRes Commun,2008,374(2):219-225.
[103] Mehta A, Block T M. Fucosylated glycoproteins as markers of liver disease[J].Dis Markers,2008,25(4-5):259-265.
[104] Breton C, Snajdrova L, Jeanneau C, et al. Structures and mechanisms ofglycosyltransferases[J]. Glycobiology,2006,16(2):29r-37r.
[105] Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth andmetastasis in Mgat5-deficient mice[J]. Nat Med,2000,6(3):306-312.
[106] Marrero JA R P, Nikolaeva O, et al. GP73, a resident Golgi glycoprotein, is anovel serum marker for hepatocellular careinorna[J]. J. Hepatol,2005,43:2007-2012.
[107] Spangenberg HC T R,.Blum HE. Serum markers of hepatoeellularcareinoma[J]. Semin Liver Dis,2006,26:385-390.
[108] Deugnier Y, David V, Brissot P, et al. Serum alpha-L-fucosidase: a newmarker for the diagnosis of primary hepatic carcinoma?[J]. Hepatology,1984,4(5):889-892.
[109]马艳平，张波，祝臣栋等. α-L-岩藻糖苷酶、甲胎蛋白及其异质体在原发性肝癌诊断中的意义[J].中国综合临床，2003，19：83-84.
[110] Man XB T L, Zhang BH, et al. Upregulation of Glypcan-3expression inhepatoeellular carcinoma but downregulation in cholangiocarcinoma indicatesits differential diagnosis value in primary liver cancers[J]. Liver Int,2005,25:962-966.
[111] Wang L, Ku X M, Li Y, et al. Regulation of matrix metalloproteinaseproduction and tumor cell invasion by four monoclonal antibodies againstdifferent epitopes of HAb18G/CD147extracellular domain[J]. Hybridoma,2006,25(2):60-67.
[112] Ormandy LA F A, Cantz T, et al. Dircect ex vivo analysis of dendritic cells inpatients with hepatoce!lular carcinoma[J]. World J Gastroenterol,2006,12:3275-3282.
[113] Qoronfleh M W, Benton B, Ignacio R, et al. Selective Enrichment ofMembrane Proteins by Partition Phase Separation for Proteomic Studies[J].Journal of biomedicine&biotechnology,2003(4):249-255.
[114] Naka R, Kamoda S, Ishizuka A, et al. Analysis of total N-glycans in cellmembrane fractions of cancer cells using a combination of serotonin affinitychromatography and normal phase chromatography[J]. Journal of proteomeresearch,2006,5(1):88-97.
[115] Rakus J F, Mahal L K. New technologies for glycomic analysis: toward asystematic understanding of the glycome[J]. Annual review of analyticalchemistry (Palo Alto, Calif),2011,4:367-392.
[116] N T. Three-dimensinal mapping of N-linked oligosaccharides usinganion-exchange, hydrophobic and hydrophilic interaction modes ofhigh-performance liquid chromatography[J]. J Chromatogr A,1996,720(1-2):217-255.
[117] Tateno H, Nakamura-Tsuruta S, Hirabayashi J. Frontal affinitychromatography: sugar-protein interactions[J]. Nature protocols,2007,2(10):2529-2537.
[118] Westerlund-Wikstrom B, Korhonen T K. Molecular structure of adhesindomains in Escherichia coli fimbriae[J]. Int J Med Microbiol,2005,295(6-7):479-486.
[119]陈国千.糖蛋白糖链结构分析与恶性肿瘤的诊断[J].国外医学临床生物化学与检脸学分册，2000，22(9)：171-174.
[120] Wang LJ L F, Sun W, et al. Concanavaion A-captured glycoproteins in healthyhuman urine[J]. Mol Cell Proteomics,2006,5:560-562.
[121] Dai Z F J, Liu YK, et al. Identification and analysis of α1,6-fucosylatedglycoproteins associated with hepatocellular carcinoma metastasis[J].Proteomics,2006,6:5857-5867.
[122] Zhao J, Simeone D M, Heidt D, et al. Comparative serum glycoproteomicsusing lectin selected sialic acid glycoproteins with mass spectrometricanalysis: Application to pancreatic cancer serum[J]. Journal of proteomeresearch,2006,5(7):1792-1802.
[123] Harvey D J. Matrix-assisted laser desorption/ionization mass spectrometry ofcarbohydrates[J]. Mass spectrometry reviews,1999,18(6):349-450.
[124] Harvey D J. Identification of protein-bound carbohydrates by massspectrometry[J]. Proteomics,2001,1(2):311-328.
[125] Froesch M, Bindila L M, Baykut G, et al. Coupling of fully automated chipelectrospray to Fourier transform ion cyclotron resonance mass spectrometryfor high-performance glycoscreening and sequencing[J]. Rapid CommunMass Spectrom,2004,18(24):3084-3092.
[126] Kameyama A, Kikuchi N, Nakaya S, et al. A strategy for identification ofoligosaccharide structures using observational multistage mass spectrallibrary[J]. Anal Chem,2005,77(15):4719-4725.
[127] Shaw G S, Sun Y, Barber K R, et al. Sequence specific analysis of theheterogeneous glycan chain from peanut peroxidase by1H-NMRspectroscopy[J]. Phytochemistry,2000,53(1):135-144.
[128] Kogelberg H, Piskarev V E, Zhang Y, et al. Determination by electrospraymass spectrometry and1H-NMR spectroscopy of primary structures ofvariously fucosylated neutral oligosaccharides based on theiso-lacto-N-octaose core[J]. European journal of biochemistry/FEBS,2004,271(6):1172-1186.
[129] Nimrichter L, Gargir A, Gortler M, et al. Intact cell adhesion to glycanmicroarrays[J]. Glycobiology,2004,14(2):197-203.
[130] Zheng T, Peelen D, Smith L M. Lectin arrays for profiling cell surfacecarbohydrate expression[J]. Journal of the American Chemical Society,2005,127(28):9982-9983.
[131] Mao X, Luo Y, Dai Z, et al. Integrated lectin affinity microfluidic chip forglycoform separation[J]. Anal Chem,2004,76(23):6941-6947.
[132] Raman R, Raguram S, Venkataraman G, et al. Glycomics: an integratedsystems approach to structure-function relationships of glycans[J]. Naturemethods,2005,2(11):817-824.
[133] Callewaert N, Geysens S, Molemans F, et al. Ultrasensitive profiling andsequencing of N-linked oligosaccharides using standard DNA-sequencingequipment[J]. Glycobiology,2001,11(4):275-281.
[134] Chen C, Schmilovitz-Weiss H, Liu X E, et al. Serum protein N-glycansprofiling for the discovery of potential biomarkers for nonalcoholicsteatohepatitis[J]. Journal of proteome research,2009,8(2):463-470.
[135]刘波，宋淼，巩新等.一种利用DSA-FACE分析寡糖链的方法[J].生物技术通讯，2008，6(19)：885-889.
[136] Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosisof liver cirrhosis using DNA sequencer-based total serum protein glycomics[J].Nat Med,2004,10(4):429-434.
[137]赵云鹏，高春芳，房萌等.原发性肝细胞癌患者血清N-糖组的表达分析[J].第二军医大学学报，2007，28(12)：1280-1283.
[138] Vanderschaeghe D, Laroy W, Sablon E, et al. GlycoFibroTest is a highlyperformant liver fibrosis biomarker derived from DNA sequencer-based serumprotein glycomics[J]. Mol Cell Proteomics,2009,8(5):986-994.
[139] Fang M, Dewaele S, Zhao Y P, et al. Serum N-glycome biomarker formonitoring development of DENA-induced hepatocellular carcinoma in rat[J].Molecular cancer,2011,9:215.
[140] Blomme B, Van Steenkiste C, Vanhuysse J, et al. Impact of elevation of totalbilirubin level and etiology of the liver disease on serum N-glycosylationpatterns in mice and humans[J]. American journal of physiology,2012,298(5):G615-624.
[141] Debruyne E N, Vanderschaeghe D, Van Vlierberghe H, et al. Diagnostic valueof the hemopexin N-glycan profile in hepatocellular carcinoma patients[J].Clinical chemistry,2011,56(5):823-831.
[142] Zhao Y P, Ruan C P, Wang H, et al. Identification and assessment of newbiomarkers for colorectal cancer with serum N-glycan profiling[J]. Cancer,2012,118(3):639-650.
[143] Gui H L, Gao C F, Wang H, et al. Altered serum N-glycomics in chronichepatitis B patients[J]. Liver Int,2012,30(2):259-267.
[144] Fang M, Zhao Y P, Zhou F G, et al. N-glycan based models improvediagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma[J].International journal of cancer,2012,127(1):148-159.
[145] Vanhooren V, Desmyter L, Liu X E, et al. N-glycomic changes in serumproteins during human aging[J]. Rejuvenation research,2007,10(4):521-531a.
[146] Vanhooren V, Dewaele S, Libert C, et al. Serum N-glycan profile shift duringhuman ageing[J]. Experimental gerontology,2011,45(10):738-743.
[147] Vanhooren V, Laroy W, Libert C, et al. N-glycan profiling in the study ofhuman aging[J]. Biogerontology,2008,9(5):351-356.
[148] Vanhooren V, Liu X E, Franceschi C, et al. N-glycan profiles as tools indiagnosis of hepatocellular carcinoma and prediction of healthy humanageing[J]. Mech Ageing Dev,2009,130(1-2):92-97.
[149] Chen C C, Engelborghs S, Dewaele S, et al. Altered serum glycomics inAlzheimer disease: a potential blood biomarker?[J]. Rejuvenation research,2012,13(4):439-444.
[150] Ding N, Nie H, Sun X, et al. Human serum N-glycan profiles are age and sexdependent[J]. Age and ageing,2012,40(5):568-575.
[151] Lee K J, Jung J H, Lee J M, et al. High-throughput quantitative analysis ofplant N-glycan using a DNA sequencer[J]. Biochem Bioph Res Co,2009,380(2):223-229.
[152] Holland N B, Qiu Y, Ruegsegger M, et al. Biomimetic engineering ofnon-adhesive glycocalyx-like surfaces using oligosaccharide surfactantpolymers[J]. Nature,1998,392(6678):799-801.
[153] Hirabayashi J, Kasai K. Separation technologies for glycomics[J]. Journal ofchromatography,2002,771(1-2):67-87.
[154] Morelle W, Michalski J C. Glycomics and mass spectrometry[J]. Currentpharmaceutical design,2005,11(20):2615-2645.
[155] Bordier C. Phase separation of integral membrane proteins in Triton X-114solution[J]. J Biol Chem,1981,256(4):1604-1607.
[156] Baik Y S, Cheong W J. Development of SPE for recovery of polysaccharidesand its application to the determination of monosaccharides composition ofthe polysaccharide sample of a lactobacillus KLB58[J]. Journal of separationscience,2007,30(10):1509-1515.
[157] Packer N H, Lawson M A, Jardine D R, et al. Analyzing glycoproteinsseparated by two-dimensional gel electrophoresis[J]. Electrophoresis,1998,19(6):981-988.
[158] Gil G C, Kim Y G, Kim B G. A relative and absolute quantification of neutralN-linked oligosaccharides using modification with carboxymethyltrimethylammonium hydrazide and matrix-assisted laser desorption/ionizationtime-of-flight mass spectrometry[J]. Analytical biochemistry,2008,379(1):45-59.
[159] Wilson J J, Brodbelt J S. Ultraviolet photodissociation at355nm offluorescently labeled oligosaccharides[J]. Anal Chem,2008,80(13):5186-5196.
[160] Schulz B L, Packer N H, Karlsson N G. Small-scale analysis of O-linkedoligosaccharides from glycoproteins and mucins separated by gelelectrophoresis[J]. Anal Chem,2002,74(23):6088-6097.
[161] Zhao J, Qiu W, Simeone D M, et al. N-linked glycosylation profiling ofpancreatic cancer serum using capillary liquid phase separation coupled withmass spectrometric analysis[J]. Journal of proteome research,2007,6(3):1126-1138.
[162] Lee K J, Jung J H, Lee J M, et al. High-throughput quantitative analysis ofplant N-glycan using a DNA sequencer[J]. Biochem Biophys Res Commun,2009,380(2):223-229.
[163] Bruix J, Boix L, Sala M, et al. Focus on hepatocellular carcinoma[J]. Cancercell,2004,5(3):215-219.
[164] Liaw Y F. Prevention and surveillance of hepatitis B virus-relatedhepatocellular carcinoma[J]. Semin Liver Dis,2005,25Suppl1:40-47.
[165] Koike K. Molecular basis of hepatitis C virus-associated hepatocarcinogenesis:lessons from animal model studies[J]. Clin Gastroenterol Hepatol,2005,3(10Suppl2): S132-135.
[166] Merican I, Guan R, Amarapuka D, et al. Chronic hepatitis B virus infection inAsian countries[J]. J Gastroenterol Hepatol,2000,15(12):1356-1361.
[167] Yuen M F, Wong D K, Fung J, et al. HBsAg Seroclearance in chronic hepatitisB in Asian patients: replicative level and risk of hepatocellular carcinoma[J].Gastroenterology,2008,135(4):1192-1199.
[168] Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosisof liver cirrhosis using DNA sequencer-based total serum protein glycomics[J].Nat Med,2004,10(4):429-434.
[169] Qu Y, Gao C F, Zhou K, et al. Serum N-glycomic markers in combination withpanels improves the diagnosis of chronic hepatitis B[J]. Annals of hepatology,2013,11(2):202-212.
[170] Laroy W, Contreras R, Callewaert N. Glycome mapping on DNA sequencingequipment[J]. Nature protocols,2006,1(1):397-405.
[171] Bram Blomme C V S, Paola Grassi, Stuart M. Haslam, et al. Alterations ofserum protein N-glycosylation in two mouse models of chronic liver diseaseare hepatocyte and not B cell driven[J]. American journal of physiology,2011,300:833-842.
[172] Vlad A M, Finn O J. Glycoprotein tumor antigens for immunotherapy ofbreast cancer[J]. Breast disease,2004,20:73-79.
[173] Banerjee A, Lang J Y, Hung M C, et al. Unfolded protein response is requiredin nu/nu mice microvasculature for treating breast tumor with tunicamycin[J].J Biol Chem,2011,286(33):29127-29138.
[174] Yamaguchi H, Uchida M. A chaperone-like function of intramolecularhigh-mannose chains in the oxidative refolding of bovine pancreatic RNaseB[J]. Journal of biochemistry,1996,120(3):474-477.
[175] Morishima S, Morita I, Tokushima T, et al. Expression and role of mannosereceptor/terminal high-mannose type oligosaccharide on osteoclast precursorsduring osteoclast formation[J]. The Journal of endocrinology,2003,176(2):285-292.
[176] Driouich A, Gonnet, P., Makkie, M., et al. The role of high-mannose andcomplex asparagine-linked glycans in the secretion and stability ofglycoproteins[J]. Planta,1989,180:96-104.
[177] Vagin O, Kraut J A, Sachs G. Role of N-glycosylation in trafficking of apicalmembrane proteins in epithelia[J]. Am J Physiol Renal Physiol,2009,296(3):F459-469.
[178] Vervecken W, Kaigorodov V, Callewaert N, et al. In vivo synthesis ofmammalian-like, hybrid-type N-glycans in Pichia pastoris[J]. Applied andenvironmental microbiology,2004,70(5):2639-2646.
[179] Lee S J, Evers S, Roeder D, et al. Mannose receptor-mediated regulation ofserum glycoprotein homeostasis[J]. Science (New York, N.Y),2002,295(5561):1898-1901.
[180] Weigel P H. Galactosyl and N-acetylgalactosaminyl homeostasis: a functionfor mammalian asialoglycoprotein receptors[J]. Bioessays,1994,16(7):519-524.
[181] Kronewitter S R, An H J, de Leoz M L, et al. The development ofretrosynthetic glycan libraries to profile and classify the human serumN-linked glycome[J]. Proteomics,2009,9(11):2986-2994.
[182] Ling Wang, Xue-en Liu, Claude Libert, et al. Alteration of liver N-glycome inpatients with hepatocellular carcinoma[J]. OJGas,2012:113-125.
[183] Handerson T, Camp R, Harigopal M, et al. Beta1,6-branched oligosaccharidesare increased in lymph node metastases and predict poor outcome in breastcarcinoma[J]. Clin Cancer Res,2005,11(8):2969-2973.
[184] Lubke T, Marquardt T, Etzioni A, et al. Complementation cloning identifiesCDG-IIc, a new type of congenital disorders of glycosylation, as aGDP-fucose transporter deficiency[J]. Nature genetics,2001,28(1):73-76.
[185] Luhn K, Wild M K, Eckhardt M, et al. The gene defective in leukocyteadhesion deficiency II encodes a putative GDP-fucose transporter[J]. Naturegenetics,2001,28(1):69-72.
[186] Wang X, Inoue S, Gu J, et al. Dysregulation of TGF-beta1receptor activationleads to abnormal lung development and emphysema-like phenotype in corefucose-deficient mice[J]. Proceedings of the National Academy of Sciences ofthe United States of America,2005,102(44):15791-15796.
[187] Wang X, Gu J, Ihara H, et al. Core fucosylation regulates epidermal growthfactor receptor-mediated intracellular signaling[J]. J Biol Chem,2006,281(5):2572-2577.