人与金黄地鼠中胰腺癌与癌旁正常组织差异蛋白质组学研究
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摘要
目的：本课题通过差异蛋白质组学方法分别对人胰腺癌、金黄地鼠胰腺癌模型癌组织与正常组织差异表达蛋白进行分析，结果通过免疫组化染色进行进一步的验证，以探讨胰腺癌相关的生物标记物与部分阐明胰腺癌的发病机制。
方法：金黄地鼠胰腺癌模型的建立；分别提取人与金黄地鼠胰腺癌组织和正常组织总蛋白，然后使用2-DE进行蛋白质分离并获得图像；采用PDQuest 7.1对2-DE胶上的蛋白点进行差异分析；切取差异表达蛋白点，然后采用MALDI-TOF-TOF-MS对差异蛋白点进行鉴定；免疫组化染色（SP法）对结果进行进一步验证。
结果：
（1）2-DE联合MALDI-TOF-MS技术在人、金黄地鼠胰腺癌组织中共分离鉴定了二十一个差异表达蛋白：尼克酰胺N-甲基转移酶(NNMT)、铁蛋白、谷胱甘肽S-转移酶、DNA拓扑异构酶、T细胞受体β-链、IKK抑制因子ε1、转胶蛋白、二甲基精氨酸二甲基氨基水解酶1（DDAH1)、半乳糖激酶1、肌球蛋白；肌动蛋白、α-烯醇(化)酶、Annexin A4、角蛋白8、胸腺嘧啶核苷激酶、蛋白酶体α1亚单位、羧肽酶B1、核糖体蛋白P1、磷脂酶A2、联接蛋白3、脑磷酯结合蛋白。
（2）其中：尼克酰胺N-甲基转移酶(NNMT)和铁蛋白2种蛋白在人胰腺癌组织中表达明显上调（＞4倍），谷胱甘肽S-转移酶、DNA拓扑异构酶、T细胞受体β-链、IKK抑制因子ε1、转胶蛋白、二甲基精氨酸二甲基氨基水解酶1（DDAH1)、半乳糖激酶1、肌球蛋白8种蛋白在人胰腺癌旁正常组织中表达明显上调（＞4倍）。肌动蛋白、α-烯醇(化)酶、Annexin A4、角蛋白8、胸腺嘧啶核苷激酶5种蛋白在金黄地鼠胰腺癌组织中表达明显上调（＞4倍），蛋白酶体α1亚单位、羧肽酶B1、核糖体蛋白P1、磷脂酶A2、铁蛋白、联接蛋白3、脑磷酯结合蛋白7种蛋白在金黄地鼠胰腺癌旁正常组织中表达明显上调（＞4倍）。
（3）免疫组化结果显示铁蛋白在人胰腺癌组织中表达上调，拓扑异构酶、谷胱甘肽-转移酶、肌球蛋白在正常组织中表达上调。
结论：实验所得的差异蛋白尼克酰胺N-甲基转移酶、转胶蛋白、DNA拓扑异构酶、二甲基精氨酸二甲基氨基水解酶1、铁蛋白、Annexin A4、联接蛋白3、α-烯醇(化)酶、羧肽酶B1、核糖体蛋白等可能与肿瘤细胞的浸润、转移、生长调节、缺氧耐受、及肿瘤组织血管形成有关；谷胱甘肽S-转移酶、肌球蛋白、核糖体蛋白P1、蛋白酶体α1亚单位与肿瘤细胞的蛋白质合成和降解有关；T细胞受体β-链、IKK抑制因子ε1与肿瘤细胞的信号转导有关；脑磷酯结合蛋白可能与肿瘤细胞膜的构建和重塑有关；这些蛋白质可能是胰腺癌早期诊断的生物学标记物和/或治疗靶标，其中Annexin A4与蛋白酶体α1亚单位等可能是胰腺癌诊断与治疗相关、新的生物学标记物。
Objective：To research biological markers related with diagnosis andtreatment of pancreatic cancer and partly clarify pathogenesis, we observeddifferential proteins of pancreas cancer tissues from normal were byproteomics in human being and golden hamster.
Methods：Golden hamster pancreatic cancer model was established, andthen total proteins of pancreatic cancer tissues and normal were respectivelyextracted from human beings and golden hamsters. 2-DE, PDQuest 7.1 andMALDI-TOF-TOF-MS were used to separate, obtain and identify differentialproteins, and part results were futher confirmed by immunohistochemicalstaining analysis.
Results：
(1) Twenty-one differentially expressed proteins were obtained asfollows: Nicotinamide N-methyltransferase (NNMT), Ferritin, glutathioneS-transferase M5, DNA topoisomerase, T-cell receptor beta chain, suppressorof IKK epsilon isoform1, transgelin, dimethylarginine dimethylamin-ohydrolase 1 (DDAH1), galactokinase 1, myosin；actin,α-enolase, annexinA4, keratin 8, thymidine kinase, PSMA1, carboxypeptidase B1, ribosomalprotein P1, phospholipaseA2, ankyrin3andphosphatidylethanolamine-bindingprotein.
(2) Among these twenty-one proteins, two proteins were up-regulated [ Nicotinamide N-methyltransferase (NNMT) and Ferritin] (>4 folds), and theeight proteins were down-regulated [glutathione S-transferase M5, DNAtopoisomerase, T-cell receptor beta chain, suppressor of IKK epsilonisoform1, transgelin, dimethylarginine dimethylamin- ohydrolase 1 (DDAH1),galactokinase 1 and myosin] (>4 folds) in human pancreatic tumor tissues；The five proteins were up-regulated [actin,α-enolase, annexin A4, keratin 8and thymidine kinase] (>4 folds), and the seven proteins were down-regulated[PSMA1, carboxypeptidase B1, ribosomal protein P1, phospholipase A2,Ferritin, ankyrin 3 and phosphatidylethanolamine-binding protein] (>4 folds)in golden hamster pancreatic tumor tissues.
(3) By immunohistochemistry staining analysis, ferritin was up-regulatedbut DNA topoisomerase, glutathione S-transferase M5 and myosin weredown-regulated in human tumor tissues.
Conclusions：Nicotinamide N-methyltransferase, transgelin, DNAtopoisomerase, dimethylarginine dimethylamin- ohydrolase 1 (DDAH1),Ferritin，Annexin A4, ankyrin 3,α-enolase, carboxypeptidase B1 andribosomal protein P1 may be associate with infiltration and immigration oftumour cell, growth control, hypoxia endure, and angiopoiesis; glutathioneS-transferase M5，myosin，ribosomal protein P1 and PSMA1 may beinvolved in protein synthesis and degradation of cancer cells; T cell acceptorBeta–chain and suppressor of IKK epsilon isoform1 were related with signaltransduction; phosphatidylethanolamine-binding protein may be associatedwith construction and remodeling of cell membrane; annexin A4 and PSMA1may be new important biological markers related with diagnosis and/ortherapy of patients with pancreatic cancer
方法：金黄地鼠胰腺癌模型的建立；分别提取人与金黄地鼠胰腺癌组织和正常组织总蛋白，然后使用2-DE进行蛋白质分离并获得图像；采用PDQuest 7.1对2-DE胶上的蛋白点进行差异分析；切取差异表达蛋白点，然后采用MALDI-TOF-TOF-MS对差异蛋白点进行鉴定；免疫组化染色（SP法）对结果进行进一步验证。
结果：
（1）2-DE联合MALDI-TOF-MS技术在人、金黄地鼠胰腺癌组织中共分离鉴定了二十一个差异表达蛋白：尼克酰胺N-甲基转移酶(NNMT)、铁蛋白、谷胱甘肽S-转移酶、DNA拓扑异构酶、T细胞受体β-链、IKK抑制因子ε1、转胶蛋白、二甲基精氨酸二甲基氨基水解酶1（DDAH1)、半乳糖激酶1、肌球蛋白；肌动蛋白、α-烯醇(化)酶、Annexin A4、角蛋白8、胸腺嘧啶核苷激酶、蛋白酶体α1亚单位、羧肽酶B1、核糖体蛋白P1、磷脂酶A2、联接蛋白3、脑磷酯结合蛋白。
（2）其中：尼克酰胺N-甲基转移酶(NNMT)和铁蛋白2种蛋白在人胰腺癌组织中表达明显上调（＞4倍），谷胱甘肽S-转移酶、DNA拓扑异构酶、T细胞受体β-链、IKK抑制因子ε1、转胶蛋白、二甲基精氨酸二甲基氨基水解酶1（DDAH1)、半乳糖激酶1、肌球蛋白8种蛋白在人胰腺癌旁正常组织中表达明显上调（＞4倍）。肌动蛋白、α-烯醇(化)酶、Annexin A4、角蛋白8、胸腺嘧啶核苷激酶5种蛋白在金黄地鼠胰腺癌组织中表达明显上调（＞4倍），蛋白酶体α1亚单位、羧肽酶B1、核糖体蛋白P1、磷脂酶A2、铁蛋白、联接蛋白3、脑磷酯结合蛋白7种蛋白在金黄地鼠胰腺癌旁正常组织中表达明显上调（＞4倍）。
（3）免疫组化结果显示铁蛋白在人胰腺癌组织中表达上调，拓扑异构酶、谷胱甘肽-转移酶、肌球蛋白在正常组织中表达上调。
结论：实验所得的差异蛋白尼克酰胺N-甲基转移酶、转胶蛋白、DNA拓扑异构酶、二甲基精氨酸二甲基氨基水解酶1、铁蛋白、Annexin A4、联接蛋白3、α-烯醇(化)酶、羧肽酶B1、核糖体蛋白等可能与肿瘤细胞的浸润、转移、生长调节、缺氧耐受、及肿瘤组织血管形成有关；谷胱甘肽S-转移酶、肌球蛋白、核糖体蛋白P1、蛋白酶体α1亚单位与肿瘤细胞的蛋白质合成和降解有关；T细胞受体β-链、IKK抑制因子ε1与肿瘤细胞的信号转导有关；脑磷酯结合蛋白可能与肿瘤细胞膜的构建和重塑有关；这些蛋白质可能是胰腺癌早期诊断的生物学标记物和/或治疗靶标，其中Annexin A4与蛋白酶体α1亚单位等可能是胰腺癌诊断与治疗相关、新的生物学标记物。
Objective：To research biological markers related with diagnosis andtreatment of pancreatic cancer and partly clarify pathogenesis, we observeddifferential proteins of pancreas cancer tissues from normal were byproteomics in human being and golden hamster.
Methods：Golden hamster pancreatic cancer model was established, andthen total proteins of pancreatic cancer tissues and normal were respectivelyextracted from human beings and golden hamsters. 2-DE, PDQuest 7.1 andMALDI-TOF-TOF-MS were used to separate, obtain and identify differentialproteins, and part results were futher confirmed by immunohistochemicalstaining analysis.
Results：
(1) Twenty-one differentially expressed proteins were obtained asfollows: Nicotinamide N-methyltransferase (NNMT), Ferritin, glutathioneS-transferase M5, DNA topoisomerase, T-cell receptor beta chain, suppressorof IKK epsilon isoform1, transgelin, dimethylarginine dimethylamin-ohydrolase 1 (DDAH1), galactokinase 1, myosin；actin,α-enolase, annexinA4, keratin 8, thymidine kinase, PSMA1, carboxypeptidase B1, ribosomalprotein P1, phospholipaseA2, ankyrin3andphosphatidylethanolamine-bindingprotein.
(2) Among these twenty-one proteins, two proteins were up-regulated [ Nicotinamide N-methyltransferase (NNMT) and Ferritin] (>4 folds), and theeight proteins were down-regulated [glutathione S-transferase M5, DNAtopoisomerase, T-cell receptor beta chain, suppressor of IKK epsilonisoform1, transgelin, dimethylarginine dimethylamin- ohydrolase 1 (DDAH1),galactokinase 1 and myosin] (>4 folds) in human pancreatic tumor tissues；The five proteins were up-regulated [actin,α-enolase, annexin A4, keratin 8and thymidine kinase] (>4 folds), and the seven proteins were down-regulated[PSMA1, carboxypeptidase B1, ribosomal protein P1, phospholipase A2,Ferritin, ankyrin 3 and phosphatidylethanolamine-binding protein] (>4 folds)in golden hamster pancreatic tumor tissues.
(3) By immunohistochemistry staining analysis, ferritin was up-regulatedbut DNA topoisomerase, glutathione S-transferase M5 and myosin weredown-regulated in human tumor tissues.
Conclusions：Nicotinamide N-methyltransferase, transgelin, DNAtopoisomerase, dimethylarginine dimethylamin- ohydrolase 1 (DDAH1),Ferritin，Annexin A4, ankyrin 3,α-enolase, carboxypeptidase B1 andribosomal protein P1 may be associate with infiltration and immigration oftumour cell, growth control, hypoxia endure, and angiopoiesis; glutathioneS-transferase M5，myosin，ribosomal protein P1 and PSMA1 may beinvolved in protein synthesis and degradation of cancer cells; T cell acceptorBeta–chain and suppressor of IKK epsilon isoform1 were related with signaltransduction; phosphatidylethanolamine-binding protein may be associatedwith construction and remodeling of cell membrane; annexin A4 and PSMA1may be new important biological markers related with diagnosis and/ortherapy of patients with pancreatic cancer
引文
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[18]Kuhlmann KF, van Till JW, Boermeester MA, de Reuver PR,Tzvetanova ID,Offerhaus GJ, et al. Evaluation of matrix metalloproteinase 7 in plasma and pancreaticjuice as a biomarker for pancreatic cancer[J]. Cancer Epidemiol Biomarkers Prev 2007;16:886-91. [PMID :17507610]
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[21]Ohuchida K, Mizumoto K, Yu J, Yamaguchi H, Konomi H,Nagai E, et al. S100A6 isincreased in a stepwise manner during pancreatic carcinogenesis: clinical value ofexpression analysis in 98 pancreatic juice samples[J]. Cancer Epidemiol BiomarkersPrev 2007;16:649-54. [PMID 17416753]
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[24]Ryu JK, Hong SM, Karikari CA, Hruban RH, Goggins MG,Maitra A. AberrantMicroRNA-155 expression is an early event in the multistep progression of pancreaticadenocarcinoma[J]. Pancreatology 2010; 10:66-73. [PMID 20332664]
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[26]Zhang L, Farrell JJ, Zhou H, Elashoff D, Akin D, Park NH, et al.Salivarytranscriptomic biomarkers for detection of resectable pancreatic cancer[J].Gastroenterology 2010; 138:949-57. [PMID19931263]
[27]Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, et al. Humanequilibrative nucleoside transporter 1 levels predict response to gemcitabine in patientswith pancreatic cancer[J].Gastroenterology 2009; 136:187-95. [PMID 18992248]
[28]Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, et al. Transcriptionanalysis of human equilibrative nucleoside transporter-1 predicts survival in pancreascancer patients treated with gemcitabine[J]. Cancer Res 2006; 66:3928-35. [PMID16585222]
[29]Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A,Fernandez-delCastillo C,Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patientswith resectable pancreatic adenocarcinoma[J].J Clin Oncol 2006; 24:2897-902. [PMID16782929]
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[32]Karanjawala ZE, Illei PB, Ashfaq R, Infante JR, Murphy K, Pandey A, et al. Newmarkers of pancreatic cancer identified through differential gene expression analyses:claudin 18 and annexin A8[J]. Am J Surg Pathol 2008; 32:188-96. [PMID 18223320]
[33]Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, et al.Exploration of global gene expression patterns in pancreatic adenocarcinoma usingcDNA microarrays[J]. Am J Pathol 2003;162:1151-62. [PMID 12651607]
[34]Chen R, Pan S, Yi EC, Donohoe S, Bronner MP, Potter JD, et al.Quantitativeproteomic profiling of pancreatic cancer juice[J]. Proteomics 2006; 6:3871-9. [PMID16739137]
[35]Chen R, Yi EC, Donohoe S, Pan S, Eng J, Cooke K, et al.Pancreatic cancer proteome:the proteins that underlie invasion, metastasis, and immunologic escape[J].Gastroenterology 2005; 129:1187-97. [PMID 16230073]
[36]Ehmann M, Felix K, Hartmann D, Schn lzer M, Nees M,Vorderwülbecke S, et al.Identification of potential markers for the detection of pancreatic cancer throughcomparative serum protein expression profiling[J]. Pancreas 2007; 34:205-14. [PMID17312459]
[37]Sun ZL, Zhu Y, Wang FQ, Chen R, Peng T, Fan ZN, et al.Serum proteomic-basedanalysis of pancreatic carcinoma for the identification of potential cancerbiomarkers[J]. Biochim Biophys Acta 2007; 1774:764-71. [PMID 17507299]
[38]Ishizone S, Yamauchi K, Kawa S, Suzuki T, Shimizu F, Harada O, et al. Clinicalutility of quantitative RT-PCR targeted to alpha1,4-N-acetylglucosaminyltransferasemRNA for detection of pancreatic cancer[J]. Cancer Sci 2006; 97:119-26. [PMID16441422]
[39]Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES,Stampfer MJ, MansonJE, et al. Circulating insulin-like growth factor binding protein-1 and the risk ofpancreatic cancer[J].Cancer Res 2007;67:7923-8. [PMID 17699799]
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