siRNA调控胰腺癌（BxPC-3）MBD1表达后的差异蛋白质组学研究
|
摘要
目的:MBD1(methyl-CpG binding domain protein 1,MBD1)基因是一个重要的转录调控因子,它可通过结合甲基化位点抑制转录,导致肿瘤甲基化相关基因表达下降。本研究将通过RNA干扰技术,观察MBD1基因沉默后胰腺癌细胞蛋白质表达的差异、肿瘤细胞生物学特性的改变,以及相关基因表达的改变,探讨MBD1在胰腺癌发病机制中的角色及其参与的信号转导通路和调控网络,从而更深入地揭示胰腺癌发病的分子机制,为寻找胰腺癌的早期有效的诊断和治疗方法提供新的思路及实验基础。
方法:(1)选择MBD1高表达的人胰腺癌细胞株BxPC-3作为研究对象,利用RNA干扰的方法沉默BxPC-3细胞株MBD1的表达,建立稳定的MBD1沉默表达的细胞克隆。(2)采用二维电泳(2-DE)和质谱技术(MALDI-TOF-MS),筛选与鉴定MBD1下调后胰腺癌细胞BxPC-3中差异表达的蛋白质,并用RT-PCR和Western blot方法进行验证。免疫组化方法验证胰腺癌组织中差异相关蛋白的表达及其与胰腺癌临床病理特征的关系。(3)通过裸鼠胰腺癌移植瘤动物模型,研究MBD1下调对胰腺癌移植瘤生长的影响。RT-PCR检测移植瘤中MBD1和甲基化相关基因及部分抑癌基因的表达情况。(4)四甲基偶氮唑蓝法(MTT)比较MBD1下调前后BxPC-3细胞的生长情况,“伤口愈合”(Wound healing)试验检测MBD1下调后BxPC-3细胞运动迁移能力的改变。
结果:(1)设计合成了针对MBD1基因的小分子干扰RNA(small interfering RNA,siRNA),成功构建MBD1-siRNA真核表达质粒,采用脂质体介导的方法将MBD1-siRNA真核表达质粒转染胰腺癌细胞系BxPC-3,并筛选到MBD1沉默稳定表达的细胞株,经RT-PCR、Western blot证实,转染后MBD1表达水平明显下调。(2)在MBD1下调前后的人胰腺癌细胞株BxPC-3中建立了重复性良好的、可靠的二维电泳图谱。质谱鉴定得到14个差异表达蛋白:有9个相关蛋白(GRP78、Tollip、HSP A8、Vimentin、Stathmin 1、cofilin 2、hnRNP K、eIF3、ZFP-36)表达下调;5个蛋白(tubulinbeta 2、splicing factor arginine/serine-rich isoform 1、ER-60、P4hb、EFHD2)表达上调,并应用Western blot法进一步验证。(3)通过免疫组化法检测16例胰腺癌组织中Vimentin、GRP78、Stathmin的表达,发现与正常胰腺组织相比,Vimentin、Stathmin在胰腺癌中存在高表达,且Vimentin与胰腺癌淋巴结转移有关。(4)MTT试验结果显示MBD1下调后胰腺癌细胞生长明显减缓。(5)动物移植瘤实验表明,转染MBD1siRNA质粒的裸鼠移植瘤生长速度明显较对照组减慢,RT-PCR检测三组移植瘤MBD1、CDH-1、Rb基因的mRNA表达变化,发现与对照组相比,转染MBD1-siRNA移植瘤组在MBD1下调的同时,抑癌基因CDH-1与Rb的表达明显上调,RT-PCR检测移植瘤中Vimentin和GRP78的表达,结果显示MBD1-siRNA移植瘤组中Vimentin和GRP78基因的表达明显低于对照组。(6)Woundhealing试验提示MBD1下调对胰腺癌细胞的迁移能力无明显影响。
结论:siRNA技术可以沉默胰腺癌细胞中MBD1基因表达,MBD1的下调可使多个与肿瘤相关蛋白的表达发生改变,并可能通过恢复抑癌基因的表达改变胰腺癌细胞的增殖生长能力及其生物学特性,MBD1相关的转录调控网络机制可能在胰腺癌的发生发展过程中起到重要的作用。
Objective:Methyl-CpG binding domain protein 1(MBD1),a suppressor of gene transcription,may be involved in inactivation of tumor suppressor genes during tumorigenesis.Over-expression of MBD1 had been detected in human pancreatic carcinomas and correlated with tumor metastasis.The purpose of this study is to investigate the different expression of methyl-related proteins and genes after the silence of MBD1 in pancreatic cancer cell line BxPC-3,observe the effects of MBD1-knockdown on tumor biological characteristics and discuss the role of MBD1 as an impotant transcription regulator in carcinogenesis of pancreatic cancer.
Methods:The stable MBD1-knockdown pancreatic cancer cell line(BxPC-3) was established by RNA interference.The differential proteins between control and MBD1-knock-down cells were detected by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.The results were confirmed by RT-PCR and western blot.The expression of MBD1-related proteins in tumor tissues of 16 specimens of resected pancreatic cancer and 10 normal pancreatic tissues were determined by immunohistochemical staining.MTT assay and wound healing test were used to detect the changes of BxPC-3 cell growth and cell migratory ability after MBD1 knockdown respectively.In vivo,the pancreatic cancer nude mice model was established to observe the tumor growth and compare the different expression of some related tumor suppressor genes and methyl-related genes between MBD1-knockdown and control group by RT-PCR assay.
Results:MBD1-siRNA recombinant plasmid were stably transfected into BxPC-3 cell line,the expression of MBD1 was significantly down-regulated after RNA interference, which was confirmed by RT-PCR and Western blot assay.By two-dimensional gel electrophoresis and mass spectrometry,five up-regulated proteins(including tubulin beta 2,splicing factor arginine/serine- rich isoform 1,ER-60,P4hb,EFHD2) and nine down-regulated proteins(including GRP78,Tollip,HSP A8,Vimentin,Stathmin 1, cofilin 2,hnRNP K,eIF3,ZFP-36) were identified clearly.Most of the identified differential proteins were involved in tumorigenesis,especially related with tumor metastasis,and some were prognostic biomarkers for human malignant tumors.The expressions of Vimentin and Stathmin in pancreatic carcinoma were significantly higher than that in normal pancreas tissues,and the positive expression of Vimentin was closely related with lymph node metastasis.The growth of BxPC-3 cell was suppressed after RNA interference targeting MBD1 while cell migratory ability remained unchanged in vivo and vitro.The mRNA expression of tumor suppressor genes CDH1 and Rb were significantly up-regulated when MBD1,Vimentin and GRP78 were down-regulated in transplanted tumor of nude mice model.
Conclusion:The expression of MBD1 in pancreatic cancer cell BxPC-3 could be down-regulated by RNAi.Down-regulation of MBD1 could relieve the inhibition of some tumor suppressor genes and affect the biological features of pancreatic cancer cell BxPC-3,resulting in significant changes of some methyl-related proteins involved in carcinogenesis and metastasis.MBD1,as a transcription regulator,might play an important role in tumorigenesis of pancreatic cancer.
方法:(1)选择MBD1高表达的人胰腺癌细胞株BxPC-3作为研究对象,利用RNA干扰的方法沉默BxPC-3细胞株MBD1的表达,建立稳定的MBD1沉默表达的细胞克隆。(2)采用二维电泳(2-DE)和质谱技术(MALDI-TOF-MS),筛选与鉴定MBD1下调后胰腺癌细胞BxPC-3中差异表达的蛋白质,并用RT-PCR和Western blot方法进行验证。免疫组化方法验证胰腺癌组织中差异相关蛋白的表达及其与胰腺癌临床病理特征的关系。(3)通过裸鼠胰腺癌移植瘤动物模型,研究MBD1下调对胰腺癌移植瘤生长的影响。RT-PCR检测移植瘤中MBD1和甲基化相关基因及部分抑癌基因的表达情况。(4)四甲基偶氮唑蓝法(MTT)比较MBD1下调前后BxPC-3细胞的生长情况,“伤口愈合”(Wound healing)试验检测MBD1下调后BxPC-3细胞运动迁移能力的改变。
结果:(1)设计合成了针对MBD1基因的小分子干扰RNA(small interfering RNA,siRNA),成功构建MBD1-siRNA真核表达质粒,采用脂质体介导的方法将MBD1-siRNA真核表达质粒转染胰腺癌细胞系BxPC-3,并筛选到MBD1沉默稳定表达的细胞株,经RT-PCR、Western blot证实,转染后MBD1表达水平明显下调。(2)在MBD1下调前后的人胰腺癌细胞株BxPC-3中建立了重复性良好的、可靠的二维电泳图谱。质谱鉴定得到14个差异表达蛋白:有9个相关蛋白(GRP78、Tollip、HSP A8、Vimentin、Stathmin 1、cofilin 2、hnRNP K、eIF3、ZFP-36)表达下调;5个蛋白(tubulinbeta 2、splicing factor arginine/serine-rich isoform 1、ER-60、P4hb、EFHD2)表达上调,并应用Western blot法进一步验证。(3)通过免疫组化法检测16例胰腺癌组织中Vimentin、GRP78、Stathmin的表达,发现与正常胰腺组织相比,Vimentin、Stathmin在胰腺癌中存在高表达,且Vimentin与胰腺癌淋巴结转移有关。(4)MTT试验结果显示MBD1下调后胰腺癌细胞生长明显减缓。(5)动物移植瘤实验表明,转染MBD1siRNA质粒的裸鼠移植瘤生长速度明显较对照组减慢,RT-PCR检测三组移植瘤MBD1、CDH-1、Rb基因的mRNA表达变化,发现与对照组相比,转染MBD1-siRNA移植瘤组在MBD1下调的同时,抑癌基因CDH-1与Rb的表达明显上调,RT-PCR检测移植瘤中Vimentin和GRP78的表达,结果显示MBD1-siRNA移植瘤组中Vimentin和GRP78基因的表达明显低于对照组。(6)Woundhealing试验提示MBD1下调对胰腺癌细胞的迁移能力无明显影响。
结论:siRNA技术可以沉默胰腺癌细胞中MBD1基因表达,MBD1的下调可使多个与肿瘤相关蛋白的表达发生改变,并可能通过恢复抑癌基因的表达改变胰腺癌细胞的增殖生长能力及其生物学特性,MBD1相关的转录调控网络机制可能在胰腺癌的发生发展过程中起到重要的作用。
Objective:Methyl-CpG binding domain protein 1(MBD1),a suppressor of gene transcription,may be involved in inactivation of tumor suppressor genes during tumorigenesis.Over-expression of MBD1 had been detected in human pancreatic carcinomas and correlated with tumor metastasis.The purpose of this study is to investigate the different expression of methyl-related proteins and genes after the silence of MBD1 in pancreatic cancer cell line BxPC-3,observe the effects of MBD1-knockdown on tumor biological characteristics and discuss the role of MBD1 as an impotant transcription regulator in carcinogenesis of pancreatic cancer.
Methods:The stable MBD1-knockdown pancreatic cancer cell line(BxPC-3) was established by RNA interference.The differential proteins between control and MBD1-knock-down cells were detected by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.The results were confirmed by RT-PCR and western blot.The expression of MBD1-related proteins in tumor tissues of 16 specimens of resected pancreatic cancer and 10 normal pancreatic tissues were determined by immunohistochemical staining.MTT assay and wound healing test were used to detect the changes of BxPC-3 cell growth and cell migratory ability after MBD1 knockdown respectively.In vivo,the pancreatic cancer nude mice model was established to observe the tumor growth and compare the different expression of some related tumor suppressor genes and methyl-related genes between MBD1-knockdown and control group by RT-PCR assay.
Results:MBD1-siRNA recombinant plasmid were stably transfected into BxPC-3 cell line,the expression of MBD1 was significantly down-regulated after RNA interference, which was confirmed by RT-PCR and Western blot assay.By two-dimensional gel electrophoresis and mass spectrometry,five up-regulated proteins(including tubulin beta 2,splicing factor arginine/serine- rich isoform 1,ER-60,P4hb,EFHD2) and nine down-regulated proteins(including GRP78,Tollip,HSP A8,Vimentin,Stathmin 1, cofilin 2,hnRNP K,eIF3,ZFP-36) were identified clearly.Most of the identified differential proteins were involved in tumorigenesis,especially related with tumor metastasis,and some were prognostic biomarkers for human malignant tumors.The expressions of Vimentin and Stathmin in pancreatic carcinoma were significantly higher than that in normal pancreas tissues,and the positive expression of Vimentin was closely related with lymph node metastasis.The growth of BxPC-3 cell was suppressed after RNA interference targeting MBD1 while cell migratory ability remained unchanged in vivo and vitro.The mRNA expression of tumor suppressor genes CDH1 and Rb were significantly up-regulated when MBD1,Vimentin and GRP78 were down-regulated in transplanted tumor of nude mice model.
Conclusion:The expression of MBD1 in pancreatic cancer cell BxPC-3 could be down-regulated by RNAi.Down-regulation of MBD1 could relieve the inhibition of some tumor suppressor genes and affect the biological features of pancreatic cancer cell BxPC-3,resulting in significant changes of some methyl-related proteins involved in carcinogenesis and metastasis.MBD1,as a transcription regulator,might play an important role in tumorigenesis of pancreatic cancer.
引文
1.李新建,郑莹,沈玉珍,等.上海市胰腺癌的流行现状和趋势研究.外科理论与实践,2002,7(5):342-345
2.Parkin DM,Bray F,Ferlay J,et al.Estimating the world cancer burden:Globocan 2000.Int J Cancer,2001,94(2):153-156
3.Li DH,Xie KP,Wolff R,et al.Pancreatic cancer.Lancet,2004,363(9414):1049-1057
4.Khosravi SP,Diaz M.Pancreatic adenocarcinoma:therapeutical update.An Med Interna,2005,22(8):390-394
5.张延龄,倪泉兴.应重视胰腺癌的早期诊断和综合治疗.中华医学杂志,2000,80(4):245-246
6.Ramirez PJ,Vickers SM.Current status of gene therapy for pancreatic cancer.Curr Surg.2004,61(1):84-92
7.Serman A,Vlahovic M,Serman L,et al.DNA methylation as a regulatory mechanism for gene expression in mammals.Coll Antropol,2006,30(3):665-671
8.Venter JC,Adams MD,Myers EW,et al.The sequence of the human genome.Science,2001,291(5507):1304-1351
9.Lander ES,Linton LM,Birren B,et al.International human genome sequencing consortium.Initial sequencing and analysis of the human genome.Nature,2001,409(6822):860-921
10.Cody DT,Huang Y.Differential DNA methylation of the p16INK4 CDKA2 a promoter in human oral cancer cells and normal human oral kerarnocytes.Oral Oncol,1999,35(5):516-522
11.Ueki T,Toyota M,Sohn T,et al.Hypermethylation of multiple genes in pancreatic adenocarcinoma.Cancer Res,2000,60(7):1835-1839
12.Gonzalez-Zulueta M,Bender CM,Yang AS,et al.Methylation of the 5'CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissue correlates with gene silencing.Cancer Res,1995,55(20):4531-4535.
13.Yu X J,Long J,Fu DL,Zhang QH,Ni QX:Analysis of gene expression profiles in pancreatic carcinoma by using cDNA microarray.Hepatobiliary Pancreat Dis Int.2003,2(3):467-470.
14.Ng HH,Jeppesen P,Bird A.Active repression of methylated genes by the chromosomal protein MBD1.Molecular and Cellular Bio,2000,20(4):1394-1406.
15.狄扬,龙江,傅德良,等.甲基化CpG结合域蛋白1在胰腺癌组织中的表达和意义.外科理论与实践,2006,11(1):35-38.
16.Fujita N,Shimotake N,Ohki I,et al.Mechanism of transcriptional regulation by methyl-CpG binding protein MBD1.Mol.Cell Biol.2000,20(14):5107-5118.
17.Marks PA,Rifkind RA,Richon VM,et al.Histonedeacetylase and cancer:cause and therapies.Nat Rev Cancer,2001,1(3):194-202
18.Cross SH,Meehan RR,Nan X,et al.Component of the transcriptional repressor MeCP1shares a motif with DNA methyltransferase and HRX proteins.Nat.Genet,1997,16(8):256-259
19.Ballestar E,Wolffe AE Methyl-CpG-binding proteins targeting specific gene repression.Eur J.Biochem.2001,268(1):1-6.
20.Lopez-Serra L,Ballestar E,Fraga MF,et al.A Profile of Methyl-CpG Binding Domain Protein Occupancy of Hypermethylated Promoter CpG Islands of Tumor Suppressor Genes in Human Cancer.Cancer Res.2006,66(17):8342-8346.
21.虞先浚,龙江,傅德良,等.利用cDNA微列阵技术分析胰腺癌相关基因表达谱.中华实验外科杂志,2002,19(4):302-303
22.傅德良,龙江,金忱,等.利用基因芯片和RT-PCR检测MBD1在胰腺癌中的表达.外科 理论与实践, 2005,10(3):241-244
23. Patra SK, Patra A, Zhao H, et al. Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochem.Biophys.Res. Commun. 2003,302(4): 759-766.
24. Hannon GJ. RNA interference. Nature,2002,418(11):244-251
25. Yu JY,DeRuiter SL,Tuner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells.Proc Natl Acad Sci USA,2002,99(9):6047-6052
26. Coppola D: Molecular prognostic markers in pancreatic cancer. Cancer Control 2000, 7(5): 421-427.
27. A. Shevchenko, M. Wilm, O. Vorm, M. Mann: Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal.Chem. 1996,68(5): 850-858.
28. Fang CY, Yi ZG, Liu F, et al. Proteome analysis of human liver carcinoma Huh7 cells harboring hepatitis C virus subgenomic replicon. Proteomics. 2006, 6 (2): 519-527
29. Lang SH, Hyde C, Reid IN, et al. Enhanced expression of Vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate 2002, 52(4): 253-263
30. Lee E, Nichols P, Spicer D, etc. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006, 66(16): 7849-7853.
31. Yuan RH, Jeng YM, Chen HL,et al. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol. 2006,209(4):549-558.
32. Bank RE, Dum MJ, Hochstrasser DF, et al. Proteomics: new perspectives, new biomedical opportunities. Lancet, 2000, 356 (9243) : 1749-1756.
33. Carr KM, Rosenblatt K, Petricoin EF, et al. Genomic and proteomic approaches for studying human cancer: prospects for true patient-tailored therapy. Hum Genomics. 2004, 1(2):134-140.
34. Wulfkuhle J, Espina V, Liotta L. Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer. 2004,40(17):2623-2632.
35. 何大澄, 肖雪媛. 差异蛋白质组学及其应用. 北京师范大学学报(自然科学版). 2002, 38(4):558-562
36. Bjellqvist, B., Ek K., Righetti, P.G, et al. Isoelectric focusing in immobilized pH gradients: principle, methodology and some applications. J Biochem. Biophys. Methods 1982, 6(4): 317-339
37. Karas, M., Hillenkamp, F. Laser Desorption Ionization of Proteins with Molecular Masses Exceeding 10,000 Daltons.Anal.Chem.1988, 60(20):2299-2301
38. Fenn JB, Mann M, Meng CK, et al. Electrospray Ionization for Mass Spectrometry of LargeBiomolecules. Science, 1989, 246(4926):64-71
39. Cornwell MM, SmithDE. SP1 activates the MDR1 promoter through one of two distinct G-rich regions that modulate promoter activity. J Biol Chem, 1993, 268(26): 19505-19511
40. Wang N, Stamenovic D. Mechanics of Vimentin intermediate filaments, J.Muscle Res.Cell Motil. 2002, 23(5-6):535-540.
41. Ivaska J, Pallari HM, Nevo J, et al. Novel functions of Vimentin in cell adhesion, migration, and signaling, Exp. Cell Res.2007,313 (10):2050-2062.
42. Korsching E, Packeisen J, Liedtke C, et al. The origin of Vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 2005; 206(4):451-457
43. Ko SH, Suh SH, Kim BJ, et al. Expression of the intermediate filament Vimentin in proliferating duct cells as a marker of pancreatic precursor cells. Pancreas 2004, 28(2): 121-128
44. 殷涛, 王春友, 熊炯炘, 等. Vimentin在胰腺癌细胞中的表达及临床意义. 世界华人消化杂志. 2007,15(36):3822-3825
45. Nakajima S, Doi R, Toyoda E, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004,10 (12 Pt 1):4125-4133.
46. Domagala W, Striker G, Szadowska A, et al. p53 protein and Vimentin in invasive ductal NOS breast carcinoma-relationship with survival and sites of metastases. Eur J Cancer. 1994,30A(10): 1527-1534.
47. Gilles C, Polette M, Piette J, Delvigne AC, et al. Vimentin expression in cervical carcinomas: association with invasive and migratory potential. J Pathol. 1996 ,180(2): 175-180.
48. Nolan LP, Heatley MK. The value of immunocytochemistry in distinguishing between clear cell carcinoma of the kidney and ovary. Int J Gynecol Pathol. 2001,20(2): 155-159
49. Zhang L, Cilley RE, Chinoy MR. Suppression subtractive hybridization to identify gene expressions in variant and classic small cell lung cancer cell lines. J Surg Res. 2000,93(1):108-119.
50. Kokkinos MI, Wafai R, Wong MK, et al. Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs. 2007,185(1-3):191-203
51. McInroy L, Maatta A. Down-regulation of Vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun. 2007 ,360(1):109-114.
52. Shah AN, Summy JM, Zhang J,et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007,14(12):3629-3637.
53. Kajiyama H, Shibata K, Terauchi M,et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 2007,31(2):277-283
54. Frederick BA, Helfrich BA, Coldren CD,et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther. 2007 ,6(6): 1683-1691.
55. Lee AS. The glucose-regulated proteins: Stress induction and clinical applications. Trends Biochem Sci 2001; 26(8): 504-510.
56. Hendershot LM. The ER function BiP is a master regulator of ER function. Mt Sinai J Med 2004; 71(5): 289-297.
57. Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med. 2006; 6(1): 45-54.
58. Xing X, Lai M, Wang Y,etc. Overexpression of glucose-regulated protein 78 in colon cancer. Clin Chim Acta 2006; 364 (1-2) :308-315.
59. Wang Q, He Z, Zhang J, etc. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev 2005(6); 29:544-551.
60. Jamora C, Dennert G, Lee AS. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 1996; 93(15): 7690-7694.
61. Dong D, Dubeau L, Bading J, etc. Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors.Hum Gene Ther.2004; 15(6): 553-561.
62. Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006; 5(7): 741-744.
63. Zhang J, Jiang Y, Jia Z,etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
64. Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007; 67(8): 3496-3499.
65. Zhang J, Jiang Y, Jia Z,etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
66. Misra UK, Deedwania R, Pizzo SV. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem 2005; 280(28): 26278-26286.
67. Gray MD, Mann M, Nitiss JL, etc. Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIalpha protein levels and decreasing sensitivity to topoisomerase-targeted drugs. Mol Pharmacol 2005; 68(6): 1699-1707.
68. Arap MA, Lahdenranta J, Mintz PJ, etc. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004; 6(3): 275-284.
69. Davidson DJ, Haskell C, Majest S,etc. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface- expressed glucose-regulated protein 78. Cancer Res 2005; 65(11): 4663-4672.
70. Mistry SJ, Atweh GF.et al. Role of Stathmin in the regulation of the mitotic spindle: potential applications in cancer therapy.Mt Sinai J Med. 2002 ,69(5):299-304.
71. Walczak CE. Microtubule dynamics and tubulin interacting proteins. Curr Opin Cell Biol. 2000,12(1): 52-56.
72. Prasad SC, Thraves PJ, Soldatenkov VA, et al. Differential expression of Stathmin during neoplastic conversion of human prostate epithelial cells is reversed by hypomethylating agent, 5-azacytidine. Int J Oncol. 1999,14(3):529-534.
73. Johnsen JL Aurelio ON, Kwaja Z, et al. p53 mediated negative regulation of Stathmin/Op18 expression is associated with G(2)/M cell cycle arrest. Int J Cancer, 2000,88(5): 685-691
74. Manceau V, Gavet O, Curmi P, et al. Stathmin interaction with HSP70 family proteins. Electrophoresis, 1999,20(2): 409-417
75. Balachandran R, Welsh MJ, Day BW. Altered levels and regulation of Stathmin in paclitaxel-resistant ovarian cancer cells. Oncogene 2003, 22(55): 8924-8930
76. Wang R, Dong K, Lin F, et al. Inhibiting proliferation and enhancing chemosensitivity to taxanes in Osteosarcoma cells by RNA interference-mediated downregulation of Stathmin expression. Mol Med. 2007, 13(11-12):567-575
77. Chen G, Wang H, Gharib TG, et al. Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas.Mol Cell Proteomics.2003,2(2):107-116.
78.Wei SH,Lin F,Wang X,et al.Prognostic significance of Stathmin expression in correlation with metastasis and clinicopathological characteristics in human ovarian carcinoma.Acta Histochem.2008,110(1):59-65.
79.Yuan RH,Jeng YM,Chen HL,et al.Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression,and is associated with tumour progression,early recurrence,and poor prognosis in hepatocellular carcinoma.J.Pathol.2006,209(4) 549-558.
80.Notari M,Neviani P,Santhanam R,et al.A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.Blood.2006,107(6) 2507-2516.
81.Carpenter B,McKay M,Dundas SR,et al.Heterogeneous nuclear ribonucleoprotein K is over expressed,aberrantly localised and is associated with poor prognosis in colorectal cancer.Br J Cancer.2006,95(7) 921-927.
82.Zhang L,Pan X,Hershey JW.Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells.J.Biol.Chem.2007,282(8) 5790-5800.
83.Boengler K,Pipp F,Broich K,et al.Identification of differentially expressed genes like cofilin2 in growing collateral arteries,Biochem.Biophys.Res.Commun.2003,300(3)751-756.
84.Li T,Hu J,Li L.Characterization of Tollip protein upon Lipopolysaccharide challenge.Mol.Immunol.2004,41(1) 85-92.
85.Didierlaurent A,Brissoni B,Velin D,et al.Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide.Mol.Cell Biol.2006,26(3) 735-742.
86.钟良,陈坚,徐近,等.锌指蛋白2在胰腺癌中的表达.胰腺病学.2007,7(4):248-250
87.Zou H,Harrington JJ,Shire AM,et al.Highly methylated genes in colorectal neoplasia:implications for screening.Cancer Epidemiol Biomarkers Prev.2007,16(12):2686-2696.
88.Chen WD,Han ZJ,Skoletsky J,et al.Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed Vimentin gene.J.Natl.Cancer Inst.2005,97(15):1124-1132.
89.Ostareck-Lederer A,Ostareck DH,Rucknagel KP,et al.Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1inhibits its interaction with c-Src.J.Biol.Chem.2006,281(16):11115-11125.
90.Yang Q,Liu S,Tian Y,et al.Methylation-associated silencing of the heat shock protein 47gene in human neuroblastoma.Cancer Res.2004,64(13):4531-4538.
91.Wang C,Gomer RH,Lazarides E.Heat shock proteins are methylated in avian and mammalian cells.Proc.Natl.Acad.Sci.USA.1981,78(6):3531-3535.
92.Gober MD,Smith CC,Ueda K,et al.Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells.J.Biol.Chem.2003,278(39):37600-37609.
93.吴瑛,赫荣乔.RNA剪接因子结构与功能研究进展.生物化学与生物物理进展.2003,30(4):503-508
94.Otsu M,Urade R,Kito M,et al.A possible role of ER-60 protease in the degradation of misfolded proteins in the endoplasmic reticulum.J.Biol.Chem.1995,270(25):14958-14961.
95.Pajunen L,Jones TA,Goddard A,et al.Regional assignment of the human gene coding for a multifunctional polypeptide(P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25. Cytogenet. Cell Genet. 1991,56(3-4): 165-168.
96. Goplen D, Wang J, Enger PO, et al. Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Cancer Res. 2006, 66(20): 9895-9902.
97. Avramidou A, Kroczek C, Lang C, et al. The novel adaptor protein Swiprosin-1 enhances BCR signals and contributes to BCR-induced apoptosis. Cell Death Differ. 2007 ,14(11):1936-1947.
98. Yeh IT, Luduena RF: The betaII isotype of tubulin is present in the cell nuclei of a variety of cancers, Cell Motil. Cytoskeleton. 2004, 57(2): 96-106.
99. Ranganathan S, Salazar H, Benetatos CA, et al. Immunohistochemical analysis of beta-tubulin isotypes in human prostate carcinoma and benign prostatic hypertrophy. Prostate, 1997,30(4): 263-268.
100. Katsetos CD, Herman MM, Mork SJ. Class III beta-tubulin in human development and cancer. Cell Motil Cytoskeleton, 2003, 55(2): 77-96.
101. Giamieri E, De Francesco GP, Carico E, et al. Alpha-and beta-tubulin expression in rectal cancer development. Anticancer Res, 2005,25(5): 3237-3241
102. Verdier-Pinard P, Wang F, Martello L, et al. Analysis of tubulin isotypes and mutations from taxol resistant cells by combined isoelectrofocusing and mass spectrometry . Biochemistry,2003,42(18): 5349-5357.
103. Shalli K, Brown I, Heys SD, et al. Alterations of beta-tubulin isotypes in breast cancer cells resistan t to docetaxel. FASEB J,2005,19(10): 1299-1301.
104. Lee KM, Cao D, Itami A, et al. Class III beta-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. Histopathology, 2007, 51 (4): 539-546
105. Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 1999,59(10): 2307-2312.
106. 胡笳, 郭燕婷, 李艳梅. 蛋白质翻译后修饰研究进展. 科学通报, 2005,50(11): 1061-1072
107. Idriss HT. Three steps to cancer: how phosphorylation of tubulin, tubulin tyrosine ligase and P-glycoprotein may generate and sustain cancer. Cancer Chemother Pharmacol, 2004, 54(2): 101-104
108. Ghosh R, Gu G, Tillman E, etc. Increased expression and differential phosphorylation of Stathmin may promote prostate cancer progression. Prostate. 2007 ,67(10): 1038-1052.
109. Wang Y, Yamaguchi Y, Watanabe H, etc. Detection of p53 gene mutations in the supernatant of pancreatic juice and plasma from patients with pancreatic carcinomas. Pancreas. 2004,28(1):13-19
110. Hua Z, Zhang YC, Hu XM, et al. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol. 2003 ,9(12):2764-2767
111. Gerdes B, Ramaswamy A, Ziegler A, et al. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann Surg. 2002 ,235(1):51-59
112. House MG, Guo M, Iacobuzio-Donahue C, et al.Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas.Carcinogenesis. 2003 ,24(2): 193-198.
113. House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003 ,238(3):423-431
114. Schlegel J, Guneysu S, Mennel HD. Expression of the genes of methyl-binding domain proteins in human gliomas. Oncol Rep. 2002 ,9(2):393-395.
115. Jang JS, Lee SJ, Choi JE, et al. Methyl-CpG binding domain 1 gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2005,14(11 Pt 1):2474-2480
116. Fujita N, Takebayashi S, Okumura K, et al. Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol Cell Biol. 1999,19(9):6415-6426
117. Ballestar E, Paz MF, Valle L, et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J, 2003, 22(23): 6335-6345.
118. Tomizawa Y, Sekido Y, Kondo M, et al. Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A. 2001 ,98(24): 13954-13959
119. Morris MR, Gentle D, Abdulrahman M, et al. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br J Cancer. 2008 ,98(2):496-501
120. Liu JW, Kim MS, Nagpal J, et al. Quantitative hypermethylation of NMDAR2B in human gastric cancer. Int J Cancer. 2007 ,121(9): 1994-2000
121. Seng TJ, Low JS, Li H, et al. The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene. 2007,26(6):934-944
122. Dansranjavin T, Mobius C, Tannapfel A,et al. E-cadherin and DAP kinase in pancreatic adenocarcinoma and corresponding lymph node metastases. Oncol Rep. 2006,15(5):1125-1131.
123. Shin SJ, Kim KO, Kim MK, et al. Expression of E-cadherin and uPA and their association with the prognosis of pancreatic cancer. Jpn J Clin Oncol. 2005 ,35(6):342-8.
124. Joo YE, Rew JS, Park CS, et al. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology. 2002;2(2): 129-37
125. Huiping C, Kristjansdottir S, Jonasson JG, et al. Alterations of E-cadherin and beta-catenin in gastric cancer. BMC Cancer. 2001,1(1): 16.
126. Winter JM, Ting AH, Vilardell F, et al. Absence of e-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res. 2008,14(2):412-418.
127. Shimizu K, Hanaoka M, Kato A,et al. Reduced expression of the E-cadherin gene and its aberrant DNA methylation in hamster pancreatic tumors. Biochem Biophys Res Commun. 2005,336(1):49-53.
128. Stirzaker C, Millar DS, Paul CL, et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res. 1997,57(11):2229-2237
129. Casanovas O, Hager JH, Chun MG, et al. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene. 2005,24(44):6597-6604.
130. Kawaguchi K, Oda Y, Saito T, et al. DNA hypermethylation status of multiple genes in soft tissue sarcomas. Mod Pathol. 2006,19(1): 106-114
131. Li H, Lu S, Fong L. Study on the status of methylation of Rb gene promoter in human esophageal cancer and effect of NMBzA on Rb gene promoter in monkey esophageal epithelium. Zhonghua Zhong Liu Za Zhi. 1998 ,20(6):412-414
132. Yin D, Xie D, Hofmann WK, et al. Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors. Oncogene. 2002,21(54):8372-8378
133. 郑海涛, 赵鸿鹏, 卢俊. 胰腺癌的浸润和转移研究进展. 世界华人消化杂志. 2005,13(10):1219-1222
134. Jiang P, Watanabe H, Okada G,et al. Diagnostic utility of aberrant methylation of tissue factor pathway inhibitor 2 in pure pancreatic juice for pancreatic carcinoma. Cancer Sci. 2006 ,97(11): 1267-1273.
135. Sato N, Parker AR, Fukushima N,et al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene. 2005,24(5):850-858
136. Liu L, Broaddus RR, Yao JC,et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol. 2005 ,18(12): 1632-1640.
137. Zhang C, Li H, Zhou G, Zhang Q, et al. Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells.J Pathol. 2007 ,212(2): 134-142.
138. Meng CF, Zhu XJ, Peng G, et al. Re-expression of methylation-induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol. 2007,13(46):6166-6171
139. Maass N, Biallek M, Rosel F,et al. Hypermethylation and histone deacetylation lead to silencing of the maspin gene in human breast cancer.Biochem Biophys Res Commun. 2002 ,297(1): 125-128.
140. Chiba T, Yokosuka O, Fukai K,et al. Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology. 2004,66(6):481-491.
141. Gahr S, Ocker M, Ganslmayer M, et al. The combination of the histone- deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells.Int J Oncol. 2007 ,31(3):567-576
142. Donadelli M, Costanzo C, Faggioli L, et al. Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells.Mol Carcinog. 2003 ,38(2):59-69
143. Piacentini P, Donadelli M, Costanzo C, et al. Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation. Virchows Arch. 2006 ,448(6):797-804
144. Liu LT, Chang HC, Chiang LC, et al.Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion.Cancer Res. 2003 ,63(12):3069-3072.
145. Kim MS, Kwon HJ, Lee YM, et al.Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.Nat Med. 2001 ,7(4):437-443.
146. Gottlicher M, Minucci S, Zhu P, et al.Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.EMBO J. 2001 ,20(24): 6969-6978.
147. Uchida H, Maruyama T, Nagashima T,et al. Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin.Endocrinology. 2005,146(12):5365-5373
148. Fan J, Yin WJ, Lu JS,et al. ERalpha negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor.J Cancer Res Clin Oncol. 2008 Feb 9 [Epub ahead of print]
1.Shiu RP,Pastan IH.Properties and purification of a glucose-regulated protein from chick embryo fibroblasts.Biochim Bopphys Acta 1979;576(1):141-150.
2.Lee AS.The glucose-regulated proteins:Stress induction and clinical applications.Trends Biochem Sci 2001;26(8):504-510.
3.Hendershot LM.The ER function BiP is a master regulator of ER function.Mt Sinai J Med 2004;71(5):289-297.
4.Banhegyi G,Baumeister P,Benedetti A,etc.Endoplasmic reticulum stress.Ann N Y Acad Sci.2007;1113(1):58-71.
5.Li J,Lee AS.Stress induction of GRP78/BiP and its role in cancer.Curr Mol Med.2006;6(1):45-54.
6.Shen x,Zhang K,Kaufman RJ.The unfolded protein response-a stress signaling pathway of the endoplasmic reticulum.J Chem Neuroanat 2004;28(1-2):79-92.
7.Luo S,Mao C,Lee B,etc.GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development.Mol Cell Bioi.2006;26(15):5688-5697.
8.Mao C,Tai WC,Bai Y,etc.In vivo regulation of Grp78/BiP transcription in the embryonic heart:role of the endoplasmic reticulum stress response element and GATA-4.J Biol Chem.2006;281(13):8877-8887.
9.Li J,Lee B,Lee AS.Endoplasmic reticulum stress-induced apoptosis:multiple pathways and activation of p53-up-regulated modulator of apoptosis(PUMA) and NOXA by p53.J Biol Chem.2006;281(11):7260-7270.
10.Dong D,Dubeau L,Bading J,etc.Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors.Hum Gene Ther.2004;15(6):553-561.
11.Lee AS.GRP78 induction in cancer:therapeutic and prognostic implications. Cancer Res. 2007; 67(8): 3496-3499.
12. Xing X, Lai M, Wang Y, etc. Overexpression of glucose-regulated protein 78 in colon cancer. Clin Chim Acta 2006; 364 (1-2) :308-315.
13. Wang Q, He Z, Zhang J, etc. Overexpression of endoplasmic reticulura molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev 2005(6); 29:544-551.
14. Jamora C, Dennert G, Lee AS. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 1996; 93(15): 7690-7694.
15. Ramsay RG, Ciznadija D, Mantamadiotis T, etc. Expression of stress response protein glucose regulated protein-78 mediated by c-Myb. Int J Biochem Cell Biol 2005; 37 (6) :1254-1268.
16. Misra UK, Deedwania R, Pizzo SV. Activation and cross-talk between Akt, NF-kappa B, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. J Biol Chem 2006; 281(19): 13694-13707.
17. Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006; 5(7): 741-744.
18. Zhang J, Jiang Y, Jia Z, etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
19. Misra UK, Deedwania R, Pizzo SV. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem 2005; 280(28): 26278-26286.
20. Tsutsumi S, Gotoh T, Tomisato W, etc. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ 2004; 11(9): 1009-1016.
21. Tsutsumi S, NambaT, TanakaKI, etc. Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells. Oncogene 2006; 25(7): 1018-1029.
22. Zu K, Bihani T, Lin A, etc. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 2006; 25(4):546-554.
23. Dong D, Ko B, Baumeister P, etc. Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. Cancer Res 2005; 65(13): 5785-5791.
24. Reddy RK, Mao C, Baumeister P, etc. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem. 2003; 278(23): 20915-20924.
25. Fu Y, Li J, Lee AS. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 2007; 67(8):3734-3740.
26. Pyrko P, Schonthal AH, Hofman FM, etc. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 2007; 67(20): 9809-9816.
27. Ranganathan AC, Zhang L, Adam AP,etc. Functional coupling of p38-induced upregulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 2006; 66(3): 1702-1711.
28. Gray MD, Mann M, Nitiss JL, etc. Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIalpha protein levels and decreasing sensitivity to topoisomerase-targeted drugs. Mol Pharmacol 2005; 68(6): 1699-1707.
29. Arap MA, Lahdenranta J, Mintz PJ, etc. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004; 6(3): 275-284.
30. Davidson DJ, Haskell C, Majest S,etc. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface- expressed glucose-regulated protein 78. Cancer Res 2005; 65(11): 4663-4672.
31. Pootrakul L, Datar RH, Shi SR, etc. Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer. Clin Cancer Res. 2006; 12(20): 5987-5993.
32. Lee E, Nichols P, Spicer D, etc. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006; 66(16): 7849-7853.
1.Bromberg JF.Activation of STAT proteins and growth control.Bioessays,2001,23(2):161-169.PMID:11169589
2.Oshiro MM,Landowski TH,Catlett-Falcone R,et al.Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase Ⅱ inhibitors in U266 myeloma cells.Clin Cancer Res,2001,7(12):4262-4271.PMID:11151528
3.Greten FR,Weber CK,Greten TF,et al.Star3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.Gastroenterology,2002,123(6):2052-2063.PMID:12454861
4.Amin HM,McDonnell TJ,Ma Y,et al.Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastie large cell lymphoma.Oncogene,2004,23(32):5426-5434.PMID:15184887
5.Xi S,Gooding WE,Grandis JR.et al.In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach:implications for cancer therapy.Oncogene,2005,24(6):910-979.PMID:15592503
6.Lebe B,Sagol O,Ulukus C,et al.The importance of cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas.Pathol Res Pract,2004,200:389-396.PMID:15239347
7.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.Cancer Res,2002,62(12):3351-3355.PMID:12067972
8.Leslie K,Lang C,Devgan G,et al.Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3.Cancer Res,2006,66(5):2544-2552.PMID:16510571
9.Bromberg J,Chen X.STAT proteins:signal tranducers and activators of transcription.Methods Enzymol,2001,333:138-151.PMID:11400331
10.Kijima T,Niwa H,Steinman RA,et al.STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo.Cell Growth & Differ,2002,13(8):355-362.PMID:12193414
11.Scholz A,Heinze S,DetjenKM,et al.Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology, 2003, 125(3): 891-905. PMID: 12949733
12. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002, 21(13): 2000-2008. PMID: 11960372
13. Wei D, Le X, Zheng L, Wang L, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329. PMID: 12545153
14. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004, 23(20): 3550-3560. PMID: 15116091
15. Udayakumar TS, Stratton MS, Nagle RB, et al. Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. Neoplasia, 2002, 4(1): 60-67. PMID: 11922392
16. Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. PNAS, 2004,101(29): 10602-10607. PMID: 15249664
17. Song L, Turkson J, Karras JG, et al. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene, 2003, 22(27): 4150-4165. PMID: 12833138
18. Toyonaga T, Nakano K, Nagano M, et al. Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer letters, 2003, 201(1): 107-116. PMID: 14580692
19. DeArmond D, Brattain MG, Jessup JM, et al. Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene, 2003,22(49): 7781-7795. PMID: 14586404
20. Garcia R, Bowman TL, Niu G, et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene, 2001, 20(20): 2499-2513. PMID: 11420660
21. Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res, 2002, 62(22) :6659-6666. PMID: 12438264
22. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005,11(4): 1386-1393. PMID: 15746037
23. Leong PL, Andrews GA, Johnson DE, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. PNAS, 2003, 100(7): 4138-4143. PMID: 12640143
24. Real PJ, Sierra A, De Juan A, et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene, 2002,21(50): 7611-7618. PMID: 12400004
25. Niu G, Shain KH, Huang M, et al. Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res, 2001,61(8): 3276-3280. PMID: 11309279
26. Burke WM, Jin X, Lin HJ, et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene, 2001,20(55): 7925-7934. PMID: 11753675
27. Ling X, Arlinghaus RB. Knockdown of STAT3 Expression by RNA Interference Inhibits the Induction of Breast Tumors in Immunocompetent Mice. Cancer Res, 2005, 65(7): 2532-2536. PMID: 15805244
1.Campbell CL,Jiang Z,Savarese DM,et al.Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma.Am J Pathol,2001,158:25-32.
2.Niedergethmann M,Hildenbrand R,Wostbrock B,et al.High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas.Pancreas,2002,25:122-129.
3.Weidner N,Semple JP,Welch WR,et al.Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma.N Engl J Med,1991,324:1-8.
4.Bromberg JF,Wrzeszczynska MH,Devgan G;et al.STAT3 as an oncogene.Cell,1999,98:295-303.
5.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.Cancer Res,2002,62:3351-3355.
6.王强,乔林,王明德,等.胰腺癌组织中血管内皮细胞生长因子、微血管密度的表达及其意义.中华肝胆外科杂志,2001,7:182.
7.潘雪,李兆申,许国铭,等.胰腺癌中血管形成因子和细胞粘附分子的表达研究.中华肝胆外科杂志,2003,9:161-164.
8.Niu G,Wright KL,Huang M,et al.Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.Oncogene,2002,21:2000-2008.
9.Wei D,Le X,Zheng L,et al.Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.Oncogene,2003,22:319-329.
1.Burke WM,Jin X,Lin HJ,et al.Inhibition of constitutively active Star3suppresses growth of human ovarian and breast cancer cells[J].Oncogene,2001,20(55):7925-7934.
2.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J].Cancer Res,2002,62(12):3351-3355.
3. Hartmann K, Artuc M, Baldus SE, et al. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis [J]. Am J Pathol, 2003, 163(3): 819-826.
4. Campbell CL, Jiang Z, Savarese DM, et al. Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma [J]. Am J Pathol, 2001, 158(1): 25-32.
5. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene [J]. Cell, 1999, 98(3): 295-303.
6. Grandis JR, Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo [J]. PNAS, 2000, 97(8): 4227-4232.
7. Sharma J, Srinivasan R, Majumdar S, et al. Bcl-XL protein levels determine apoptotic index in pancreatic carcinoma [J]. Pancreas, 2005, 30(4): 337-342.
8. Lebe B, Sagol O, Ulukus C, et al. The importance of Cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas [J]. Pathol Res Pract, 2004,200(5): 389-396.
9. Meggiato T, Calabrese F, Valente M, et al. Spontaneous apoptosis and proliferation in human pancreatic cancer [J]. Pancreas, 2000, 20(2): 117-122.
2.Parkin DM,Bray F,Ferlay J,et al.Estimating the world cancer burden:Globocan 2000.Int J Cancer,2001,94(2):153-156
3.Li DH,Xie KP,Wolff R,et al.Pancreatic cancer.Lancet,2004,363(9414):1049-1057
4.Khosravi SP,Diaz M.Pancreatic adenocarcinoma:therapeutical update.An Med Interna,2005,22(8):390-394
5.张延龄,倪泉兴.应重视胰腺癌的早期诊断和综合治疗.中华医学杂志,2000,80(4):245-246
6.Ramirez PJ,Vickers SM.Current status of gene therapy for pancreatic cancer.Curr Surg.2004,61(1):84-92
7.Serman A,Vlahovic M,Serman L,et al.DNA methylation as a regulatory mechanism for gene expression in mammals.Coll Antropol,2006,30(3):665-671
8.Venter JC,Adams MD,Myers EW,et al.The sequence of the human genome.Science,2001,291(5507):1304-1351
9.Lander ES,Linton LM,Birren B,et al.International human genome sequencing consortium.Initial sequencing and analysis of the human genome.Nature,2001,409(6822):860-921
10.Cody DT,Huang Y.Differential DNA methylation of the p16INK4 CDKA2 a promoter in human oral cancer cells and normal human oral kerarnocytes.Oral Oncol,1999,35(5):516-522
11.Ueki T,Toyota M,Sohn T,et al.Hypermethylation of multiple genes in pancreatic adenocarcinoma.Cancer Res,2000,60(7):1835-1839
12.Gonzalez-Zulueta M,Bender CM,Yang AS,et al.Methylation of the 5'CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissue correlates with gene silencing.Cancer Res,1995,55(20):4531-4535.
13.Yu X J,Long J,Fu DL,Zhang QH,Ni QX:Analysis of gene expression profiles in pancreatic carcinoma by using cDNA microarray.Hepatobiliary Pancreat Dis Int.2003,2(3):467-470.
14.Ng HH,Jeppesen P,Bird A.Active repression of methylated genes by the chromosomal protein MBD1.Molecular and Cellular Bio,2000,20(4):1394-1406.
15.狄扬,龙江,傅德良,等.甲基化CpG结合域蛋白1在胰腺癌组织中的表达和意义.外科理论与实践,2006,11(1):35-38.
16.Fujita N,Shimotake N,Ohki I,et al.Mechanism of transcriptional regulation by methyl-CpG binding protein MBD1.Mol.Cell Biol.2000,20(14):5107-5118.
17.Marks PA,Rifkind RA,Richon VM,et al.Histonedeacetylase and cancer:cause and therapies.Nat Rev Cancer,2001,1(3):194-202
18.Cross SH,Meehan RR,Nan X,et al.Component of the transcriptional repressor MeCP1shares a motif with DNA methyltransferase and HRX proteins.Nat.Genet,1997,16(8):256-259
19.Ballestar E,Wolffe AE Methyl-CpG-binding proteins targeting specific gene repression.Eur J.Biochem.2001,268(1):1-6.
20.Lopez-Serra L,Ballestar E,Fraga MF,et al.A Profile of Methyl-CpG Binding Domain Protein Occupancy of Hypermethylated Promoter CpG Islands of Tumor Suppressor Genes in Human Cancer.Cancer Res.2006,66(17):8342-8346.
21.虞先浚,龙江,傅德良,等.利用cDNA微列阵技术分析胰腺癌相关基因表达谱.中华实验外科杂志,2002,19(4):302-303
22.傅德良,龙江,金忱,等.利用基因芯片和RT-PCR检测MBD1在胰腺癌中的表达.外科 理论与实践, 2005,10(3):241-244
23. Patra SK, Patra A, Zhao H, et al. Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochem.Biophys.Res. Commun. 2003,302(4): 759-766.
24. Hannon GJ. RNA interference. Nature,2002,418(11):244-251
25. Yu JY,DeRuiter SL,Tuner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells.Proc Natl Acad Sci USA,2002,99(9):6047-6052
26. Coppola D: Molecular prognostic markers in pancreatic cancer. Cancer Control 2000, 7(5): 421-427.
27. A. Shevchenko, M. Wilm, O. Vorm, M. Mann: Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal.Chem. 1996,68(5): 850-858.
28. Fang CY, Yi ZG, Liu F, et al. Proteome analysis of human liver carcinoma Huh7 cells harboring hepatitis C virus subgenomic replicon. Proteomics. 2006, 6 (2): 519-527
29. Lang SH, Hyde C, Reid IN, et al. Enhanced expression of Vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate 2002, 52(4): 253-263
30. Lee E, Nichols P, Spicer D, etc. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006, 66(16): 7849-7853.
31. Yuan RH, Jeng YM, Chen HL,et al. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol. 2006,209(4):549-558.
32. Bank RE, Dum MJ, Hochstrasser DF, et al. Proteomics: new perspectives, new biomedical opportunities. Lancet, 2000, 356 (9243) : 1749-1756.
33. Carr KM, Rosenblatt K, Petricoin EF, et al. Genomic and proteomic approaches for studying human cancer: prospects for true patient-tailored therapy. Hum Genomics. 2004, 1(2):134-140.
34. Wulfkuhle J, Espina V, Liotta L. Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer. 2004,40(17):2623-2632.
35. 何大澄, 肖雪媛. 差异蛋白质组学及其应用. 北京师范大学学报(自然科学版). 2002, 38(4):558-562
36. Bjellqvist, B., Ek K., Righetti, P.G, et al. Isoelectric focusing in immobilized pH gradients: principle, methodology and some applications. J Biochem. Biophys. Methods 1982, 6(4): 317-339
37. Karas, M., Hillenkamp, F. Laser Desorption Ionization of Proteins with Molecular Masses Exceeding 10,000 Daltons.Anal.Chem.1988, 60(20):2299-2301
38. Fenn JB, Mann M, Meng CK, et al. Electrospray Ionization for Mass Spectrometry of LargeBiomolecules. Science, 1989, 246(4926):64-71
39. Cornwell MM, SmithDE. SP1 activates the MDR1 promoter through one of two distinct G-rich regions that modulate promoter activity. J Biol Chem, 1993, 268(26): 19505-19511
40. Wang N, Stamenovic D. Mechanics of Vimentin intermediate filaments, J.Muscle Res.Cell Motil. 2002, 23(5-6):535-540.
41. Ivaska J, Pallari HM, Nevo J, et al. Novel functions of Vimentin in cell adhesion, migration, and signaling, Exp. Cell Res.2007,313 (10):2050-2062.
42. Korsching E, Packeisen J, Liedtke C, et al. The origin of Vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 2005; 206(4):451-457
43. Ko SH, Suh SH, Kim BJ, et al. Expression of the intermediate filament Vimentin in proliferating duct cells as a marker of pancreatic precursor cells. Pancreas 2004, 28(2): 121-128
44. 殷涛, 王春友, 熊炯炘, 等. Vimentin在胰腺癌细胞中的表达及临床意义. 世界华人消化杂志. 2007,15(36):3822-3825
45. Nakajima S, Doi R, Toyoda E, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004,10 (12 Pt 1):4125-4133.
46. Domagala W, Striker G, Szadowska A, et al. p53 protein and Vimentin in invasive ductal NOS breast carcinoma-relationship with survival and sites of metastases. Eur J Cancer. 1994,30A(10): 1527-1534.
47. Gilles C, Polette M, Piette J, Delvigne AC, et al. Vimentin expression in cervical carcinomas: association with invasive and migratory potential. J Pathol. 1996 ,180(2): 175-180.
48. Nolan LP, Heatley MK. The value of immunocytochemistry in distinguishing between clear cell carcinoma of the kidney and ovary. Int J Gynecol Pathol. 2001,20(2): 155-159
49. Zhang L, Cilley RE, Chinoy MR. Suppression subtractive hybridization to identify gene expressions in variant and classic small cell lung cancer cell lines. J Surg Res. 2000,93(1):108-119.
50. Kokkinos MI, Wafai R, Wong MK, et al. Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs. 2007,185(1-3):191-203
51. McInroy L, Maatta A. Down-regulation of Vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun. 2007 ,360(1):109-114.
52. Shah AN, Summy JM, Zhang J,et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007,14(12):3629-3637.
53. Kajiyama H, Shibata K, Terauchi M,et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 2007,31(2):277-283
54. Frederick BA, Helfrich BA, Coldren CD,et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther. 2007 ,6(6): 1683-1691.
55. Lee AS. The glucose-regulated proteins: Stress induction and clinical applications. Trends Biochem Sci 2001; 26(8): 504-510.
56. Hendershot LM. The ER function BiP is a master regulator of ER function. Mt Sinai J Med 2004; 71(5): 289-297.
57. Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med. 2006; 6(1): 45-54.
58. Xing X, Lai M, Wang Y,etc. Overexpression of glucose-regulated protein 78 in colon cancer. Clin Chim Acta 2006; 364 (1-2) :308-315.
59. Wang Q, He Z, Zhang J, etc. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev 2005(6); 29:544-551.
60. Jamora C, Dennert G, Lee AS. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 1996; 93(15): 7690-7694.
61. Dong D, Dubeau L, Bading J, etc. Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors.Hum Gene Ther.2004; 15(6): 553-561.
62. Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006; 5(7): 741-744.
63. Zhang J, Jiang Y, Jia Z,etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
64. Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007; 67(8): 3496-3499.
65. Zhang J, Jiang Y, Jia Z,etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
66. Misra UK, Deedwania R, Pizzo SV. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem 2005; 280(28): 26278-26286.
67. Gray MD, Mann M, Nitiss JL, etc. Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIalpha protein levels and decreasing sensitivity to topoisomerase-targeted drugs. Mol Pharmacol 2005; 68(6): 1699-1707.
68. Arap MA, Lahdenranta J, Mintz PJ, etc. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004; 6(3): 275-284.
69. Davidson DJ, Haskell C, Majest S,etc. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface- expressed glucose-regulated protein 78. Cancer Res 2005; 65(11): 4663-4672.
70. Mistry SJ, Atweh GF.et al. Role of Stathmin in the regulation of the mitotic spindle: potential applications in cancer therapy.Mt Sinai J Med. 2002 ,69(5):299-304.
71. Walczak CE. Microtubule dynamics and tubulin interacting proteins. Curr Opin Cell Biol. 2000,12(1): 52-56.
72. Prasad SC, Thraves PJ, Soldatenkov VA, et al. Differential expression of Stathmin during neoplastic conversion of human prostate epithelial cells is reversed by hypomethylating agent, 5-azacytidine. Int J Oncol. 1999,14(3):529-534.
73. Johnsen JL Aurelio ON, Kwaja Z, et al. p53 mediated negative regulation of Stathmin/Op18 expression is associated with G(2)/M cell cycle arrest. Int J Cancer, 2000,88(5): 685-691
74. Manceau V, Gavet O, Curmi P, et al. Stathmin interaction with HSP70 family proteins. Electrophoresis, 1999,20(2): 409-417
75. Balachandran R, Welsh MJ, Day BW. Altered levels and regulation of Stathmin in paclitaxel-resistant ovarian cancer cells. Oncogene 2003, 22(55): 8924-8930
76. Wang R, Dong K, Lin F, et al. Inhibiting proliferation and enhancing chemosensitivity to taxanes in Osteosarcoma cells by RNA interference-mediated downregulation of Stathmin expression. Mol Med. 2007, 13(11-12):567-575
77. Chen G, Wang H, Gharib TG, et al. Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas.Mol Cell Proteomics.2003,2(2):107-116.
78.Wei SH,Lin F,Wang X,et al.Prognostic significance of Stathmin expression in correlation with metastasis and clinicopathological characteristics in human ovarian carcinoma.Acta Histochem.2008,110(1):59-65.
79.Yuan RH,Jeng YM,Chen HL,et al.Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression,and is associated with tumour progression,early recurrence,and poor prognosis in hepatocellular carcinoma.J.Pathol.2006,209(4) 549-558.
80.Notari M,Neviani P,Santhanam R,et al.A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.Blood.2006,107(6) 2507-2516.
81.Carpenter B,McKay M,Dundas SR,et al.Heterogeneous nuclear ribonucleoprotein K is over expressed,aberrantly localised and is associated with poor prognosis in colorectal cancer.Br J Cancer.2006,95(7) 921-927.
82.Zhang L,Pan X,Hershey JW.Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells.J.Biol.Chem.2007,282(8) 5790-5800.
83.Boengler K,Pipp F,Broich K,et al.Identification of differentially expressed genes like cofilin2 in growing collateral arteries,Biochem.Biophys.Res.Commun.2003,300(3)751-756.
84.Li T,Hu J,Li L.Characterization of Tollip protein upon Lipopolysaccharide challenge.Mol.Immunol.2004,41(1) 85-92.
85.Didierlaurent A,Brissoni B,Velin D,et al.Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide.Mol.Cell Biol.2006,26(3) 735-742.
86.钟良,陈坚,徐近,等.锌指蛋白2在胰腺癌中的表达.胰腺病学.2007,7(4):248-250
87.Zou H,Harrington JJ,Shire AM,et al.Highly methylated genes in colorectal neoplasia:implications for screening.Cancer Epidemiol Biomarkers Prev.2007,16(12):2686-2696.
88.Chen WD,Han ZJ,Skoletsky J,et al.Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed Vimentin gene.J.Natl.Cancer Inst.2005,97(15):1124-1132.
89.Ostareck-Lederer A,Ostareck DH,Rucknagel KP,et al.Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1inhibits its interaction with c-Src.J.Biol.Chem.2006,281(16):11115-11125.
90.Yang Q,Liu S,Tian Y,et al.Methylation-associated silencing of the heat shock protein 47gene in human neuroblastoma.Cancer Res.2004,64(13):4531-4538.
91.Wang C,Gomer RH,Lazarides E.Heat shock proteins are methylated in avian and mammalian cells.Proc.Natl.Acad.Sci.USA.1981,78(6):3531-3535.
92.Gober MD,Smith CC,Ueda K,et al.Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells.J.Biol.Chem.2003,278(39):37600-37609.
93.吴瑛,赫荣乔.RNA剪接因子结构与功能研究进展.生物化学与生物物理进展.2003,30(4):503-508
94.Otsu M,Urade R,Kito M,et al.A possible role of ER-60 protease in the degradation of misfolded proteins in the endoplasmic reticulum.J.Biol.Chem.1995,270(25):14958-14961.
95.Pajunen L,Jones TA,Goddard A,et al.Regional assignment of the human gene coding for a multifunctional polypeptide(P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25. Cytogenet. Cell Genet. 1991,56(3-4): 165-168.
96. Goplen D, Wang J, Enger PO, et al. Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Cancer Res. 2006, 66(20): 9895-9902.
97. Avramidou A, Kroczek C, Lang C, et al. The novel adaptor protein Swiprosin-1 enhances BCR signals and contributes to BCR-induced apoptosis. Cell Death Differ. 2007 ,14(11):1936-1947.
98. Yeh IT, Luduena RF: The betaII isotype of tubulin is present in the cell nuclei of a variety of cancers, Cell Motil. Cytoskeleton. 2004, 57(2): 96-106.
99. Ranganathan S, Salazar H, Benetatos CA, et al. Immunohistochemical analysis of beta-tubulin isotypes in human prostate carcinoma and benign prostatic hypertrophy. Prostate, 1997,30(4): 263-268.
100. Katsetos CD, Herman MM, Mork SJ. Class III beta-tubulin in human development and cancer. Cell Motil Cytoskeleton, 2003, 55(2): 77-96.
101. Giamieri E, De Francesco GP, Carico E, et al. Alpha-and beta-tubulin expression in rectal cancer development. Anticancer Res, 2005,25(5): 3237-3241
102. Verdier-Pinard P, Wang F, Martello L, et al. Analysis of tubulin isotypes and mutations from taxol resistant cells by combined isoelectrofocusing and mass spectrometry . Biochemistry,2003,42(18): 5349-5357.
103. Shalli K, Brown I, Heys SD, et al. Alterations of beta-tubulin isotypes in breast cancer cells resistan t to docetaxel. FASEB J,2005,19(10): 1299-1301.
104. Lee KM, Cao D, Itami A, et al. Class III beta-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. Histopathology, 2007, 51 (4): 539-546
105. Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 1999,59(10): 2307-2312.
106. 胡笳, 郭燕婷, 李艳梅. 蛋白质翻译后修饰研究进展. 科学通报, 2005,50(11): 1061-1072
107. Idriss HT. Three steps to cancer: how phosphorylation of tubulin, tubulin tyrosine ligase and P-glycoprotein may generate and sustain cancer. Cancer Chemother Pharmacol, 2004, 54(2): 101-104
108. Ghosh R, Gu G, Tillman E, etc. Increased expression and differential phosphorylation of Stathmin may promote prostate cancer progression. Prostate. 2007 ,67(10): 1038-1052.
109. Wang Y, Yamaguchi Y, Watanabe H, etc. Detection of p53 gene mutations in the supernatant of pancreatic juice and plasma from patients with pancreatic carcinomas. Pancreas. 2004,28(1):13-19
110. Hua Z, Zhang YC, Hu XM, et al. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol. 2003 ,9(12):2764-2767
111. Gerdes B, Ramaswamy A, Ziegler A, et al. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann Surg. 2002 ,235(1):51-59
112. House MG, Guo M, Iacobuzio-Donahue C, et al.Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas.Carcinogenesis. 2003 ,24(2): 193-198.
113. House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003 ,238(3):423-431
114. Schlegel J, Guneysu S, Mennel HD. Expression of the genes of methyl-binding domain proteins in human gliomas. Oncol Rep. 2002 ,9(2):393-395.
115. Jang JS, Lee SJ, Choi JE, et al. Methyl-CpG binding domain 1 gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2005,14(11 Pt 1):2474-2480
116. Fujita N, Takebayashi S, Okumura K, et al. Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol Cell Biol. 1999,19(9):6415-6426
117. Ballestar E, Paz MF, Valle L, et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J, 2003, 22(23): 6335-6345.
118. Tomizawa Y, Sekido Y, Kondo M, et al. Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A. 2001 ,98(24): 13954-13959
119. Morris MR, Gentle D, Abdulrahman M, et al. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br J Cancer. 2008 ,98(2):496-501
120. Liu JW, Kim MS, Nagpal J, et al. Quantitative hypermethylation of NMDAR2B in human gastric cancer. Int J Cancer. 2007 ,121(9): 1994-2000
121. Seng TJ, Low JS, Li H, et al. The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene. 2007,26(6):934-944
122. Dansranjavin T, Mobius C, Tannapfel A,et al. E-cadherin and DAP kinase in pancreatic adenocarcinoma and corresponding lymph node metastases. Oncol Rep. 2006,15(5):1125-1131.
123. Shin SJ, Kim KO, Kim MK, et al. Expression of E-cadherin and uPA and their association with the prognosis of pancreatic cancer. Jpn J Clin Oncol. 2005 ,35(6):342-8.
124. Joo YE, Rew JS, Park CS, et al. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology. 2002;2(2): 129-37
125. Huiping C, Kristjansdottir S, Jonasson JG, et al. Alterations of E-cadherin and beta-catenin in gastric cancer. BMC Cancer. 2001,1(1): 16.
126. Winter JM, Ting AH, Vilardell F, et al. Absence of e-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res. 2008,14(2):412-418.
127. Shimizu K, Hanaoka M, Kato A,et al. Reduced expression of the E-cadherin gene and its aberrant DNA methylation in hamster pancreatic tumors. Biochem Biophys Res Commun. 2005,336(1):49-53.
128. Stirzaker C, Millar DS, Paul CL, et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res. 1997,57(11):2229-2237
129. Casanovas O, Hager JH, Chun MG, et al. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene. 2005,24(44):6597-6604.
130. Kawaguchi K, Oda Y, Saito T, et al. DNA hypermethylation status of multiple genes in soft tissue sarcomas. Mod Pathol. 2006,19(1): 106-114
131. Li H, Lu S, Fong L. Study on the status of methylation of Rb gene promoter in human esophageal cancer and effect of NMBzA on Rb gene promoter in monkey esophageal epithelium. Zhonghua Zhong Liu Za Zhi. 1998 ,20(6):412-414
132. Yin D, Xie D, Hofmann WK, et al. Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors. Oncogene. 2002,21(54):8372-8378
133. 郑海涛, 赵鸿鹏, 卢俊. 胰腺癌的浸润和转移研究进展. 世界华人消化杂志. 2005,13(10):1219-1222
134. Jiang P, Watanabe H, Okada G,et al. Diagnostic utility of aberrant methylation of tissue factor pathway inhibitor 2 in pure pancreatic juice for pancreatic carcinoma. Cancer Sci. 2006 ,97(11): 1267-1273.
135. Sato N, Parker AR, Fukushima N,et al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene. 2005,24(5):850-858
136. Liu L, Broaddus RR, Yao JC,et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol. 2005 ,18(12): 1632-1640.
137. Zhang C, Li H, Zhou G, Zhang Q, et al. Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells.J Pathol. 2007 ,212(2): 134-142.
138. Meng CF, Zhu XJ, Peng G, et al. Re-expression of methylation-induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol. 2007,13(46):6166-6171
139. Maass N, Biallek M, Rosel F,et al. Hypermethylation and histone deacetylation lead to silencing of the maspin gene in human breast cancer.Biochem Biophys Res Commun. 2002 ,297(1): 125-128.
140. Chiba T, Yokosuka O, Fukai K,et al. Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology. 2004,66(6):481-491.
141. Gahr S, Ocker M, Ganslmayer M, et al. The combination of the histone- deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells.Int J Oncol. 2007 ,31(3):567-576
142. Donadelli M, Costanzo C, Faggioli L, et al. Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells.Mol Carcinog. 2003 ,38(2):59-69
143. Piacentini P, Donadelli M, Costanzo C, et al. Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation. Virchows Arch. 2006 ,448(6):797-804
144. Liu LT, Chang HC, Chiang LC, et al.Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion.Cancer Res. 2003 ,63(12):3069-3072.
145. Kim MS, Kwon HJ, Lee YM, et al.Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.Nat Med. 2001 ,7(4):437-443.
146. Gottlicher M, Minucci S, Zhu P, et al.Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.EMBO J. 2001 ,20(24): 6969-6978.
147. Uchida H, Maruyama T, Nagashima T,et al. Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin.Endocrinology. 2005,146(12):5365-5373
148. Fan J, Yin WJ, Lu JS,et al. ERalpha negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor.J Cancer Res Clin Oncol. 2008 Feb 9 [Epub ahead of print]
1.Shiu RP,Pastan IH.Properties and purification of a glucose-regulated protein from chick embryo fibroblasts.Biochim Bopphys Acta 1979;576(1):141-150.
2.Lee AS.The glucose-regulated proteins:Stress induction and clinical applications.Trends Biochem Sci 2001;26(8):504-510.
3.Hendershot LM.The ER function BiP is a master regulator of ER function.Mt Sinai J Med 2004;71(5):289-297.
4.Banhegyi G,Baumeister P,Benedetti A,etc.Endoplasmic reticulum stress.Ann N Y Acad Sci.2007;1113(1):58-71.
5.Li J,Lee AS.Stress induction of GRP78/BiP and its role in cancer.Curr Mol Med.2006;6(1):45-54.
6.Shen x,Zhang K,Kaufman RJ.The unfolded protein response-a stress signaling pathway of the endoplasmic reticulum.J Chem Neuroanat 2004;28(1-2):79-92.
7.Luo S,Mao C,Lee B,etc.GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development.Mol Cell Bioi.2006;26(15):5688-5697.
8.Mao C,Tai WC,Bai Y,etc.In vivo regulation of Grp78/BiP transcription in the embryonic heart:role of the endoplasmic reticulum stress response element and GATA-4.J Biol Chem.2006;281(13):8877-8887.
9.Li J,Lee B,Lee AS.Endoplasmic reticulum stress-induced apoptosis:multiple pathways and activation of p53-up-regulated modulator of apoptosis(PUMA) and NOXA by p53.J Biol Chem.2006;281(11):7260-7270.
10.Dong D,Dubeau L,Bading J,etc.Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors.Hum Gene Ther.2004;15(6):553-561.
11.Lee AS.GRP78 induction in cancer:therapeutic and prognostic implications. Cancer Res. 2007; 67(8): 3496-3499.
12. Xing X, Lai M, Wang Y, etc. Overexpression of glucose-regulated protein 78 in colon cancer. Clin Chim Acta 2006; 364 (1-2) :308-315.
13. Wang Q, He Z, Zhang J, etc. Overexpression of endoplasmic reticulura molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev 2005(6); 29:544-551.
14. Jamora C, Dennert G, Lee AS. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 1996; 93(15): 7690-7694.
15. Ramsay RG, Ciznadija D, Mantamadiotis T, etc. Expression of stress response protein glucose regulated protein-78 mediated by c-Myb. Int J Biochem Cell Biol 2005; 37 (6) :1254-1268.
16. Misra UK, Deedwania R, Pizzo SV. Activation and cross-talk between Akt, NF-kappa B, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. J Biol Chem 2006; 281(19): 13694-13707.
17. Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006; 5(7): 741-744.
18. Zhang J, Jiang Y, Jia Z, etc. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006; 23(7-8): 401-410.
19. Misra UK, Deedwania R, Pizzo SV. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem 2005; 280(28): 26278-26286.
20. Tsutsumi S, Gotoh T, Tomisato W, etc. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ 2004; 11(9): 1009-1016.
21. Tsutsumi S, NambaT, TanakaKI, etc. Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells. Oncogene 2006; 25(7): 1018-1029.
22. Zu K, Bihani T, Lin A, etc. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 2006; 25(4):546-554.
23. Dong D, Ko B, Baumeister P, etc. Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. Cancer Res 2005; 65(13): 5785-5791.
24. Reddy RK, Mao C, Baumeister P, etc. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem. 2003; 278(23): 20915-20924.
25. Fu Y, Li J, Lee AS. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 2007; 67(8):3734-3740.
26. Pyrko P, Schonthal AH, Hofman FM, etc. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 2007; 67(20): 9809-9816.
27. Ranganathan AC, Zhang L, Adam AP,etc. Functional coupling of p38-induced upregulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 2006; 66(3): 1702-1711.
28. Gray MD, Mann M, Nitiss JL, etc. Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIalpha protein levels and decreasing sensitivity to topoisomerase-targeted drugs. Mol Pharmacol 2005; 68(6): 1699-1707.
29. Arap MA, Lahdenranta J, Mintz PJ, etc. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004; 6(3): 275-284.
30. Davidson DJ, Haskell C, Majest S,etc. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface- expressed glucose-regulated protein 78. Cancer Res 2005; 65(11): 4663-4672.
31. Pootrakul L, Datar RH, Shi SR, etc. Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer. Clin Cancer Res. 2006; 12(20): 5987-5993.
32. Lee E, Nichols P, Spicer D, etc. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006; 66(16): 7849-7853.
1.Bromberg JF.Activation of STAT proteins and growth control.Bioessays,2001,23(2):161-169.PMID:11169589
2.Oshiro MM,Landowski TH,Catlett-Falcone R,et al.Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase Ⅱ inhibitors in U266 myeloma cells.Clin Cancer Res,2001,7(12):4262-4271.PMID:11151528
3.Greten FR,Weber CK,Greten TF,et al.Star3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.Gastroenterology,2002,123(6):2052-2063.PMID:12454861
4.Amin HM,McDonnell TJ,Ma Y,et al.Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastie large cell lymphoma.Oncogene,2004,23(32):5426-5434.PMID:15184887
5.Xi S,Gooding WE,Grandis JR.et al.In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach:implications for cancer therapy.Oncogene,2005,24(6):910-979.PMID:15592503
6.Lebe B,Sagol O,Ulukus C,et al.The importance of cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas.Pathol Res Pract,2004,200:389-396.PMID:15239347
7.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.Cancer Res,2002,62(12):3351-3355.PMID:12067972
8.Leslie K,Lang C,Devgan G,et al.Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3.Cancer Res,2006,66(5):2544-2552.PMID:16510571
9.Bromberg J,Chen X.STAT proteins:signal tranducers and activators of transcription.Methods Enzymol,2001,333:138-151.PMID:11400331
10.Kijima T,Niwa H,Steinman RA,et al.STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo.Cell Growth & Differ,2002,13(8):355-362.PMID:12193414
11.Scholz A,Heinze S,DetjenKM,et al.Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology, 2003, 125(3): 891-905. PMID: 12949733
12. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002, 21(13): 2000-2008. PMID: 11960372
13. Wei D, Le X, Zheng L, Wang L, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329. PMID: 12545153
14. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004, 23(20): 3550-3560. PMID: 15116091
15. Udayakumar TS, Stratton MS, Nagle RB, et al. Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. Neoplasia, 2002, 4(1): 60-67. PMID: 11922392
16. Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. PNAS, 2004,101(29): 10602-10607. PMID: 15249664
17. Song L, Turkson J, Karras JG, et al. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene, 2003, 22(27): 4150-4165. PMID: 12833138
18. Toyonaga T, Nakano K, Nagano M, et al. Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer letters, 2003, 201(1): 107-116. PMID: 14580692
19. DeArmond D, Brattain MG, Jessup JM, et al. Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene, 2003,22(49): 7781-7795. PMID: 14586404
20. Garcia R, Bowman TL, Niu G, et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene, 2001, 20(20): 2499-2513. PMID: 11420660
21. Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res, 2002, 62(22) :6659-6666. PMID: 12438264
22. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005,11(4): 1386-1393. PMID: 15746037
23. Leong PL, Andrews GA, Johnson DE, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. PNAS, 2003, 100(7): 4138-4143. PMID: 12640143
24. Real PJ, Sierra A, De Juan A, et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene, 2002,21(50): 7611-7618. PMID: 12400004
25. Niu G, Shain KH, Huang M, et al. Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res, 2001,61(8): 3276-3280. PMID: 11309279
26. Burke WM, Jin X, Lin HJ, et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene, 2001,20(55): 7925-7934. PMID: 11753675
27. Ling X, Arlinghaus RB. Knockdown of STAT3 Expression by RNA Interference Inhibits the Induction of Breast Tumors in Immunocompetent Mice. Cancer Res, 2005, 65(7): 2532-2536. PMID: 15805244
1.Campbell CL,Jiang Z,Savarese DM,et al.Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma.Am J Pathol,2001,158:25-32.
2.Niedergethmann M,Hildenbrand R,Wostbrock B,et al.High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas.Pancreas,2002,25:122-129.
3.Weidner N,Semple JP,Welch WR,et al.Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma.N Engl J Med,1991,324:1-8.
4.Bromberg JF,Wrzeszczynska MH,Devgan G;et al.STAT3 as an oncogene.Cell,1999,98:295-303.
5.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.Cancer Res,2002,62:3351-3355.
6.王强,乔林,王明德,等.胰腺癌组织中血管内皮细胞生长因子、微血管密度的表达及其意义.中华肝胆外科杂志,2001,7:182.
7.潘雪,李兆申,许国铭,等.胰腺癌中血管形成因子和细胞粘附分子的表达研究.中华肝胆外科杂志,2003,9:161-164.
8.Niu G,Wright KL,Huang M,et al.Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.Oncogene,2002,21:2000-2008.
9.Wei D,Le X,Zheng L,et al.Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.Oncogene,2003,22:319-329.
1.Burke WM,Jin X,Lin HJ,et al.Inhibition of constitutively active Star3suppresses growth of human ovarian and breast cancer cells[J].Oncogene,2001,20(55):7925-7934.
2.Masuda M,Suzui M,Yasumatu R,et al.Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J].Cancer Res,2002,62(12):3351-3355.
3. Hartmann K, Artuc M, Baldus SE, et al. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis [J]. Am J Pathol, 2003, 163(3): 819-826.
4. Campbell CL, Jiang Z, Savarese DM, et al. Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma [J]. Am J Pathol, 2001, 158(1): 25-32.
5. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene [J]. Cell, 1999, 98(3): 295-303.
6. Grandis JR, Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo [J]. PNAS, 2000, 97(8): 4227-4232.
7. Sharma J, Srinivasan R, Majumdar S, et al. Bcl-XL protein levels determine apoptotic index in pancreatic carcinoma [J]. Pancreas, 2005, 30(4): 337-342.
8. Lebe B, Sagol O, Ulukus C, et al. The importance of Cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas [J]. Pathol Res Pract, 2004,200(5): 389-396.
9. Meggiato T, Calabrese F, Valente M, et al. Spontaneous apoptosis and proliferation in human pancreatic cancer [J]. Pancreas, 2000, 20(2): 117-122.