食管癌相关基因4在食管鳞状细胞癌中的功能研究
摘要
食管癌是严重危害人类健康的常见消化道恶性肿瘤之一,其发病率在世界上位居恶性肿瘤的第七位,死亡率位于第六位。中国是食管癌的高发区,诊断的食管癌中90%是食管鳞状细胞癌(ESCC)。目前关于ESCC发生的机制还不清楚,本研究旨在探讨食管癌相关基因4(ECRG4)在ESCC发生中的作用。
ECRG4是我室克隆和鉴定的新基因,并在Genbank(AF 268198)登记。激光扫描共聚焦显微镜成像显示,内源性和外源性ECRG4蛋白主要定位在细胞质和细胞膜。Western blot方法在细胞无血清培养液中检测到ECRG4蛋白存在,提示ECRG4可能是分泌蛋白。我们制作了特异识别ECRG4蛋白的兔多克隆抗体,通过ESCC组织芯片以免疫组织化学和Western blot方法,分析了130对食管癌与癌旁组织,发现在68.5%(89/130)的ESCC组织中ECRG4蛋白表达下调。抑癌基因在肿瘤组织表达下调常常是由于其启动子高甲基化,而我们用去甲基化药物5-aza-2'-deoxycytidine处理可以恢复EC9706细胞ECRG4 mRNA的表达,说明启动子高甲基化可能是ECRG4在ESCC转录失活的主要机制。ECRG4蛋白表达下调与ESCC局部淋巴结转移、原发肿瘤大小和临床病理分期成正相关(P＜0.05)。ECRG4蛋白表达与ESCC病人的术后生存时间成正相关,是ESCC的独立预后指标(P＜0.05)。
ECRG4基因转染到EC9706细胞能抑制细胞增殖、平板克隆形成率、软琼脂克隆形成率、细胞周期进展和裸鼠移植瘤生长(P＜0.05)。纯化的重组ECRG4蛋白可以体外抑制EC9706细胞的增殖,抑制率随着ECRG4蛋白浓度增加而升高,成剂量-效应关系(P＜0.05)。ECRG4基因转染到EC9706细胞,可以抑制EC9706细胞NF-κB的表达和核转位,以及NF-κB靶基因COX-2的表达。
我们的研究结果表明,ECRG4是ESCC的候选抑癌基因,ECRG4蛋白是预测ESCC预后的候选标志物。启动子高甲基化可能是ECRG4在ESCC转录失活的主要机制。ECRG4可能通过参与NF-κB通路调控COX-2的表达来发挥其抑癌功能。ECRG4重组蛋白可以作为ESCC的潜在治疗药物。
Esophageal cancer is the sixth most frequent cause of deaths from cancer worldwide, and occurs at very high frequency in certain areas of China. Esophageal squamous cell carcinoma (ESCC) is the most prevalent type which accounts for～90% of esophageal carcinomas diagnosed in China. Until now, the underlying molecular mechanism for ESCC is still unclear. The present study is to investigate the function of esophageal cancer related gene 4 (ECRG4) in ESCC.
The ECRG4 gene was identified and cloned in our laboratory, and then it was registered at Genbank (AF325503). The images of laser-scanning confocal microscopy analysis indicated that endogenous and exogenous ECRG4 proteins were localized in the cytoplasm and cell membrane. We also found ECRG4 protein in cellular medium by Western blot, indicting ECRG4 is a secreted protein. We have prepared anti-ECRG4 rabbit polyclonal antibody and found that the expression of ECRG4 protein was down-regulated in 68.5% (89/130) ESCC samples using tissue microarray and analysis of immunohistochemical staining and Western blot. The expression of tumor suppressor gene is often down-regulated in tumor tissues due to the hypermethylation in the gene promoter, and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored ECRG4 mRNA expression in EC9706 cell line, it showed that promoter hypermethylation may be one main mechanism leading to the silencing of ECRG4 in ESCC. ECRG4 protein down-regulation was significantly associated with regional lymph node metastasis, primary tumor volume and tumor stage in ESCC (P < 0.05). ESCC patients with high ECRG4 expression had longer overall survival than those with low ECRG4 expression by Kaplan-Meier survival analysis (P < 0.05). ECRG4 protein was an independent prognostic factor for ESCC by multivariable Cox proportional hazards regression analysis (P < 0.05).
The transfection of ECRG4 gene in EC9706 cell line inhibited cell proliferation, colony formation, anchorage-independent growth, cell cycle progression and tumor growth in vivo (P < 0.05). Purified recombinant ECRG4 protein could inhibit EC9706 cells proliferation in vitro exhibiting dose-effect relationship (P < 0.05). The transfection of ECRG4 gene inhibited NF-κB expression and nuclear translocation, and inhibited NF-κB target gene COX-2 expression in EC9706 cell line.
In conclusion, ECRG4 is a novel candidate tumor suppressor in ESCC, and ECRG4 protein is a candidate prognostic marker for ESCC. Aberrant promoter hypermethylation is one of the major mechanisms leading to the silencing of ECRG4 gene in ESCC. ECRG4 might induce COX-2 down-regulation through NF-κB pathway to inhibit tumor growth in ESCC. The recombinant ECRG4 protein is a prospective candidate of anti-tumor drugs for ESCC.
ECRG4是我室克隆和鉴定的新基因,并在Genbank(AF 268198)登记。激光扫描共聚焦显微镜成像显示,内源性和外源性ECRG4蛋白主要定位在细胞质和细胞膜。Western blot方法在细胞无血清培养液中检测到ECRG4蛋白存在,提示ECRG4可能是分泌蛋白。我们制作了特异识别ECRG4蛋白的兔多克隆抗体,通过ESCC组织芯片以免疫组织化学和Western blot方法,分析了130对食管癌与癌旁组织,发现在68.5%(89/130)的ESCC组织中ECRG4蛋白表达下调。抑癌基因在肿瘤组织表达下调常常是由于其启动子高甲基化,而我们用去甲基化药物5-aza-2'-deoxycytidine处理可以恢复EC9706细胞ECRG4 mRNA的表达,说明启动子高甲基化可能是ECRG4在ESCC转录失活的主要机制。ECRG4蛋白表达下调与ESCC局部淋巴结转移、原发肿瘤大小和临床病理分期成正相关(P＜0.05)。ECRG4蛋白表达与ESCC病人的术后生存时间成正相关,是ESCC的独立预后指标(P＜0.05)。
ECRG4基因转染到EC9706细胞能抑制细胞增殖、平板克隆形成率、软琼脂克隆形成率、细胞周期进展和裸鼠移植瘤生长(P＜0.05)。纯化的重组ECRG4蛋白可以体外抑制EC9706细胞的增殖,抑制率随着ECRG4蛋白浓度增加而升高,成剂量-效应关系(P＜0.05)。ECRG4基因转染到EC9706细胞,可以抑制EC9706细胞NF-κB的表达和核转位,以及NF-κB靶基因COX-2的表达。
我们的研究结果表明,ECRG4是ESCC的候选抑癌基因,ECRG4蛋白是预测ESCC预后的候选标志物。启动子高甲基化可能是ECRG4在ESCC转录失活的主要机制。ECRG4可能通过参与NF-κB通路调控COX-2的表达来发挥其抑癌功能。ECRG4重组蛋白可以作为ESCC的潜在治疗药物。
Esophageal cancer is the sixth most frequent cause of deaths from cancer worldwide, and occurs at very high frequency in certain areas of China. Esophageal squamous cell carcinoma (ESCC) is the most prevalent type which accounts for～90% of esophageal carcinomas diagnosed in China. Until now, the underlying molecular mechanism for ESCC is still unclear. The present study is to investigate the function of esophageal cancer related gene 4 (ECRG4) in ESCC.
The ECRG4 gene was identified and cloned in our laboratory, and then it was registered at Genbank (AF325503). The images of laser-scanning confocal microscopy analysis indicated that endogenous and exogenous ECRG4 proteins were localized in the cytoplasm and cell membrane. We also found ECRG4 protein in cellular medium by Western blot, indicting ECRG4 is a secreted protein. We have prepared anti-ECRG4 rabbit polyclonal antibody and found that the expression of ECRG4 protein was down-regulated in 68.5% (89/130) ESCC samples using tissue microarray and analysis of immunohistochemical staining and Western blot. The expression of tumor suppressor gene is often down-regulated in tumor tissues due to the hypermethylation in the gene promoter, and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored ECRG4 mRNA expression in EC9706 cell line, it showed that promoter hypermethylation may be one main mechanism leading to the silencing of ECRG4 in ESCC. ECRG4 protein down-regulation was significantly associated with regional lymph node metastasis, primary tumor volume and tumor stage in ESCC (P < 0.05). ESCC patients with high ECRG4 expression had longer overall survival than those with low ECRG4 expression by Kaplan-Meier survival analysis (P < 0.05). ECRG4 protein was an independent prognostic factor for ESCC by multivariable Cox proportional hazards regression analysis (P < 0.05).
The transfection of ECRG4 gene in EC9706 cell line inhibited cell proliferation, colony formation, anchorage-independent growth, cell cycle progression and tumor growth in vivo (P < 0.05). Purified recombinant ECRG4 protein could inhibit EC9706 cells proliferation in vitro exhibiting dose-effect relationship (P < 0.05). The transfection of ECRG4 gene inhibited NF-κB expression and nuclear translocation, and inhibited NF-κB target gene COX-2 expression in EC9706 cell line.
In conclusion, ECRG4 is a novel candidate tumor suppressor in ESCC, and ECRG4 protein is a candidate prognostic marker for ESCC. Aberrant promoter hypermethylation is one of the major mechanisms leading to the silencing of ECRG4 gene in ESCC. ECRG4 might induce COX-2 down-regulation through NF-κB pathway to inhibit tumor growth in ESCC. The recombinant ECRG4 protein is a prospective candidate of anti-tumor drugs for ESCC.
引文
[1] Parkin D. M., F. Bray, J. Ferlay, et al. Global Cancer Statistics, 2002[J]. CA Cancer JClin, 2005, 55 (2) : 74-108.
[2] Lu S. H. Alterations of Oncogenes and Tumor Suppressor Genes in Esophageal Cancer in China[J]. Mutat Res, 2000, 462 (2-3) : 343-353.
[3] " Roth M. J., W. Guo-Qing, K. J. Lewin, et al. Histopathologic Changes Seen in Esophagectomy Specimens from the High-Risk Region of Linxian, China: Potential Clues to an Etiologic Exposure?[J]. Hum Pathol, 1998, 29 (11) : 1294-1298.
[4] Parkin D. M., P. Pisani, J. Ferlay. Estimates of the Worldwide Incidence of Eighteen Major Cancers in 1985[J]. Int J Cancer, 1993, 54 (4) : 594-606.
[5] Ruggieri M, F. Tosato, K. De Rocco, et al. [Epidemiological Aspects of Esophageal Cancer][J]. Recenti Prog Med, 1981, 70 (5) : 545-556.
[6] Ke L. Mortality and Incidence Trends from Esophagus Cancer in Selected Geographic Areas of China Circa 1970-90[J]. Int J Cancer, 2002, 102(3) : 271-274.
[7] Lu S. H., S. X. Chui, W. X. Yang, et al. Relevance of N-Nitrosamines to Oesophageal Cancer in China[J].IARC Sci Publ, 1991, (105) : 11-17.
[8] Gao Y. T., J. K. McLaughlin, W. J. Blot, et al. Risk Factors for Esophageal Cancer in Shanghai, China. I. Role of Cigarette Smoking and Alcohol Drinking[J]. Int J Cancer, 1994, 58 (2) : 192-196.
[9] Franceschi S., E. Bidoli, E. Negri, et al. Role of Macronutrients, Vitamins and Minerals in the Aetiology of Squamous-Cell Carcinoma of the Oesophagus[J]. IntJ Cancer, 2000, 86 (5) : 626-631.
[10] Yoshizawa T., A. Yamashita, Y. Luo. Fumonisin Occurrence in Corn from High- and Low-Risk Areas for Human Esophageal Cancer in China[J]. Appl Environ Microbiol, 1994, 60 (5) : 1626-1629.
[11] Engel L. S., W. H. Chow, T. L. Vaughan, et al. Population Attributable Risks of Esophageal and Gastric Cancers[J]. J Natl Cancer Inst, 2003, 95 (18) : 1404-1413.
[12] Luo A., J. Kong, G. Hu, et al. Discovery of Ca2+-Relevant and Differentiation-Associated Genes Downregulated in Esophageal Squamous Cell Carcinoma Using Cdna Microarray[J]. Oncogene, 2004, 23 (6) : 1291-1299.
[13] Yang Z. Q., I. Imoto, Y. Fukuda, et al. Identification of a Novel Gene, Gasc1, within an Amplicon at 9p23-24 Frequently Detected in Esophageal Cancer Cell Lines[J]. Cancer Res, 2000, 60 (17) : 4735-4739.
[14] Su T., H. Liu, S. Lu. [Cloning and Identification of Cdna Fragments Related to Human Esophageal Cancer][J]. Zhonghua Zhong Liu Za Zhi, 1998, 20(4) : 254-257.
[15] Bi M. X., W. D. Han, S. X. Lu. Using Lab on-Line to Clone and Identify the Esophageal Cancer Related Gene 4[J]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 2001, 33 (3) : 257-261.
[16] Steck E., S. Breit, S. J. Breusch, et al. Enhanced Expression of the Human Chitinase 3-Like 2 Gene (Ykl-39) but Not Chitinase 3-Like 1 Gene (Ykl-40) in Osteoarthritic Cartilage[J]. Biochem Biophys Res Commun, 2002,299(1): 109-115.
[17] Yue C. M., D. J. Deng, M. X. Bi, et al. Expression of Ecrg4, a Novel Esophageal Cancer-Related Gene, Downregulated by Cpg Island Hypermethylation in Human Esophageal Squamous Cell Carcinoma[J]. World J Gastroenterol, 2003, 9 (6) : 1174-1178.
[18] Blin N., D. W. Stafford. A General Method for Isolation of High Molecular Weight DNA from Eukaryotes[J]. Nucleic Acids Res, 1976, 3(9): 2303-2308.
[19] Li Y., X. Zhang, G. Huang, et al. Identification of a Novel Polymorphism Arg290gln of Esophageal Cancer Related Gene 1 (Ecrg1) and Its Related Risk to Esophageal Squamous Cell Carcinoma[J]. Carcinogenesis, 2006, 27 (4) : 798-802.
[20] Mori Y., H. Ishiguro, Y. Kuwabara, et al. Expression of Ecrg4 Is an Independent Prognostic Factor for Poor Survival in Patients with Esophageal Squamous Cell Carcinoma[J]. Oncol Rep, 2007, 18 (4) : 981-985.
[21] Thiagalingam S., R. L. Foy, K. H. Cheng, et al. Loss of Heterozygosity as a Predictor to Map Tumor Suppressor Genes in Cancer: Molecular Basis of Its Occurrence[J]. CurrOpin Oncol, 2002, 14 (1) : 65-72.
[22] Han Y., F. Wei, X. Xu, et al. [Establishment and Comparative Genomic Hybridization Analysis of Human Esophageal Carcinomas Cell Line Ec9706][J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2002, 19(6): 455-457.
[23] Yen C. C, Y. J. Chen, J. T. Chen, et al. Comparative Genomic Hybridization of Esophageal Squamous Cell Carcinoma: Correlations between Chromosomal Aberrations and Disease Progression/Prognosis[J]. Cancer, 2001, 92 (11) : 2769-2777.
[24] Jones P. A., S. B. Baylin. The Fundamental Role of Epigenetic Events in Cancer[J]. Nat Rev Genet, 2002, 3 (6) : 415-428.
[25] Herman J. G., S. B. Baylin. Gene Silencing in Cancer in Association with Promoter Hypermethylation[J].N Engl J Med, 2003, 349(21) : 2042-2054.
[26] Laird P. W. The Power and the Promise of DNA Methylation Markers[J]. Nat Rev Cancer, 2003, 3 (4) : 253-266.
[27] Egger G., G. Liang, A. Aparicio, et al. Epigenetics in Human Disease and Prospects for Epigenetic Therapy[J]. Nature, 2004, 429 (6990) : 457-463.
[28] Baylin S. B., J. E. Ohm. Epigenetic Gene Silencing in Cancer - a Mechanism for Early Oncogenic Pathway Addiction?[J]. Nat Rev Cancer, 2006, 6 (2) : 107-116.
[29] Feinberg A. P., R. Ohlsson, S. Henikoff. The Epigenetic Progenitor Origin of Human Cancer[J]. Nat Rev Genet, 2006, 7 (1) : 21-33.
[30] Xing E. P., Y. Nie, Y. Song, et al. Mechanisms of Inactivation of P14arf, P15ink4b, and P16ink4a Genes in Human Esophageal Squamous Cell Carcinoma[J]. Clin Cancer Res, 1999, 5 (10) : 2704-2713.
[31] Wong D. J., M. T. Barrett, R. Stoger, et al. P16ink4a Promoter Is Hypermethylated at a High Frequency in Esophageal Adenocarcinomas[J]. Cancer Res, 1997, 57 (13) : 2619-2622.
[32] Si H. X., S. W. Tsao, K. Y. Lam, et al. E-Cadherin Expression Is Commonly Downregulated by Cpg Island Hypermethylation in Esophageal Carcinoma Cells[J]. Cancer Lett, 2001, 173 (1) : 71-78.
[33] Tanaka H., Y. Shimada, H. Harada, et al. Methylation of the 5' Cpg Island of the Fhit Gene Is Closely Associated with Transcriptional Inactivation in Esophageal Squamous Cell Carcinomas[J]. Cancer Res, 1998, 58 (15) : 3429-3434.
[34] Cihak A. Biological Effects of 5-Azacytidine in Eukaryotes[J]. Oncology, 1974, 30 (5) : 405-422.
[35] Jones P. A., S. M. Taylor. Cellular Differentiation, Cytidine Analogs and DNA Methylation[J].Cell, 1980, 20 (1) : 85-93.
[36] Lubbert M. DNA Methylation Inhibitors in the Treatment of Leukemias, Myelodysplastic Syndromes and Hemoglobinopathies: Clinical Results and Possible Mechanisms of Action[J]. Curr Top Microbiol Immunol, 2000, 249: 135-164.
[37] Bird A. DNA Methylation Patterns and Epigenetic Memory[J]. Genes Dev, 2002, 16 (1) : 6-21.
[38] Bird A. P., A. P. Wolffe. Methylation-Induced Repression-Belts, Braces, and Chromatin[J]. Cell, 1999, 99 (5) : 451-454.
[39] Wolf S. F., B. R. Migeon. Studies of X Chromosome DNA Methylation in Normal Human Cells[J]. Nature, 1982, 295 (5851) : 667-671.
[40] Mohandas T., R. S. Sparkes, L. J. Shapiro. Reactivation of an Inactive Human X Chromosome: Evidence for X Inactivation by DNA Methylation[J]. Science, 1981, 211 (4480) : 393-396.
[41] Jaenisch R., A. Schnieke, K. Harbers. Treatment of Mice with 5-Azacytidine Efficiently Activates Silent Retroviral Genomes in Different Tissues[J]. Proc Natl Acad Sci U S A, 1985, 82 (5) : 1451-1455.
[42] Liang G., F. A. Gonzales, P. A. Jones, et al. Analysis of Gene Induction in Human Fibroblasts and Bladder Cancer Cells Exposed to the Methylation Inhibitor 5-Aza-2'-Deoxycytidine[J]. Cancer Res, 2002, 62 (4) : 961-966.
[43] Soengas M. S., P. Capodieci, D. Polsky, et al. Inactivation of the Apoptosis Effector Apaf-1 in Malignant Melanoma[J]. Nature, 2001, 409 (6817) : 207-211.
[44] Cameron E. E., K. E. Bachman, S. Myohanen, et al. Synergy of Demethylation and Histone Deacetylase Inhibition in the Re-Expression of Genes Silenced in Cancer[J]. Nat Genet, 1999, 21 (1) : 103-107.
[45] Suzuki H., E. Gabrielson, W. Chen, et al. A Genomic Screen for Genes Upregulated by Demethylation and Histone Deacetylase Inhibition in Human Colorectal Cancer[J]. Nat Genet, 2002, 31 (2) : 141-149.
[46] Bender C. M., M. L. Gonzalgo, F. A. Gonzales, et al. Roles of Cell Division and Gene Transcription in the Methylation of Cpg Islands[J]. Mol Cell Biol, 1999, 19 (10) : 6690-6698.
[47] Bardy S. L., S. Y. Ng, K. F. Jarrell. Recent Advances in the Structure and Assembly of the Archaeal Flagellum[J]. J Mol Microbiol Biotechnol, 2004, 7 (1-2) : 41-51.
[48] Carrio M. M., A. Villaverde. Construction and Deconstruction of Bacterial Inclusion Bodies[J].J Biotechnol, 2002, 96 (1) : 3-12.
[49] Fahnert B., H. Lilie, P. Neubauer. Inclusion Bodies: Formation and Utilisation[J]. Adv Biochem Eng Biotechnol, 2004, 89: 93-142.
[50] Vincentelli R., S. Canaan, V. Campanacci, et al. High-Throughput Automated Refolding Screening of Inclusion Bodies[J]. Protein Sci, 2004, 13 (10) : 2782-2792.
[51] Magistrelli G., F. Gueneau, M. Muslmani, et al. Chemokines Derived from Soluble Fusion Proteins Expressed in Escherichia Coli Are Biologically Active[J]. Biochem Biophys Res Commun, 2005, 334 (2) : 370-375.
[52] Roosbeek S., H. Caster, Q. Z. Liu, et al. Expression and Activity of the Nucleotide-Binding Domains of the Human Abcal Transporter[J]. Protein ExprPurif, 2004, 35 (1) : 102-110.
[53] Karmodiya K., R. K. Srivastav, N. Surolia. Production and Purification of Refolded Recombinant Plasmodium Falciparum Beta-Ketoacyl-Acp Reductase from Inclusion Bodies[J]. Protein Expr Purif, 2005, 42 (1) : 131-136.
[54] Hashimoto Y., T. Ikenaga, K. Tanigawa, et al. Expression and Characterization of Human Rheumatoid Factor Single-Chain Fv[J]. Biol Pharm Bull, 2000, 23 (8) : 941-945.
[55] Balkwill F., A. Mantovani. Inflammation and Cancer: Back to Virchow?[J]. Lancet, 2001, 357 (9255) : 539-545.
[56] Bharti A. C, B. B. Aggarwal. Chemopreventive Agents Induce Suppression of Nuclear Factor-Kappab Leading to Chemosensitization[J]. Ann N Y Acad Sci, 2002, 973: 392-395.
[57] Karin M., Y. Cao, F. R. Greten, et al. Nf-Kappab in Cancer: From Innocent Bystander to Major Culprit[J]. Nat Rev Cancer, 2002, 2 (4) : 301-310.
[58] Greten F. R., L. Eckmann, T. F. Greten, et al. Ikkbeta Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer[J]. Cell, 2004, 118 (3) : 285-296.
[59] Pikarsky E., R. M. Porat, I. Stein, et al. Nf-Kappab Functions as a Tumour Promoter in Inflammation-Associated Cancer[J]. Nature, 2004, 431 (7007) : 461-466.
[60] Luo J. L., S. Maeda, L. C. Hsu, et al. Inhibition of Nf-Kappab in Cancer Cells Converts Inflammation- Induced Tumor Growth Mediated by Tnfalpha to Trail-Mediated Tumor Regression[J]. Cancer Cell, 2004, 6 (3) : 297-305.
[61] Shattuck-Brandt R. L., A. Richmond. Enhanced Degradation of I-Kappab Alpha Contributes to Endogenous Activation of Nf-Kappab in Hs294t Melanoma Cells[J]. Cancer Res, 1997, 57 (14) : 3032-3039.
[62] Amiri K. I., A. Richmond. Role of Nuclear Factor-Kappa B in Melanoma[J]. Cancer Metastasis Rev, 2005, 24 (2) : 301-313.
[63] Sovak M. A., R. E. Bellas, D. W. Kim, et al. Aberrant Nuclear Factor-Kappab/Rel Expression and the Pathogenesis of Breast Cancer[J]. J Clin Invest, 1997, 100 (12) : 2952-2960.
[64] Kalaitzidis D., T. D. Gilmore. Transcription Factor Cross-Talk: The Estrogen Receptor and Nf-Kappab[J]. Trends Endocrinol Metab, 2005, 16(2) : 46-52.
[65] Huang S., C. A. Pettaway, H. Uehara, et al. Blockade of Nf-Kappab Activity in Human Prostate Cancer Cells Is Associated with Suppression of Angiogenesis, Invasion, and Metastasis[J]. Oncogene, 2001, 20 (31) : 4188-4197.
[66] Sweeney C, L. Li, R. Shanmugam, et al. Nuclear Factor-Kappab Is Constitutively Activated in Prostate Cancer in Vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate[J]. Clin Cancer Res, 2004, 10 (16) : 5501-5507.
[67] Huang S., J. B. Robinson, A. Deguzman, et al. Blockade of Nuclear Factor-Kappab Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 8[J]. Cancer Res, 2000, 60(19) : 5334-5339.
[68] Mabuchi S., M. Ohmichi, Y. Nishio, et al. Inhibition of Nfkappab Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models[J]. J Biol Chem, 2004, 279 (22) : 23477-23485.
[69] Wang W., J. L. Abbruzzese, D. B. Evans, et al. The Nuclear Factor-Kappa B Rela Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells[J]. Clin Cancer Res, 1999, 5 (1) : 119-127.
[70] Sclabas G. M., T. Uwagawa, C. Schmidt, et al. Nuclear Factor Kappa B Activation Is a Potential Target for Preventing Pancreatic Carcinoma by Aspirin[J]. Cancer, 2005, 103 (12) : 2485-2490.
[71] Kojima M., T. Morisaki, N. Sasaki, et al. Increased Nuclear Factor-Kb Activation in Human Colorectal Carcinoma and Its Correlation with Tumor Progression[J]. Anticancer Res, 2004, 24 (2B) : 675-681.
[72] Dejardin E., V. Deregowski, M. Chapelier, et al. Regulation of Nf-Kappab Activity by I Kappab-Related Proteins in Adenocarcinoma Cells[J]. Oncogene, 1999, 18 (16) : 2567-2577.
[73] Visconti R., J. Cerutti, S. Battista, et al. Expression of the Neoplastic Phenotype by Human Thyroid Carcinoma Cell Lines Requires Nfkappab P65 Protein Expression[J]. Oncogene, 1997, 15 (16) : 1987-1994.
[74] Pacifico F., C. Mauro, C. Barone, et al. Oncogenic and Anti-Apoptotic Activity of Nf-Kappa B in Human Thyroid Carcinomas[J]. J Biol Chem, 2004, 279 (52) : 54610-54619.
[75] Smith W. L., D. L. DeWitt, R. M. Garavito. Cyclooxygenases: Structural, Cellular, and Molecular Biology[J]. Annu Rev Biochem, 2000, 69: 145-182.
[76] Smith W. L., R. M. Garavito, D. L. DeWitt. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2[J]. J Biol Chem, 1996, 271 (52) : 33157-33160.
[77] Buckman S. Y., A. Gresham, P. Hale, et al. Cox-2 Expression Is Induced by Uvb Exposure in Human Skin: Implications for the Development of Skin Cancer[J]. Carcinogenesis, 1998, 19 (5) : 723-729.
[78] Wolff H., K. Saukkonen, S. Anttila, et al. Expression of Cyclooxygenase-2 in Human Lung Carcinoma[J]. Cancer Res, 1998, 58 (22) : 4997-5001.
[79] Hwang D., D. Scollard, J. Byrne, et al. Expression of Cyclooxygenase-1 and Cyclooxygenase-2 in Human Breast Cancer[J]. J Natl Cancer Inst, 1998, 90 (6) : 455-460.
[80] Gupta S., M. Srivastava, N. Ahmad, et al. Over-Expression of Cyclooxygenase-2 in Human Prostate Adenocarcinoma[J]. Prostate, 2000, 42 (1) : 73-78.
[81] Mohammed S. I., D. W. Knapp, D. G. Bostwick, et al. Expression of Cyclooxygenase-2 (Cox-2) in Human Invasive Transitional Cell Carcinoma (Tcc) of the Urinary Bladder[J]. Cancer Res, 1999, 59(22) : 5647-5650.
[82] Tucker O. N., A. J. Dannenberg, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Human Pancreatic Cancer[J]. Cancer Res, 1999, 59 (5) : 987-990.
[83] Chan G., J. O. Boyle, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Squamous Cell Carcinoma of the Head and Neck[J]. Cancer Res, 1999, 59 (5) : 991-994.
[84] Zimmermann K. C, M. Sarbia, A. A. Weber, et al. Cyclooxygenase-2 Expression in Human Esophageal Carcinoma[J]. Cancer Res, 1999, 59 (1) : 198-204.
[85] Zhi H., L. Wang, J. Zhang, et al. Significance of Cox-2 Expression in Human Esophageal Squamous Cell Carcinoma[J]. Carcinogenesis, 2006, 27 (6) : 1214-1221.
[86] Ghosh S., M. Karin. Missing Pieces in the Nf-Kappab Puzzle[J]. Cell, 2002, 109 Suppl: S81-96.
[87] Gilmore T. D. The Rel/Nf-Kappab Signal Transduction Pathway: Introduction[J]. Oncogene, 1999, 18 (49) : 6842-6844.
[88] Bonizzi G., M. Karin. The Two Nf-Kappab Activation Pathways and Their Role in Innate and Adaptive Immunity[J]. Trends Immunol, 2004, 25 (6) : 280-288.
[89] Rothwarf D. M., M. Karin. The Nf-Kappa B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus[J]. Sci STKE, 1999, 1999 (5) : RE1.
[90] Karin M., Y. Ben-Neriah. Phosphorylation Meets Ubiquitination: The Control of Nf-[Kappa]B Activity[J]. Annu Rev Immunol, 2000, 18: 621-663.
[91] Hayden M. S., S. Ghosh. Signaling to Nf-Kappab[J]. Genes Dev, 2004, 18 (18) : 2195-2224.
[92] Werner S. L., D. Barken, A. Hoffmann. Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of Ikk Activity[J]. Science, 2005, 309 (5742) : 1857-1861.
[93] Park J. M., F. R. Greten, A. Wong, et al. Signaling Pathways and Genes That Inhibit Pathogen-Induced Macrophage Apoptosis-Creb and Nf-Kappab as Key Regulators[J]. Immunity, 2005, 23 (3) : 319-329.
[94] Covert M. W., T. H. Leung, J. E. Gaston, et al. Achieving Stability of Lipopolysaccharide-Induced Nf-Kappab Activation[J]. Science, 2005, 309 (5742) : 1854-1857.
[95] Campbell K. J., S. Rocha, N. D. Perkins. Active Repression of Antiapoptotic Gene Expression by Rela(P65) Nf-Kappa B[J]. Mol Cell, 2004, 13 (6) : 853-865.
[96] Chun K. S., Y. J. Surh. Signal Transduction Pathways Regulating Cyclooxygenase-2 Expression: Potential Molecular Targets for Chemoprevention[J]. Biochem Pharmacol, 2004, 68 (6) : 1089-1100.
[97] Jung Y. J., J. S. Isaacs, S. Lee, et al. Il-1 beta-Mediated up-Regulation of Hif-1 alpha Via an Nfkappab/Cox-2 Pathway Identifies Hif-1 as a Critical Link between Inflammation and Oncogenesis[J]. Faseb J, 2003, 17 (14) : 2115-2117.
[98] Konturek P. C, A. Nikiforuk, J. Kania, et al. Activation of Nfkappab Represents the Central Event in the Neoplastic Progression Associated with Barrett's Esophagus: A Possible Link to the Inflammation and Overexpression of Cox-2, Ppargamma and Growth Factors[J]. Dig DisSci, 2004, 49(7-8) : 1075-1083.
[99] Benoit V., E. de Moraes, N. A. Dar, et al. Transcriptional Activation of Cyclooxygenase-2 by Tumor Suppressor P53 Requires Nuclear Factor-Kappab[J]. Oncogene, 2006, 25 (42) : 5708-5718.
[100] Poligone B., A. S. Baldwin. Positive and Negative Regulation of Nf-Kappab by Cox-2: Roles of Different Prostaglandins[J]. J Biol Chem, 2001, 276(42): 38658-38664.
[101] Garkavtsev I., S. V. Kozin, O. Chernova, et al. The Candidate Tumour Suppressor Protein Ing4 Regulates Brain Tumour Growth and Angiogenesis[J]. Nature, 2004, 428 (6980) : 328-332.
[102] Wang W. H., J. Q. Huang, G. F. Zheng, et al. Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Gastric Cancer: A Systematic Review and Meta-Analysis[J]. J Natl Cancer Inst, 2003, 95 (23): 1784-1791.
[103] Chang E. T., T. Zheng, E. G. Weir, et al. Aspirin and the Risk of Hodgkin's Lymphoma in a Population-Based Case-Control Study[J].J Natl Cancer Inst,2004,96(4):305-315.
[1]Kuper H.,H.O.Adami,D.Trichopoulos.Infections as a Major Preventable Cause of Human Cancer[J].J Intern Med,2000,248(3):171-183.
[2]Balkwill F.,A.Mantovani.Inflammation and Cancer:Back to Virchow?[J].Lancet,2001,357(9255):539-545.
[3]Coussens L.M.,Z.Werb.Inflammation and Cancer[J].Nature,2002,420 (6917): 860-867.
[4] Roder D. M. The Epidemiology of Gastric Cancer[J]. Gastric Cancer, 2002, 5 Suppl 1: 5-11.
[5] Keates S., Y. S. Hitti, M. Upton, et al. Helicobacter Pylori Infection Activates Nf-Kappa B in Gastric Epithelial Cells[J]. Gastroenterology, 1997, 113 (4): 1099-1109.
[6] Wang W. H., J. Q. Huang, G. F. Zheng, et al. Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Gastric Cancer: A Systematic Review and Meta-Analysis[J]. J Natl Cancer Inst, 2003, 95 (23): 1784-1791.
[7] Chang E. T., T. Zheng, E. G. Weir, et al. Aspirin and the Risk of Hodgkin's Lymphoma in a Population-Based Case-Control Study [J]. J Natl Cancer Inst, 2004, 96 (4): 305-315.
[8] Bharti A. C, B. B. Aggarwal. Chemopreventive Agents Induce Suppression of Nuclear Factor-Kappab Leading to Chemosensitization[J]. Ann N Y Acad Sci, 2002, 973: 392-395.
[9] Cerhan J. R., K. E. Anderson, C. A. Janney, et al. Association of Aspirin and Other Non-Steroidal Anti-Inflammatory Drug Use with Incidence of Non-Hodgkin Lymphoma[J]. Int J Cancer, 2003, 106 (5): 784-788.
[10] Schernhammer E. S., J. H. Kang, A. T. Chan, et al. A Prospective Study of Aspirin Use and the Risk of Pancreatic Cancer in Women[J]. J Natl Cancer Inst, 2004, 96 (1): 22-28.
[11] Karin M., Y. Cao, F. R. Greten, et al. Nf-Kappab in Cancer: From Innocent Bystander to Major Culprit[J]. Nat Rev Cancer, 2002, 2 (4): 301-310.
[12] Greten F. R., L. Eckmann, T. F. Greten, et al. Ikkbeta Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer[J]. Cell, 2004, 118 (3): 285-296.
[13] Pikarsky E., R. M. Porat, I. Stein, et al. Nf-Kappab Functions as a Tumour Promoter in Inflammation-Associated Cancer[J]. Nature, 2004, 431 (7007): 461-466.
[14] Ghosh S., M. Karin. Missing Pieces in the Nf-Kappab Puzzle[J]. Cell, 2002, 109 Suppl: S81-96.
[15] Gilmore T. D. The Rel/Nf-Kappab Signal Transduction Pathway: Introduction[J].Oncogene, 1999, 18 (49): 6842-6844.
[16] Gilmore T. D. Multiple Mutations Contribute to the Oncogenicity of the Retroviral Oncoprotein V-Rel[J].Oncogene, 1999, 18 (49): 6925-6937.
[17] Rayet B., C. Gelinas. Aberrant Rel/Nfkb Genes and Activity in Human Cancer[J].Oncogene, 1999, 18 (49): 6938-6947.
[18] Bonizzi G, M. Karin. The Two Nf-Kappab Activation Pathways and Their Role in Innate and Adaptive Immunity[J]. Trends Immunol, 2004, 25 (6): 280-288.
[19] Rothwarf D. M., M. Karin. The Nf-Kappa B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus[J]. Sci STKE, 1999, 1999 (5): RE1.
[20] Karin M., Y. Ben-Neriah. Phosphorylation Meets Ubiquitination: The Control of Nf-[Kappa]B Activity[J]. Annu Rev Immunol, 2000, 18: 621-663.
[21] Hayden M. S., S. Ghosh. Signaling to Nf-Kappab[J]. Genes Dev, 2004, 18 (18): 2195-2224.
[22] Werner S. L., D. Barken, A. Hoffmann. Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of Ikk Activity[J]. Science, 2005, 309 (5742): 1857-1861.
[23] Park J. M., F. R. Greten, A. Wong, et al. Signaling Pathways and Genes That Inhibit Pathogen-Induced Macrophage Apoptosis-Creb and Nf-Kappab as Key Regulators[J]. Immunity, 2005, 23 (3): 319-329.
[24] Covert M. W, T. H. Leung, J. E. Gaston, et al. Achieving Stability of Lipopolysaccharide-Induced Nf-Kappab Activation[J]. Science, 2005, 309 (5742): 1854-1857.
[25] Senftleben U., Y. Cao, G. Xiao, et al. Activation by Ikkalpha of a Second, Evolutionary Conserved, Nf-Kappa B Signaling Pathway [J]. Science, 2001, 293 (5534): 1495-1499.
[26] Lawrence T., M. Bebien, G. Y. Liu, et al. Ikkalpha Limits Macrophage Nf-Kappab Activation and Contributes to the Resolution of Inflammation[J]. Nature, 2005, 434 (7037): 1138-1143.
[27] Neri A., C. C. Chang, L. Lombardi, et al. B Cell Lymphoma-Associated Chromosomal Translocation Involves Candidate Oncogene Lyt-10, Homologous to Nf-Kappa B P50[J]. Cell, 1991, 67 (6): 1075-1087.
[28] Demicco E. G, K. T. Kavanagh, R. Romieu-Mourez, et al. Relb/P52 Nf-Kappab Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor Ikappab-Alpha Expression and Promote Carcinogenesis of the Mammary Gland[J]. Mol Cell Biol, 2005, 25 (22): 10136-10147.
[29] Gilmore T. D. The Rel/Nf-Kappa B/I Kappa B Signal Transduction Pathway and Cancer[J]. Cancer Treat Res, 2003, 115: 241-265.
[30] Kato T., Jr., M. Delhase, A. Hoffmann, et al. Ck2 Is a C-Terminal Ikappab Kinase Responsible for Nf-Kappab Activation During the Uv Response[J]. Mol Cell, 2003, 12 (4): 829-839.
[31] Maeda S., H. Kamata, J. L. Luo, et al. Ikkbeta Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation That Promotes Chemical Hepatocarcinogenesis[J].Cell, 2005, 121 (7): 977-990.
[32] Burnet F. M. The Concept of Immunological Surveillance[J]. Prog Exp Tumor Res, 1970, 13: 1-27.
[33] Dunn G. P., L. J. Old, R. D. Schreiber. The Immunobiology of Cancer Immunosurveillance and Immunoediting[J]. Immunity, 2004, 21(2): 137-148.
[34] Pardoll D. Does the Immune System See Tumors as Foreign or Self?[J]. Annu Rev Immunol, 2003, 21: 807-839.
[35] Philip M., D. A. Rowley, H. Schreiber. Inflammation as a Tumor Promoter in Cancer Induction[J]. Semin Cancer Biol, 2004, 14(6): 433-439.
[36] Luo J. L., S. Maeda, L. C. Hsu, et al. Inhibition of Nf-Kappab in Cancer Cells Converts Inflammation- Induced Tumor Growth Mediated by Tnfalpha to Trail-Mediated Tumor Regression[J]. Cancer Cell, 2004, 6 (3): 297-305.
[37] de Visser K. E., L. V. Korets, L. M. Coussens. De Novo Carcinogenesis Promoted by Chronic Inflammation Is B Lymphocyte Dependent[J]. Cancer Cell, 2005, 7 (5): 411-423.
[38] Chisari F. V. Hepatitis B Virus Transgenic Mice: Insights into the Virus and the Disease[J].Hepatology, 1995, 22 (4 Pt 1): 1316-1325.
[39] Shattuck-Brandt R. L., A. Richmond. Enhanced Degradation of I-Kappab Alpha Contributes to Endogenous Activation of Nf-Kappab in Hs294t Melanoma Cells[J]. Cancer Res, 1997, 57 (14): 3032-3039.
[40] Amiri K. I., A. Richmond. Role of Nuclear Factor-Kappa B in Melanoma[J]. Cancer Metastasis Rev, 2005, 24 (2): 301-313.
[41] Sovak M. A., R. E. Bellas, D. W. Kim, et al. Aberrant Nuclear Factor-Kappab/Rel Expression and the Pathogenesis of Breast Cancer[J]. J Clin Invest, 1997, 100 (12): 2952-2960.
[42] Kalaitzidis D., T. D. Gilmore. Transcription Factor Cross-Talk: The Estrogen Receptor and Nf-Kappab[J]. Trends Endocrinol Metab, 2005, 16(2): 46-52.
[43] Huang S., C. A. Pettaway, H. Uehara, et al. Blockade of Nf-Kappab Activity in Human Prostate Cancer Cells Is Associated with Suppression of Angiogenesis, Invasion, and Metastasis[J]. Oncogene, 2001, 20 (31): 4188-4197.
[44] Sweeney C, L. Li, R. Shanmugam, et al. Nuclear Factor-Kappab Is Constitutively Activated in Prostate Cancer in Vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate[J]. Clin Cancer Res, 2004, 10 (16): 5501-5507.
[45] Huang S., J. B. Robinson, A. Deguzman, et al. Blockade of Nuclear Factor-Kappab Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 8[J]. Cancer Res, 2000, 60(19): 5334-5339.
[46] Mabuchi S., M. Ohmichi, Y. Nishio, et al. Inhibition of Nfkappab Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models[J]. J Biol Chem, 2004, 279 (22): 23477-23485.
[47] Wang W., J. L. Abbruzzese, D. B. Evans, et al. The Nuclear Factor-Kappa B Rela Transcription Factor Is Constitutively Activated in Human Pancreatic AdenocarcinomaCells[J]. Ciin Cancer Res, 1999, 5(1): 119-127.
[48] Sclabas G. M., T. Uwagawa, C. Schmidt, et al. Nuclear Factor Kappa B Activation Is a Potential Target for Preventing Pancreatic Carcinoma by Aspirin[J]. Cancer, 2005, 103 (12): 2485-2490.
[49] Kojima M., T. Morisaki, N. Sasaki, et al. Increased Nuclear Factor-Kb Activation in Human Colorectal Carcinoma and Its Correlation with Tumor Progression[J].Anticancer Res, 2004, 24 (2B): 675-681.
[50] Dejardin E., V. Deregowski, M. Chapelier, et al. Regulation of Nf-Kappab Activity by I Kappab-Related Proteins in Adenocarcinoma Cells[J]. Oncogene, 1999, 18 (16): 2567-2577.
[51] Visconti R., J. Cerutti, S. Battista, et al. Expression of the Neoplastic Phenotype by Human Thyroid Carcinoma Cell Lines Requires Nfkappab P65 Protein Expression[J]. Oncogene, 1997, 15 (16): 1987-1994.
[52] Pacifico F., C. Mauro, C. Barone, et al. Oncogenic and Anti-Apoptotic Activity of Nf-Kappa B in Human Thyroid Carcinomas[J]. J Biol Chem, 2004, 279 (52): 54610-54619.
[53] Hanahan D., R. A. Weinberg. The Hallmarks of Cancer[J]. Cell, 2000, 100 (1): 57-70.
[54] Aggarwal B. B. Nuclear Factor-Kappab: The Enemy Within[J]. Cancer Cell, 2004, 6 (3): 203-208.
[55] Karin M. Nuclear Factor-Kappab in Cancer Development and Progression[J]. Nature, 2006, 441 (7092): 431-436.
[56] Guttridge D. C, C. Albanese, J. Y. Reuther, et al. Nf-Kappab Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1[J].Mol Cell Biol, 1999, 19(8): 5785-5799.
[57] Perkins N. D., L. K. Felzien, J. C. Betts, et al. Regulation of Nf-Kappab by Cyclin-Dependent Kinases Associated with the P300 Coactivator[J]. Science, 1997, 275 (5299): 523-527.
[58] Kim D. W., L. Gazourian, S. A. Quadri, et al. The Rela Nf-Kappab Subunit and the Aryl Hydrocarbon Receptor (Ahr) Cooperate to Transactivate the C-Myc Promoter in Mammary Cells[J]. Oncogene, 2000, 19(48): 5498-5506.
[59] Pahl H. L. Activators and Target Genes of Rel/Nf-Kappab Transcription Factors[J]. Oncogene, 1999, 18 (49): 6853-6866.
[60] Biswas D. K., A. P. Cruz, E. Gansberger, et al. Epidermal Growth Factor-Induced Nuclear Factor Kappa B Activation: A Major Pathway of Cell-Cycle Progression in Estrogen-Receptor Negative Breast Cancer Cells[J]. Proc Natl Acad Sci U S A, 2000, 97 (15): 8542-8547.
[61] Farina A. R., A. Tacconelli, A. Vacca, et al. Transcriptional up-Regulation of Matrix Metalloproteinase-9 Expression During Spontaneous Epithelial to Neuroblast Phenotype Conversion by Sk-N-Sh Neuroblastoma Cells, Involved in Enhanced Invasivity, Depends Upon Gt-Box and Nuclear Factor Kappab Elements[J]. Cell Growth Differ, 1999, 10 (5): 353-367.
[62] Yasumoto K., S. Okamoto, N. Mukaida, et al. Tumor Necrosis Factor Alpha and Interferon Gamma Synergistically Induce Interleukin 8 Production in a Human Gastric Cancer Cell Line through Acting Concurrently on Ap-1 and Nf-Kb-Like Binding Sites of the Interleukin 8 Gene[J]. J Biol Chem, 1992, 267 (31): 22506-22511.
[63] Kunsch C, C. A. Rosen. Nf-Kappa B Subunit-Specific Regulation of the Interleukin-8 Promoter[J]. Mol Cell Biol, 1993, 13 (10): 6137-6146.
[64] van de Stolpe A., E. Caldenhoven, B. G Stade, et al. 12-O-Tetradecanoylphorbol-13-Acetate- and Tumor Necrosis Factor Alpha-Mediated Induction of Intercellular Adhesion Molecule-1 Is Inhibited by Dexamethasone. Functional Analysis of the Human Intercellular Adhesion Molecular-1 Promoter[J].J Biol Chem, 1994, 269(8): 6185-6192.
[65] Helbig G., K. W. Christopherson, 2nd, P. Bhat-Nakshatri, et al. Nf-Kappab Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor Cxcr4[J]. J Biol Chem, 2003, 278 (24): 21631-21638.
[66] Kiriakidis S., E. Andreakos, C. Monaco, et al. Vegf Expression in Human Macrophages Is Nf-Kappab-Dependent: Studies Using Adenoviruses Expressing the Endogenous Nf-Kappab Inhibitor Ikappabalpha and a Kinase-Defective Form of the Ikappab Kinase 2[J]. J Cell Sci, 2003, 116 (Pt 4): 665-674.
[67] Karin M., A. Lin. Nf-Kappab at the Crossroads of Life and Death[J]. Nat Immunol, 2002, 3 (3): 221-227.
[68] Wang C. Y., M. W. Mayo, R. G. Korneluk, et al. Nf-Kappab Antiapoptosis: Induction of Traf1 and Traf2 and C-Iap1 and C-Iap2 to Suppress Caspase-8 Activation[J]. Science, 1998, 281 (5383): 1680-1683.
[69] Deveraux Q. L., N. Roy, H. R. Stennicke, et al. Iaps Block Apoptotic Events Induced by Caspase-8 and Cytochrome C by Direct Inhibition of Distinct Caspases[J].Embo J, 1998, 17 (8): 2215-2223.
[70] Boise L. H., M. Gonzalez-Garcia, C. E. Postema, et al. Bcl-X, a Bcl-2-Related Gene That Functions as a Dominant Regulator of Apoptotic Cell Death[J]. Cell, 1993, 74 (4): 597-608.
[71] Yeh W. C, A. Itie, A. J. Elia, et al. Requirement for Casper (C-Flip) in Regulation of Death Receptor-Induced Apoptosis and Embryonic Development[J]. Immunity, 2000, 12 (6): 633-642.
[72] De Smaele E., F. Zazzeroni, S. Papa, et al. Induction of Gadd45beta by Nf-Kappab Downregulates Pro-Apoptotic Jnk Signalling[J]. Nature, 2001,414 (6861): 308-313.
[73] Pham C. G, C. Bubici, F. Zazzeroni, et al. Ferritin Heavy Chain Upregulation by Nf-Kappab Inhibits Tnfalpha-Induced Apoptosis by Suppressing Reactive Oxygen Species[J]. Cell, 2004, 119 (4): 529-542.
[74] Kluiver J., A. van den Berg, D. de Jong, et al. Regulation of Pri-Microrna Bic Transcription and Processing in Burkitt Lymphoma[J]. Oncogene, 2007, 26 (26): 3769-3776.
[75] Fernandez-Majada V., C. Aguilera, A. Villanueva, et al. Nuclear Ikk Activity Leads to Dysregulated Notch-Dependent Gene Expression in Colorectal Cancer[J]. Proc Natl Acad Sci U S A, 2007, 104 (1): 276-281.
[76] Prajapati S., Z. Tu, Y. Yamamoto, et al. Ikkalpha Regulates the Mitotic Phase of the Cell Cycle by Modulating Aurora a Phosphorylation[J]. Cell Cycle, 2006, 5 (20): 2371-2380.
[77] Hu M. C, D. F. Lee, W. Xia, et al. Ikappab Kinase Promotes Tumorigenesis through Inhibition of Forkhead Foxo3a[J]. Cell, 2004, 117 (2): 225-237.
[78] Lee D. F., H. P. Kuo, C. T. Chen, et al. Ikk Beta Suppression of Tsc1 Links Inflammation and Tumor Angiogenesis Via the Mtor Pathway[J]. Cell, 2007, 130 (3): 440-455.
[79] Li Q., I. M. Verma. Nf-Kappab Regulation in the Immune System[J]. Nat Rev Immunol, 2002, 2 (10): 725-734.
[80] Lind M. H., B. Rozell, R. P. Wallin, et al. Tumor Necrosis Factor Receptor 1-Mediated Signaling Is Required for Skin Cancer Development Induced by Nf-Kappab Inhibition[J]. Proc Natl Acad Sci U S A, 2004, 101 (14): 4972-4977.
[81] Holla V R., D. Wang, J. R. Brown, et al. Prostaglandin E2 Regulates the Complement Inhibitor Cd55/Decay-Accelerating Factor in Colorectal Cancer[J]. J Biol Chem, 2005, 280 (1): 476-483.
[82] Sparmann A., D. Bar-Sagi. Ras-Induced Interleukin-8 Expression Plays a Critical Role in Tumor Growth and Angiogenesis[J]. Cancer Cell, 2004,6(5): 447-458.
[83] Garkavtsev I., S. V. Kozin, O. Chernova, et al. The Candidate Tumour Suppressor Protein Ing4 Regulates Brain Tumour Growth and Angiogenesis[J]. Nature, 2004, 428 (6980): 328-332.
[84] Joyce D., C. Albanese, J. Steer, et al. Nf-Kappab and Cell-Cycle Regulation: The Cyclin Connection[J]. Cytokine Growth Factor Rev, 2001, 12 (1): 73-90.
[85] Cao Y., G. Bonizzi, T. N. Seagroves, et al. Ikkalpha Provides an Essential Link between Rank Signaling and Cyclin D1 Expression During Mammary Gland Development[J].Cell, 2001, 107 (6): 763-775.
[86] Dajee M., M. Lazarov, J. Y. Zhang, et al. Nf-Kappab Blockade and Oncogenic Ras Trigger Invasive Human Epidermal Neoplasia[J]. Nature, 2003, 421 (6923): 639-643.
[87] Zhang J. Y., C. L. Green, S. Tao, et al. Nf-Kappab Rela Opposes Epidermal Proliferation Driven by Tnfr1 and Jnk[J]. Genes Dev, 2004, 18(1): 17-22.
[88] Herschman H. R. Prostaglandin Synthase 2[J]. Biochim Biophys Acta, 1996, 1299 (1): 125-140.
[89] Dubois R. N., S. B. Abramson, L. Crofford, et al. Cyclooxygenase in Biology and Disease[J].Faseb J, 1998, 12 (12): 1063-1073.
[90] Herschman H. R., W. Xie, S. Reddy. Inflammation, Reproduction, Cancer and All That.... The Regulation and Role of the Inducible Prostaglandin Synthase[J].Bioessays, 1995, 17(12): 1031-1037.
[91] Smith W. L., D. L. DeWitt, R. M. Garavito. Cyclooxygenases: Structural, Cellular, and Molecular Biology[J]. Annu Rev Biochem, 2000, 69: 145-182.
[92] Raz A., A. Wyche, N. Siegel, et al. Regulation of Fibroblast Cyclooxygenase Synthesis by Interleukin-1[J]. J Biol Chem, 1988, 263 (6): 3022-3028.
[93] Fu J. Y, J. L. Masferrer, K. Seibert, et al. The Induction and Suppression of Prostaglandin H2 Synthase (Cyclooxygenase) in Human Monocytes[J]. J Biol Chem, 1990, 265 (28): 16737-16740.
[94] Xie W. L., J. G. Chipman, D. L. Robertson, et al. Expression of a Mitogen-Responsive Gene Encoding Prostaglandin Synthase Is Regulated by Mrna Splicing[J].Proc Natl Acad Sci U S A, 1991, 88 (7): 2692-2696.
[95] Kujubu D. A., B. S. Fletcher, B. C. Varnum, et al. Tis10, a Phorbol Ester Tumor Promoter-Inducible Mrna from Swiss 3t3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologue[J]. J Biol Chem, 1991, 266 (20): 12866-12872.
[96] Smith W. L., R. M. Garavito, D. L. DeWitt. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2[J]. J Biol Chem, 1996, 271 (52): 33157-33160.
[97] Masferrer J. L., B. S. Zweifel, P. T. Manning, et al. Selective Inhibition of Inducible Cyclooxygenase 2 in Vivo Is Antiinflammatory and Nonulcerogenic[JJ. Proc Natl Acad Sci U S A, 1994, 91 (8): 3228-3232.
[98] Marnett L. J., A. S. Kalgutkar. Cyclooxygenase 2 Inhibitors: Discovery, Selectivity and the Future[J]. Trends Pharmacol Sci, 1999, 20 (11): 465-469.
[99] Laine L., S. Harper, T. Simon, et al. A Randomized Trial Comparing the Effect of Rofecoxib, a Cyclooxygenase 2-Specific Inhibitor, with That of Ibuprofen on the Gastroduodenal Mucosa of Patients with Osteoarthritis.Rofecoxib Osteoarthritis Endoscopy Study Group[J]. Gastroenterology, 1999, 117 (4): 776-783.
[100] Emery P., H. Zeidler, T. K. Kvien, et al. Celecoxib Versus Diclofenac in Long-Term Management of Rheumatoid Arthritis: Randomised Double-Blind Comparison[J]. Lancet, 1999, 354 (9196): 2106-2111.
[101] Kinzler K. W., B. Vogelstein. Landscaping the Cancer Terrain[J]. Science, 1998, 280 (5366): 1036-1037.
[102] Jung Y. J., J. S. Isaacs, S. Lee, et al. Il-1 beta-Mediated up-Regulation of Hif-1alpha Via an Nfkappab/Cox-2 Pathway Identifies Hif-1 as a Critical Link between Inflammation and Oncogenesis[J]. Faseb J,2003,17( 14):2115-2117.
[103] Majima M., M. Isono, Y. Ikeda, et al. Significant Roles of Inducible Cyclooxygenase (Cox)-2 in Angiogenesis in Rat Sponge Implants[J]. Jpn J Pharmacol, 1997, 75 (2): 305-114.
[104] Majima M., I. Hayashi, M. Muramatsu, et al. Cyclo-Oxygenase-2 Enhances Basic Fibroblast Growth Factor-Induced Angiogenesis through Induction of Vascular Endothelial Growth Factor in Rat Sponge Implants[J]. Br J Pharmacol, 2000, 130 (3): 641-649.
[105] Daniel T. O., H. Liu, J. D. Morrow, et al. Thromboxane A2 Is a Mediator of Cyclooxygenase-2-Dependent Endothelial Migration and Angiogenesis[J]. Cancer Res, 1999, 59 (18): 4574-4577.
[106] Masferrer J. L., K. M. Leahy, A. T. Koki, et al. Antiangiogenic and Antitumor Activities of Cyclooxygenase-2 Inhibitors[J]. Cancer Res, 2000, 60 (5): 1306-1311.
[107] Jones M. K., H. Wang, B. M. Peskar, et al. Inhibition of Angiogenesis by Nonsteroidal Anti-Inflammatory Drugs: Insight into Mechanisms and Implications for Cancer Growth and Ulcer Healing[J]. Nat Med, 1999, 5(12): 1418-1423.
[108] Williams C. S., M. Tsujii, J. Reese, et al. Host Cyclooxygenase-2 Modulates Carcinoma Growth[J]. J Clin Invest, 2000, 105 (11): 1589-1594.
[109] Sheng H., J. Shao, S. C. Kirkland, et al. Inhibition of Human Colon Cancer Cell Growth by Selective Inhibition of Cyclooxygenase-2[J]. J Clin Invest, 1997, 99 (9): 2254-2259.
[110] Tsujii M., R. N. DuBois. Alterations in Cellular Adhesion and Apoptosis in Epithelial Cells Overexpressing Prostaglandin Endoperoxide Synthase 2[J]. Cell, 1995, 83 (3): 493-501.
[111] Tsujii M., S. Kawano, R. N. DuBois. Cyclooxygenase-2 Expression in Human Colon Cancer Cells Increases Metastatic Potential[J]. Proc Natl Acad Sci U S A, 1997, 94 (7): 3336-3340.
[112] Tsujii M., S. Kawano, S. Tsuji, et al. Cyclooxygenase Regulates Angiogenesis Induced by Colon Cancer Cells[J]. Cell, 1998, 93 (5): 705-716.
[113] Chinery R., R. J. Coffey, R. Graves-Deal, et al. Prostaglandin J2 and 15-Deoxy-Delta12,14-Prostaglandin J2 Induce Proliferation of Cyclooxygenase-Depleted Colorectal Cancer Cells[J]. Cancer Res, 1999, 59 (11): 2739-2746.
[114] Buckman S. Y., A. Gresham, P. Hale, et al. Cox-2 Expression Is Induced by Uvb Exposure in Human Skin: Implications for the Development of Skin Cancer[J].Carcinogenesis, 1998, 19 (5): 723-729.
[115] Wolff H., K. Saukkonen, S. Anttila, et al. Expression of Cyclooxygenase-2 in Human Lung Carcinoma[J]. Cancer Res, 1998, 58 (22): 4997-5001.
[116] Hwang D., D. Scollard, J. Byrne, et al. Expression of Cyclooxygenase-1 and Cyclooxygenase-2 in Human Breast Cancer[J]. J Natl Cancer Inst, 1998, 90(6): 455-460.
[117] Gupta S., M. Srivastava, N. Ahmad, et al. Over-Expression of Cyclooxygenase-2 in Human Prostate Adenocarcinoma[J]. Prostate, 2000, 42 (1): 73-78.
[118] Mohammed S. I., D. W. Knapp, D. G. Bostwick, et al. Expression of Cyclooxygenase-2 (Cox-2) in Human Invasive Transitional Cell Carcinoma (Tcc) of the Urinary Bladder[J]. Cancer Res, 1999, 59 (22): 5647-5650.
[119] Tucker O. N., A. J. Dannenberg, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Human Pancreatic Cancer[J]. Cancer Res, 1999, 59 (5): 987-990.
[120] Chan G, J. O. Boyle, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Squamous Cell Carcinoma of the Head and Neck[J]. Cancer Res, 1999, 59 (5): 991-994.
[121] Grubbs C. J., R. A. Lubet, A. T. Koki, et al. Celecoxib Inhibits N-Butyl-N-(4-Hydroxybutyl)-Nitrosamine-Induced Urinary Bladder Cancers in Male B6d2f1 Mice and Female Fischer-344 Rats[J]. Cancer Res, 2000, 60 (20): 5599-5602.
[122] Fischer S. M., H. H. Lo, G. B. Gordon, et al. Chemopreventive Activity of Celecoxib, a Specific Cyclooxygenase-2 Inhibitor, and Indomethacin against Ultraviolet Light-Induced Skin Carcinogenesis[J]. Mol Carcinog, 1999, 25 (4): 231-240.
[123] Farrow D. C, T. L. Vaughan, P. D. Hansten, et al. Use of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Cancer[J]. Cancer Epidemiol Biomarkers Prev, 1998, 7 (2): 97-102.
[124] Coogan P. F., L. Rosenberg, J. R. Palmer, et al. Nonsteroidal Anti-Inflammatory Drugs and Risk of Digestive Cancers at Sites Other Than the Large Bowel[J]. Cancer Epidemiol Biomarkers Prev, 2000,9(1): 119-123.
[125] Sharpe C. R., J. P. Collet, M. McNutt, et al. Nested Case-Control Study of the Effects of Non-Steroidal Anti-Inflammatory Drugs on Breast Cancer Risk and Stage[J].Br J Cancer, 2000, 83 (1): 112-120.
[126] Egan K. M., M. J. Stampfer, E. Giovannucci, et al. Prospective Study of Regular Aspirin Use and the Risk of Breast Cancer[J]. J Natl Cancer Inst, 1996, 88 (14): 988-993.
[127] Norrish A. E., R. T. Jackson, C. U. McRae. Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Progression[J]. Int JCancer, 1998,77(4): 511-515.
[128] Castelao J. E., J. M. Yuan, M. Gago-Dominguez, et al. Non-Steroidal Anti-Inflammatory Drugs and Bladder Cancer Prevention[J]. Br J Cancer, 2000, 82 (7): 1364-1369.
[129] Rosenberg L., J. R. Palmer, R. S. Rao, et al. A Case-Control Study of Analgesic Use and Ovarian Cancer[J]. Cancer Epidemiol Biomarkers Prev, 2000, 9 (9): 933-937.
[130] Cramer D. W., B. L. Harlow, L. Titus-Ernstoff, et al. Over-the-Counter Analgesics and Risk of Ovarian Cancer[J]. Lancet, 1998, 351 (9096): 104-107.
[131] Dranoff G. Cytokines in Cancer Pathogenesis and Cancer Therapy[J]. Nat Rev Cancer, 2004, 4(1): 11-22.
[132] Koehne C. H., R. N. Dubois. Cox-2 Inhibition and Colorectal Cancer[J]. Semin Oncol, 2004, 31 (2 Suppl 7): 12-21.
[133] Steinbach G, P. M. Lynch, R. K. Phillips, et al. The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis[J]. N Engl J Med, 2000, 342 (26): 1946-1952.
[134] Solomon S. D., J. J. McMurray, M. A. Pfeffer, et al. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention[J].N Engl J Med, 2005, 352(11): 1071-1080.
[135] Bresalier R. S., R. S. Sandier, H. Quan, et al. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial[J].N Engl J Med, 2005, 352 (11): 1092-1102.
[136] Karin M., Y. Yamamoto, Q. M. Wang. The Ikk Nf-Kappa B System: A Treasure Trove for Drug Development[J]. Nat Rev Drug Discov, 2004, 3(1): 17-26.
[2] Lu S. H. Alterations of Oncogenes and Tumor Suppressor Genes in Esophageal Cancer in China[J]. Mutat Res, 2000, 462 (2-3) : 343-353.
[3] " Roth M. J., W. Guo-Qing, K. J. Lewin, et al. Histopathologic Changes Seen in Esophagectomy Specimens from the High-Risk Region of Linxian, China: Potential Clues to an Etiologic Exposure?[J]. Hum Pathol, 1998, 29 (11) : 1294-1298.
[4] Parkin D. M., P. Pisani, J. Ferlay. Estimates of the Worldwide Incidence of Eighteen Major Cancers in 1985[J]. Int J Cancer, 1993, 54 (4) : 594-606.
[5] Ruggieri M, F. Tosato, K. De Rocco, et al. [Epidemiological Aspects of Esophageal Cancer][J]. Recenti Prog Med, 1981, 70 (5) : 545-556.
[6] Ke L. Mortality and Incidence Trends from Esophagus Cancer in Selected Geographic Areas of China Circa 1970-90[J]. Int J Cancer, 2002, 102(3) : 271-274.
[7] Lu S. H., S. X. Chui, W. X. Yang, et al. Relevance of N-Nitrosamines to Oesophageal Cancer in China[J].IARC Sci Publ, 1991, (105) : 11-17.
[8] Gao Y. T., J. K. McLaughlin, W. J. Blot, et al. Risk Factors for Esophageal Cancer in Shanghai, China. I. Role of Cigarette Smoking and Alcohol Drinking[J]. Int J Cancer, 1994, 58 (2) : 192-196.
[9] Franceschi S., E. Bidoli, E. Negri, et al. Role of Macronutrients, Vitamins and Minerals in the Aetiology of Squamous-Cell Carcinoma of the Oesophagus[J]. IntJ Cancer, 2000, 86 (5) : 626-631.
[10] Yoshizawa T., A. Yamashita, Y. Luo. Fumonisin Occurrence in Corn from High- and Low-Risk Areas for Human Esophageal Cancer in China[J]. Appl Environ Microbiol, 1994, 60 (5) : 1626-1629.
[11] Engel L. S., W. H. Chow, T. L. Vaughan, et al. Population Attributable Risks of Esophageal and Gastric Cancers[J]. J Natl Cancer Inst, 2003, 95 (18) : 1404-1413.
[12] Luo A., J. Kong, G. Hu, et al. Discovery of Ca2+-Relevant and Differentiation-Associated Genes Downregulated in Esophageal Squamous Cell Carcinoma Using Cdna Microarray[J]. Oncogene, 2004, 23 (6) : 1291-1299.
[13] Yang Z. Q., I. Imoto, Y. Fukuda, et al. Identification of a Novel Gene, Gasc1, within an Amplicon at 9p23-24 Frequently Detected in Esophageal Cancer Cell Lines[J]. Cancer Res, 2000, 60 (17) : 4735-4739.
[14] Su T., H. Liu, S. Lu. [Cloning and Identification of Cdna Fragments Related to Human Esophageal Cancer][J]. Zhonghua Zhong Liu Za Zhi, 1998, 20(4) : 254-257.
[15] Bi M. X., W. D. Han, S. X. Lu. Using Lab on-Line to Clone and Identify the Esophageal Cancer Related Gene 4[J]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 2001, 33 (3) : 257-261.
[16] Steck E., S. Breit, S. J. Breusch, et al. Enhanced Expression of the Human Chitinase 3-Like 2 Gene (Ykl-39) but Not Chitinase 3-Like 1 Gene (Ykl-40) in Osteoarthritic Cartilage[J]. Biochem Biophys Res Commun, 2002,299(1): 109-115.
[17] Yue C. M., D. J. Deng, M. X. Bi, et al. Expression of Ecrg4, a Novel Esophageal Cancer-Related Gene, Downregulated by Cpg Island Hypermethylation in Human Esophageal Squamous Cell Carcinoma[J]. World J Gastroenterol, 2003, 9 (6) : 1174-1178.
[18] Blin N., D. W. Stafford. A General Method for Isolation of High Molecular Weight DNA from Eukaryotes[J]. Nucleic Acids Res, 1976, 3(9): 2303-2308.
[19] Li Y., X. Zhang, G. Huang, et al. Identification of a Novel Polymorphism Arg290gln of Esophageal Cancer Related Gene 1 (Ecrg1) and Its Related Risk to Esophageal Squamous Cell Carcinoma[J]. Carcinogenesis, 2006, 27 (4) : 798-802.
[20] Mori Y., H. Ishiguro, Y. Kuwabara, et al. Expression of Ecrg4 Is an Independent Prognostic Factor for Poor Survival in Patients with Esophageal Squamous Cell Carcinoma[J]. Oncol Rep, 2007, 18 (4) : 981-985.
[21] Thiagalingam S., R. L. Foy, K. H. Cheng, et al. Loss of Heterozygosity as a Predictor to Map Tumor Suppressor Genes in Cancer: Molecular Basis of Its Occurrence[J]. CurrOpin Oncol, 2002, 14 (1) : 65-72.
[22] Han Y., F. Wei, X. Xu, et al. [Establishment and Comparative Genomic Hybridization Analysis of Human Esophageal Carcinomas Cell Line Ec9706][J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2002, 19(6): 455-457.
[23] Yen C. C, Y. J. Chen, J. T. Chen, et al. Comparative Genomic Hybridization of Esophageal Squamous Cell Carcinoma: Correlations between Chromosomal Aberrations and Disease Progression/Prognosis[J]. Cancer, 2001, 92 (11) : 2769-2777.
[24] Jones P. A., S. B. Baylin. The Fundamental Role of Epigenetic Events in Cancer[J]. Nat Rev Genet, 2002, 3 (6) : 415-428.
[25] Herman J. G., S. B. Baylin. Gene Silencing in Cancer in Association with Promoter Hypermethylation[J].N Engl J Med, 2003, 349(21) : 2042-2054.
[26] Laird P. W. The Power and the Promise of DNA Methylation Markers[J]. Nat Rev Cancer, 2003, 3 (4) : 253-266.
[27] Egger G., G. Liang, A. Aparicio, et al. Epigenetics in Human Disease and Prospects for Epigenetic Therapy[J]. Nature, 2004, 429 (6990) : 457-463.
[28] Baylin S. B., J. E. Ohm. Epigenetic Gene Silencing in Cancer - a Mechanism for Early Oncogenic Pathway Addiction?[J]. Nat Rev Cancer, 2006, 6 (2) : 107-116.
[29] Feinberg A. P., R. Ohlsson, S. Henikoff. The Epigenetic Progenitor Origin of Human Cancer[J]. Nat Rev Genet, 2006, 7 (1) : 21-33.
[30] Xing E. P., Y. Nie, Y. Song, et al. Mechanisms of Inactivation of P14arf, P15ink4b, and P16ink4a Genes in Human Esophageal Squamous Cell Carcinoma[J]. Clin Cancer Res, 1999, 5 (10) : 2704-2713.
[31] Wong D. J., M. T. Barrett, R. Stoger, et al. P16ink4a Promoter Is Hypermethylated at a High Frequency in Esophageal Adenocarcinomas[J]. Cancer Res, 1997, 57 (13) : 2619-2622.
[32] Si H. X., S. W. Tsao, K. Y. Lam, et al. E-Cadherin Expression Is Commonly Downregulated by Cpg Island Hypermethylation in Esophageal Carcinoma Cells[J]. Cancer Lett, 2001, 173 (1) : 71-78.
[33] Tanaka H., Y. Shimada, H. Harada, et al. Methylation of the 5' Cpg Island of the Fhit Gene Is Closely Associated with Transcriptional Inactivation in Esophageal Squamous Cell Carcinomas[J]. Cancer Res, 1998, 58 (15) : 3429-3434.
[34] Cihak A. Biological Effects of 5-Azacytidine in Eukaryotes[J]. Oncology, 1974, 30 (5) : 405-422.
[35] Jones P. A., S. M. Taylor. Cellular Differentiation, Cytidine Analogs and DNA Methylation[J].Cell, 1980, 20 (1) : 85-93.
[36] Lubbert M. DNA Methylation Inhibitors in the Treatment of Leukemias, Myelodysplastic Syndromes and Hemoglobinopathies: Clinical Results and Possible Mechanisms of Action[J]. Curr Top Microbiol Immunol, 2000, 249: 135-164.
[37] Bird A. DNA Methylation Patterns and Epigenetic Memory[J]. Genes Dev, 2002, 16 (1) : 6-21.
[38] Bird A. P., A. P. Wolffe. Methylation-Induced Repression-Belts, Braces, and Chromatin[J]. Cell, 1999, 99 (5) : 451-454.
[39] Wolf S. F., B. R. Migeon. Studies of X Chromosome DNA Methylation in Normal Human Cells[J]. Nature, 1982, 295 (5851) : 667-671.
[40] Mohandas T., R. S. Sparkes, L. J. Shapiro. Reactivation of an Inactive Human X Chromosome: Evidence for X Inactivation by DNA Methylation[J]. Science, 1981, 211 (4480) : 393-396.
[41] Jaenisch R., A. Schnieke, K. Harbers. Treatment of Mice with 5-Azacytidine Efficiently Activates Silent Retroviral Genomes in Different Tissues[J]. Proc Natl Acad Sci U S A, 1985, 82 (5) : 1451-1455.
[42] Liang G., F. A. Gonzales, P. A. Jones, et al. Analysis of Gene Induction in Human Fibroblasts and Bladder Cancer Cells Exposed to the Methylation Inhibitor 5-Aza-2'-Deoxycytidine[J]. Cancer Res, 2002, 62 (4) : 961-966.
[43] Soengas M. S., P. Capodieci, D. Polsky, et al. Inactivation of the Apoptosis Effector Apaf-1 in Malignant Melanoma[J]. Nature, 2001, 409 (6817) : 207-211.
[44] Cameron E. E., K. E. Bachman, S. Myohanen, et al. Synergy of Demethylation and Histone Deacetylase Inhibition in the Re-Expression of Genes Silenced in Cancer[J]. Nat Genet, 1999, 21 (1) : 103-107.
[45] Suzuki H., E. Gabrielson, W. Chen, et al. A Genomic Screen for Genes Upregulated by Demethylation and Histone Deacetylase Inhibition in Human Colorectal Cancer[J]. Nat Genet, 2002, 31 (2) : 141-149.
[46] Bender C. M., M. L. Gonzalgo, F. A. Gonzales, et al. Roles of Cell Division and Gene Transcription in the Methylation of Cpg Islands[J]. Mol Cell Biol, 1999, 19 (10) : 6690-6698.
[47] Bardy S. L., S. Y. Ng, K. F. Jarrell. Recent Advances in the Structure and Assembly of the Archaeal Flagellum[J]. J Mol Microbiol Biotechnol, 2004, 7 (1-2) : 41-51.
[48] Carrio M. M., A. Villaverde. Construction and Deconstruction of Bacterial Inclusion Bodies[J].J Biotechnol, 2002, 96 (1) : 3-12.
[49] Fahnert B., H. Lilie, P. Neubauer. Inclusion Bodies: Formation and Utilisation[J]. Adv Biochem Eng Biotechnol, 2004, 89: 93-142.
[50] Vincentelli R., S. Canaan, V. Campanacci, et al. High-Throughput Automated Refolding Screening of Inclusion Bodies[J]. Protein Sci, 2004, 13 (10) : 2782-2792.
[51] Magistrelli G., F. Gueneau, M. Muslmani, et al. Chemokines Derived from Soluble Fusion Proteins Expressed in Escherichia Coli Are Biologically Active[J]. Biochem Biophys Res Commun, 2005, 334 (2) : 370-375.
[52] Roosbeek S., H. Caster, Q. Z. Liu, et al. Expression and Activity of the Nucleotide-Binding Domains of the Human Abcal Transporter[J]. Protein ExprPurif, 2004, 35 (1) : 102-110.
[53] Karmodiya K., R. K. Srivastav, N. Surolia. Production and Purification of Refolded Recombinant Plasmodium Falciparum Beta-Ketoacyl-Acp Reductase from Inclusion Bodies[J]. Protein Expr Purif, 2005, 42 (1) : 131-136.
[54] Hashimoto Y., T. Ikenaga, K. Tanigawa, et al. Expression and Characterization of Human Rheumatoid Factor Single-Chain Fv[J]. Biol Pharm Bull, 2000, 23 (8) : 941-945.
[55] Balkwill F., A. Mantovani. Inflammation and Cancer: Back to Virchow?[J]. Lancet, 2001, 357 (9255) : 539-545.
[56] Bharti A. C, B. B. Aggarwal. Chemopreventive Agents Induce Suppression of Nuclear Factor-Kappab Leading to Chemosensitization[J]. Ann N Y Acad Sci, 2002, 973: 392-395.
[57] Karin M., Y. Cao, F. R. Greten, et al. Nf-Kappab in Cancer: From Innocent Bystander to Major Culprit[J]. Nat Rev Cancer, 2002, 2 (4) : 301-310.
[58] Greten F. R., L. Eckmann, T. F. Greten, et al. Ikkbeta Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer[J]. Cell, 2004, 118 (3) : 285-296.
[59] Pikarsky E., R. M. Porat, I. Stein, et al. Nf-Kappab Functions as a Tumour Promoter in Inflammation-Associated Cancer[J]. Nature, 2004, 431 (7007) : 461-466.
[60] Luo J. L., S. Maeda, L. C. Hsu, et al. Inhibition of Nf-Kappab in Cancer Cells Converts Inflammation- Induced Tumor Growth Mediated by Tnfalpha to Trail-Mediated Tumor Regression[J]. Cancer Cell, 2004, 6 (3) : 297-305.
[61] Shattuck-Brandt R. L., A. Richmond. Enhanced Degradation of I-Kappab Alpha Contributes to Endogenous Activation of Nf-Kappab in Hs294t Melanoma Cells[J]. Cancer Res, 1997, 57 (14) : 3032-3039.
[62] Amiri K. I., A. Richmond. Role of Nuclear Factor-Kappa B in Melanoma[J]. Cancer Metastasis Rev, 2005, 24 (2) : 301-313.
[63] Sovak M. A., R. E. Bellas, D. W. Kim, et al. Aberrant Nuclear Factor-Kappab/Rel Expression and the Pathogenesis of Breast Cancer[J]. J Clin Invest, 1997, 100 (12) : 2952-2960.
[64] Kalaitzidis D., T. D. Gilmore. Transcription Factor Cross-Talk: The Estrogen Receptor and Nf-Kappab[J]. Trends Endocrinol Metab, 2005, 16(2) : 46-52.
[65] Huang S., C. A. Pettaway, H. Uehara, et al. Blockade of Nf-Kappab Activity in Human Prostate Cancer Cells Is Associated with Suppression of Angiogenesis, Invasion, and Metastasis[J]. Oncogene, 2001, 20 (31) : 4188-4197.
[66] Sweeney C, L. Li, R. Shanmugam, et al. Nuclear Factor-Kappab Is Constitutively Activated in Prostate Cancer in Vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate[J]. Clin Cancer Res, 2004, 10 (16) : 5501-5507.
[67] Huang S., J. B. Robinson, A. Deguzman, et al. Blockade of Nuclear Factor-Kappab Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 8[J]. Cancer Res, 2000, 60(19) : 5334-5339.
[68] Mabuchi S., M. Ohmichi, Y. Nishio, et al. Inhibition of Nfkappab Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models[J]. J Biol Chem, 2004, 279 (22) : 23477-23485.
[69] Wang W., J. L. Abbruzzese, D. B. Evans, et al. The Nuclear Factor-Kappa B Rela Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells[J]. Clin Cancer Res, 1999, 5 (1) : 119-127.
[70] Sclabas G. M., T. Uwagawa, C. Schmidt, et al. Nuclear Factor Kappa B Activation Is a Potential Target for Preventing Pancreatic Carcinoma by Aspirin[J]. Cancer, 2005, 103 (12) : 2485-2490.
[71] Kojima M., T. Morisaki, N. Sasaki, et al. Increased Nuclear Factor-Kb Activation in Human Colorectal Carcinoma and Its Correlation with Tumor Progression[J]. Anticancer Res, 2004, 24 (2B) : 675-681.
[72] Dejardin E., V. Deregowski, M. Chapelier, et al. Regulation of Nf-Kappab Activity by I Kappab-Related Proteins in Adenocarcinoma Cells[J]. Oncogene, 1999, 18 (16) : 2567-2577.
[73] Visconti R., J. Cerutti, S. Battista, et al. Expression of the Neoplastic Phenotype by Human Thyroid Carcinoma Cell Lines Requires Nfkappab P65 Protein Expression[J]. Oncogene, 1997, 15 (16) : 1987-1994.
[74] Pacifico F., C. Mauro, C. Barone, et al. Oncogenic and Anti-Apoptotic Activity of Nf-Kappa B in Human Thyroid Carcinomas[J]. J Biol Chem, 2004, 279 (52) : 54610-54619.
[75] Smith W. L., D. L. DeWitt, R. M. Garavito. Cyclooxygenases: Structural, Cellular, and Molecular Biology[J]. Annu Rev Biochem, 2000, 69: 145-182.
[76] Smith W. L., R. M. Garavito, D. L. DeWitt. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2[J]. J Biol Chem, 1996, 271 (52) : 33157-33160.
[77] Buckman S. Y., A. Gresham, P. Hale, et al. Cox-2 Expression Is Induced by Uvb Exposure in Human Skin: Implications for the Development of Skin Cancer[J]. Carcinogenesis, 1998, 19 (5) : 723-729.
[78] Wolff H., K. Saukkonen, S. Anttila, et al. Expression of Cyclooxygenase-2 in Human Lung Carcinoma[J]. Cancer Res, 1998, 58 (22) : 4997-5001.
[79] Hwang D., D. Scollard, J. Byrne, et al. Expression of Cyclooxygenase-1 and Cyclooxygenase-2 in Human Breast Cancer[J]. J Natl Cancer Inst, 1998, 90 (6) : 455-460.
[80] Gupta S., M. Srivastava, N. Ahmad, et al. Over-Expression of Cyclooxygenase-2 in Human Prostate Adenocarcinoma[J]. Prostate, 2000, 42 (1) : 73-78.
[81] Mohammed S. I., D. W. Knapp, D. G. Bostwick, et al. Expression of Cyclooxygenase-2 (Cox-2) in Human Invasive Transitional Cell Carcinoma (Tcc) of the Urinary Bladder[J]. Cancer Res, 1999, 59(22) : 5647-5650.
[82] Tucker O. N., A. J. Dannenberg, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Human Pancreatic Cancer[J]. Cancer Res, 1999, 59 (5) : 987-990.
[83] Chan G., J. O. Boyle, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Squamous Cell Carcinoma of the Head and Neck[J]. Cancer Res, 1999, 59 (5) : 991-994.
[84] Zimmermann K. C, M. Sarbia, A. A. Weber, et al. Cyclooxygenase-2 Expression in Human Esophageal Carcinoma[J]. Cancer Res, 1999, 59 (1) : 198-204.
[85] Zhi H., L. Wang, J. Zhang, et al. Significance of Cox-2 Expression in Human Esophageal Squamous Cell Carcinoma[J]. Carcinogenesis, 2006, 27 (6) : 1214-1221.
[86] Ghosh S., M. Karin. Missing Pieces in the Nf-Kappab Puzzle[J]. Cell, 2002, 109 Suppl: S81-96.
[87] Gilmore T. D. The Rel/Nf-Kappab Signal Transduction Pathway: Introduction[J]. Oncogene, 1999, 18 (49) : 6842-6844.
[88] Bonizzi G., M. Karin. The Two Nf-Kappab Activation Pathways and Their Role in Innate and Adaptive Immunity[J]. Trends Immunol, 2004, 25 (6) : 280-288.
[89] Rothwarf D. M., M. Karin. The Nf-Kappa B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus[J]. Sci STKE, 1999, 1999 (5) : RE1.
[90] Karin M., Y. Ben-Neriah. Phosphorylation Meets Ubiquitination: The Control of Nf-[Kappa]B Activity[J]. Annu Rev Immunol, 2000, 18: 621-663.
[91] Hayden M. S., S. Ghosh. Signaling to Nf-Kappab[J]. Genes Dev, 2004, 18 (18) : 2195-2224.
[92] Werner S. L., D. Barken, A. Hoffmann. Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of Ikk Activity[J]. Science, 2005, 309 (5742) : 1857-1861.
[93] Park J. M., F. R. Greten, A. Wong, et al. Signaling Pathways and Genes That Inhibit Pathogen-Induced Macrophage Apoptosis-Creb and Nf-Kappab as Key Regulators[J]. Immunity, 2005, 23 (3) : 319-329.
[94] Covert M. W., T. H. Leung, J. E. Gaston, et al. Achieving Stability of Lipopolysaccharide-Induced Nf-Kappab Activation[J]. Science, 2005, 309 (5742) : 1854-1857.
[95] Campbell K. J., S. Rocha, N. D. Perkins. Active Repression of Antiapoptotic Gene Expression by Rela(P65) Nf-Kappa B[J]. Mol Cell, 2004, 13 (6) : 853-865.
[96] Chun K. S., Y. J. Surh. Signal Transduction Pathways Regulating Cyclooxygenase-2 Expression: Potential Molecular Targets for Chemoprevention[J]. Biochem Pharmacol, 2004, 68 (6) : 1089-1100.
[97] Jung Y. J., J. S. Isaacs, S. Lee, et al. Il-1 beta-Mediated up-Regulation of Hif-1 alpha Via an Nfkappab/Cox-2 Pathway Identifies Hif-1 as a Critical Link between Inflammation and Oncogenesis[J]. Faseb J, 2003, 17 (14) : 2115-2117.
[98] Konturek P. C, A. Nikiforuk, J. Kania, et al. Activation of Nfkappab Represents the Central Event in the Neoplastic Progression Associated with Barrett's Esophagus: A Possible Link to the Inflammation and Overexpression of Cox-2, Ppargamma and Growth Factors[J]. Dig DisSci, 2004, 49(7-8) : 1075-1083.
[99] Benoit V., E. de Moraes, N. A. Dar, et al. Transcriptional Activation of Cyclooxygenase-2 by Tumor Suppressor P53 Requires Nuclear Factor-Kappab[J]. Oncogene, 2006, 25 (42) : 5708-5718.
[100] Poligone B., A. S. Baldwin. Positive and Negative Regulation of Nf-Kappab by Cox-2: Roles of Different Prostaglandins[J]. J Biol Chem, 2001, 276(42): 38658-38664.
[101] Garkavtsev I., S. V. Kozin, O. Chernova, et al. The Candidate Tumour Suppressor Protein Ing4 Regulates Brain Tumour Growth and Angiogenesis[J]. Nature, 2004, 428 (6980) : 328-332.
[102] Wang W. H., J. Q. Huang, G. F. Zheng, et al. Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Gastric Cancer: A Systematic Review and Meta-Analysis[J]. J Natl Cancer Inst, 2003, 95 (23): 1784-1791.
[103] Chang E. T., T. Zheng, E. G. Weir, et al. Aspirin and the Risk of Hodgkin's Lymphoma in a Population-Based Case-Control Study[J].J Natl Cancer Inst,2004,96(4):305-315.
[1]Kuper H.,H.O.Adami,D.Trichopoulos.Infections as a Major Preventable Cause of Human Cancer[J].J Intern Med,2000,248(3):171-183.
[2]Balkwill F.,A.Mantovani.Inflammation and Cancer:Back to Virchow?[J].Lancet,2001,357(9255):539-545.
[3]Coussens L.M.,Z.Werb.Inflammation and Cancer[J].Nature,2002,420 (6917): 860-867.
[4] Roder D. M. The Epidemiology of Gastric Cancer[J]. Gastric Cancer, 2002, 5 Suppl 1: 5-11.
[5] Keates S., Y. S. Hitti, M. Upton, et al. Helicobacter Pylori Infection Activates Nf-Kappa B in Gastric Epithelial Cells[J]. Gastroenterology, 1997, 113 (4): 1099-1109.
[6] Wang W. H., J. Q. Huang, G. F. Zheng, et al. Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Gastric Cancer: A Systematic Review and Meta-Analysis[J]. J Natl Cancer Inst, 2003, 95 (23): 1784-1791.
[7] Chang E. T., T. Zheng, E. G. Weir, et al. Aspirin and the Risk of Hodgkin's Lymphoma in a Population-Based Case-Control Study [J]. J Natl Cancer Inst, 2004, 96 (4): 305-315.
[8] Bharti A. C, B. B. Aggarwal. Chemopreventive Agents Induce Suppression of Nuclear Factor-Kappab Leading to Chemosensitization[J]. Ann N Y Acad Sci, 2002, 973: 392-395.
[9] Cerhan J. R., K. E. Anderson, C. A. Janney, et al. Association of Aspirin and Other Non-Steroidal Anti-Inflammatory Drug Use with Incidence of Non-Hodgkin Lymphoma[J]. Int J Cancer, 2003, 106 (5): 784-788.
[10] Schernhammer E. S., J. H. Kang, A. T. Chan, et al. A Prospective Study of Aspirin Use and the Risk of Pancreatic Cancer in Women[J]. J Natl Cancer Inst, 2004, 96 (1): 22-28.
[11] Karin M., Y. Cao, F. R. Greten, et al. Nf-Kappab in Cancer: From Innocent Bystander to Major Culprit[J]. Nat Rev Cancer, 2002, 2 (4): 301-310.
[12] Greten F. R., L. Eckmann, T. F. Greten, et al. Ikkbeta Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer[J]. Cell, 2004, 118 (3): 285-296.
[13] Pikarsky E., R. M. Porat, I. Stein, et al. Nf-Kappab Functions as a Tumour Promoter in Inflammation-Associated Cancer[J]. Nature, 2004, 431 (7007): 461-466.
[14] Ghosh S., M. Karin. Missing Pieces in the Nf-Kappab Puzzle[J]. Cell, 2002, 109 Suppl: S81-96.
[15] Gilmore T. D. The Rel/Nf-Kappab Signal Transduction Pathway: Introduction[J].Oncogene, 1999, 18 (49): 6842-6844.
[16] Gilmore T. D. Multiple Mutations Contribute to the Oncogenicity of the Retroviral Oncoprotein V-Rel[J].Oncogene, 1999, 18 (49): 6925-6937.
[17] Rayet B., C. Gelinas. Aberrant Rel/Nfkb Genes and Activity in Human Cancer[J].Oncogene, 1999, 18 (49): 6938-6947.
[18] Bonizzi G, M. Karin. The Two Nf-Kappab Activation Pathways and Their Role in Innate and Adaptive Immunity[J]. Trends Immunol, 2004, 25 (6): 280-288.
[19] Rothwarf D. M., M. Karin. The Nf-Kappa B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus[J]. Sci STKE, 1999, 1999 (5): RE1.
[20] Karin M., Y. Ben-Neriah. Phosphorylation Meets Ubiquitination: The Control of Nf-[Kappa]B Activity[J]. Annu Rev Immunol, 2000, 18: 621-663.
[21] Hayden M. S., S. Ghosh. Signaling to Nf-Kappab[J]. Genes Dev, 2004, 18 (18): 2195-2224.
[22] Werner S. L., D. Barken, A. Hoffmann. Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of Ikk Activity[J]. Science, 2005, 309 (5742): 1857-1861.
[23] Park J. M., F. R. Greten, A. Wong, et al. Signaling Pathways and Genes That Inhibit Pathogen-Induced Macrophage Apoptosis-Creb and Nf-Kappab as Key Regulators[J]. Immunity, 2005, 23 (3): 319-329.
[24] Covert M. W, T. H. Leung, J. E. Gaston, et al. Achieving Stability of Lipopolysaccharide-Induced Nf-Kappab Activation[J]. Science, 2005, 309 (5742): 1854-1857.
[25] Senftleben U., Y. Cao, G. Xiao, et al. Activation by Ikkalpha of a Second, Evolutionary Conserved, Nf-Kappa B Signaling Pathway [J]. Science, 2001, 293 (5534): 1495-1499.
[26] Lawrence T., M. Bebien, G. Y. Liu, et al. Ikkalpha Limits Macrophage Nf-Kappab Activation and Contributes to the Resolution of Inflammation[J]. Nature, 2005, 434 (7037): 1138-1143.
[27] Neri A., C. C. Chang, L. Lombardi, et al. B Cell Lymphoma-Associated Chromosomal Translocation Involves Candidate Oncogene Lyt-10, Homologous to Nf-Kappa B P50[J]. Cell, 1991, 67 (6): 1075-1087.
[28] Demicco E. G, K. T. Kavanagh, R. Romieu-Mourez, et al. Relb/P52 Nf-Kappab Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor Ikappab-Alpha Expression and Promote Carcinogenesis of the Mammary Gland[J]. Mol Cell Biol, 2005, 25 (22): 10136-10147.
[29] Gilmore T. D. The Rel/Nf-Kappa B/I Kappa B Signal Transduction Pathway and Cancer[J]. Cancer Treat Res, 2003, 115: 241-265.
[30] Kato T., Jr., M. Delhase, A. Hoffmann, et al. Ck2 Is a C-Terminal Ikappab Kinase Responsible for Nf-Kappab Activation During the Uv Response[J]. Mol Cell, 2003, 12 (4): 829-839.
[31] Maeda S., H. Kamata, J. L. Luo, et al. Ikkbeta Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation That Promotes Chemical Hepatocarcinogenesis[J].Cell, 2005, 121 (7): 977-990.
[32] Burnet F. M. The Concept of Immunological Surveillance[J]. Prog Exp Tumor Res, 1970, 13: 1-27.
[33] Dunn G. P., L. J. Old, R. D. Schreiber. The Immunobiology of Cancer Immunosurveillance and Immunoediting[J]. Immunity, 2004, 21(2): 137-148.
[34] Pardoll D. Does the Immune System See Tumors as Foreign or Self?[J]. Annu Rev Immunol, 2003, 21: 807-839.
[35] Philip M., D. A. Rowley, H. Schreiber. Inflammation as a Tumor Promoter in Cancer Induction[J]. Semin Cancer Biol, 2004, 14(6): 433-439.
[36] Luo J. L., S. Maeda, L. C. Hsu, et al. Inhibition of Nf-Kappab in Cancer Cells Converts Inflammation- Induced Tumor Growth Mediated by Tnfalpha to Trail-Mediated Tumor Regression[J]. Cancer Cell, 2004, 6 (3): 297-305.
[37] de Visser K. E., L. V. Korets, L. M. Coussens. De Novo Carcinogenesis Promoted by Chronic Inflammation Is B Lymphocyte Dependent[J]. Cancer Cell, 2005, 7 (5): 411-423.
[38] Chisari F. V. Hepatitis B Virus Transgenic Mice: Insights into the Virus and the Disease[J].Hepatology, 1995, 22 (4 Pt 1): 1316-1325.
[39] Shattuck-Brandt R. L., A. Richmond. Enhanced Degradation of I-Kappab Alpha Contributes to Endogenous Activation of Nf-Kappab in Hs294t Melanoma Cells[J]. Cancer Res, 1997, 57 (14): 3032-3039.
[40] Amiri K. I., A. Richmond. Role of Nuclear Factor-Kappa B in Melanoma[J]. Cancer Metastasis Rev, 2005, 24 (2): 301-313.
[41] Sovak M. A., R. E. Bellas, D. W. Kim, et al. Aberrant Nuclear Factor-Kappab/Rel Expression and the Pathogenesis of Breast Cancer[J]. J Clin Invest, 1997, 100 (12): 2952-2960.
[42] Kalaitzidis D., T. D. Gilmore. Transcription Factor Cross-Talk: The Estrogen Receptor and Nf-Kappab[J]. Trends Endocrinol Metab, 2005, 16(2): 46-52.
[43] Huang S., C. A. Pettaway, H. Uehara, et al. Blockade of Nf-Kappab Activity in Human Prostate Cancer Cells Is Associated with Suppression of Angiogenesis, Invasion, and Metastasis[J]. Oncogene, 2001, 20 (31): 4188-4197.
[44] Sweeney C, L. Li, R. Shanmugam, et al. Nuclear Factor-Kappab Is Constitutively Activated in Prostate Cancer in Vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate[J]. Clin Cancer Res, 2004, 10 (16): 5501-5507.
[45] Huang S., J. B. Robinson, A. Deguzman, et al. Blockade of Nuclear Factor-Kappab Signaling Inhibits Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular Endothelial Growth Factor and Interleukin 8[J]. Cancer Res, 2000, 60(19): 5334-5339.
[46] Mabuchi S., M. Ohmichi, Y. Nishio, et al. Inhibition of Nfkappab Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models[J]. J Biol Chem, 2004, 279 (22): 23477-23485.
[47] Wang W., J. L. Abbruzzese, D. B. Evans, et al. The Nuclear Factor-Kappa B Rela Transcription Factor Is Constitutively Activated in Human Pancreatic AdenocarcinomaCells[J]. Ciin Cancer Res, 1999, 5(1): 119-127.
[48] Sclabas G. M., T. Uwagawa, C. Schmidt, et al. Nuclear Factor Kappa B Activation Is a Potential Target for Preventing Pancreatic Carcinoma by Aspirin[J]. Cancer, 2005, 103 (12): 2485-2490.
[49] Kojima M., T. Morisaki, N. Sasaki, et al. Increased Nuclear Factor-Kb Activation in Human Colorectal Carcinoma and Its Correlation with Tumor Progression[J].Anticancer Res, 2004, 24 (2B): 675-681.
[50] Dejardin E., V. Deregowski, M. Chapelier, et al. Regulation of Nf-Kappab Activity by I Kappab-Related Proteins in Adenocarcinoma Cells[J]. Oncogene, 1999, 18 (16): 2567-2577.
[51] Visconti R., J. Cerutti, S. Battista, et al. Expression of the Neoplastic Phenotype by Human Thyroid Carcinoma Cell Lines Requires Nfkappab P65 Protein Expression[J]. Oncogene, 1997, 15 (16): 1987-1994.
[52] Pacifico F., C. Mauro, C. Barone, et al. Oncogenic and Anti-Apoptotic Activity of Nf-Kappa B in Human Thyroid Carcinomas[J]. J Biol Chem, 2004, 279 (52): 54610-54619.
[53] Hanahan D., R. A. Weinberg. The Hallmarks of Cancer[J]. Cell, 2000, 100 (1): 57-70.
[54] Aggarwal B. B. Nuclear Factor-Kappab: The Enemy Within[J]. Cancer Cell, 2004, 6 (3): 203-208.
[55] Karin M. Nuclear Factor-Kappab in Cancer Development and Progression[J]. Nature, 2006, 441 (7092): 431-436.
[56] Guttridge D. C, C. Albanese, J. Y. Reuther, et al. Nf-Kappab Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1[J].Mol Cell Biol, 1999, 19(8): 5785-5799.
[57] Perkins N. D., L. K. Felzien, J. C. Betts, et al. Regulation of Nf-Kappab by Cyclin-Dependent Kinases Associated with the P300 Coactivator[J]. Science, 1997, 275 (5299): 523-527.
[58] Kim D. W., L. Gazourian, S. A. Quadri, et al. The Rela Nf-Kappab Subunit and the Aryl Hydrocarbon Receptor (Ahr) Cooperate to Transactivate the C-Myc Promoter in Mammary Cells[J]. Oncogene, 2000, 19(48): 5498-5506.
[59] Pahl H. L. Activators and Target Genes of Rel/Nf-Kappab Transcription Factors[J]. Oncogene, 1999, 18 (49): 6853-6866.
[60] Biswas D. K., A. P. Cruz, E. Gansberger, et al. Epidermal Growth Factor-Induced Nuclear Factor Kappa B Activation: A Major Pathway of Cell-Cycle Progression in Estrogen-Receptor Negative Breast Cancer Cells[J]. Proc Natl Acad Sci U S A, 2000, 97 (15): 8542-8547.
[61] Farina A. R., A. Tacconelli, A. Vacca, et al. Transcriptional up-Regulation of Matrix Metalloproteinase-9 Expression During Spontaneous Epithelial to Neuroblast Phenotype Conversion by Sk-N-Sh Neuroblastoma Cells, Involved in Enhanced Invasivity, Depends Upon Gt-Box and Nuclear Factor Kappab Elements[J]. Cell Growth Differ, 1999, 10 (5): 353-367.
[62] Yasumoto K., S. Okamoto, N. Mukaida, et al. Tumor Necrosis Factor Alpha and Interferon Gamma Synergistically Induce Interleukin 8 Production in a Human Gastric Cancer Cell Line through Acting Concurrently on Ap-1 and Nf-Kb-Like Binding Sites of the Interleukin 8 Gene[J]. J Biol Chem, 1992, 267 (31): 22506-22511.
[63] Kunsch C, C. A. Rosen. Nf-Kappa B Subunit-Specific Regulation of the Interleukin-8 Promoter[J]. Mol Cell Biol, 1993, 13 (10): 6137-6146.
[64] van de Stolpe A., E. Caldenhoven, B. G Stade, et al. 12-O-Tetradecanoylphorbol-13-Acetate- and Tumor Necrosis Factor Alpha-Mediated Induction of Intercellular Adhesion Molecule-1 Is Inhibited by Dexamethasone. Functional Analysis of the Human Intercellular Adhesion Molecular-1 Promoter[J].J Biol Chem, 1994, 269(8): 6185-6192.
[65] Helbig G., K. W. Christopherson, 2nd, P. Bhat-Nakshatri, et al. Nf-Kappab Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor Cxcr4[J]. J Biol Chem, 2003, 278 (24): 21631-21638.
[66] Kiriakidis S., E. Andreakos, C. Monaco, et al. Vegf Expression in Human Macrophages Is Nf-Kappab-Dependent: Studies Using Adenoviruses Expressing the Endogenous Nf-Kappab Inhibitor Ikappabalpha and a Kinase-Defective Form of the Ikappab Kinase 2[J]. J Cell Sci, 2003, 116 (Pt 4): 665-674.
[67] Karin M., A. Lin. Nf-Kappab at the Crossroads of Life and Death[J]. Nat Immunol, 2002, 3 (3): 221-227.
[68] Wang C. Y., M. W. Mayo, R. G. Korneluk, et al. Nf-Kappab Antiapoptosis: Induction of Traf1 and Traf2 and C-Iap1 and C-Iap2 to Suppress Caspase-8 Activation[J]. Science, 1998, 281 (5383): 1680-1683.
[69] Deveraux Q. L., N. Roy, H. R. Stennicke, et al. Iaps Block Apoptotic Events Induced by Caspase-8 and Cytochrome C by Direct Inhibition of Distinct Caspases[J].Embo J, 1998, 17 (8): 2215-2223.
[70] Boise L. H., M. Gonzalez-Garcia, C. E. Postema, et al. Bcl-X, a Bcl-2-Related Gene That Functions as a Dominant Regulator of Apoptotic Cell Death[J]. Cell, 1993, 74 (4): 597-608.
[71] Yeh W. C, A. Itie, A. J. Elia, et al. Requirement for Casper (C-Flip) in Regulation of Death Receptor-Induced Apoptosis and Embryonic Development[J]. Immunity, 2000, 12 (6): 633-642.
[72] De Smaele E., F. Zazzeroni, S. Papa, et al. Induction of Gadd45beta by Nf-Kappab Downregulates Pro-Apoptotic Jnk Signalling[J]. Nature, 2001,414 (6861): 308-313.
[73] Pham C. G, C. Bubici, F. Zazzeroni, et al. Ferritin Heavy Chain Upregulation by Nf-Kappab Inhibits Tnfalpha-Induced Apoptosis by Suppressing Reactive Oxygen Species[J]. Cell, 2004, 119 (4): 529-542.
[74] Kluiver J., A. van den Berg, D. de Jong, et al. Regulation of Pri-Microrna Bic Transcription and Processing in Burkitt Lymphoma[J]. Oncogene, 2007, 26 (26): 3769-3776.
[75] Fernandez-Majada V., C. Aguilera, A. Villanueva, et al. Nuclear Ikk Activity Leads to Dysregulated Notch-Dependent Gene Expression in Colorectal Cancer[J]. Proc Natl Acad Sci U S A, 2007, 104 (1): 276-281.
[76] Prajapati S., Z. Tu, Y. Yamamoto, et al. Ikkalpha Regulates the Mitotic Phase of the Cell Cycle by Modulating Aurora a Phosphorylation[J]. Cell Cycle, 2006, 5 (20): 2371-2380.
[77] Hu M. C, D. F. Lee, W. Xia, et al. Ikappab Kinase Promotes Tumorigenesis through Inhibition of Forkhead Foxo3a[J]. Cell, 2004, 117 (2): 225-237.
[78] Lee D. F., H. P. Kuo, C. T. Chen, et al. Ikk Beta Suppression of Tsc1 Links Inflammation and Tumor Angiogenesis Via the Mtor Pathway[J]. Cell, 2007, 130 (3): 440-455.
[79] Li Q., I. M. Verma. Nf-Kappab Regulation in the Immune System[J]. Nat Rev Immunol, 2002, 2 (10): 725-734.
[80] Lind M. H., B. Rozell, R. P. Wallin, et al. Tumor Necrosis Factor Receptor 1-Mediated Signaling Is Required for Skin Cancer Development Induced by Nf-Kappab Inhibition[J]. Proc Natl Acad Sci U S A, 2004, 101 (14): 4972-4977.
[81] Holla V R., D. Wang, J. R. Brown, et al. Prostaglandin E2 Regulates the Complement Inhibitor Cd55/Decay-Accelerating Factor in Colorectal Cancer[J]. J Biol Chem, 2005, 280 (1): 476-483.
[82] Sparmann A., D. Bar-Sagi. Ras-Induced Interleukin-8 Expression Plays a Critical Role in Tumor Growth and Angiogenesis[J]. Cancer Cell, 2004,6(5): 447-458.
[83] Garkavtsev I., S. V. Kozin, O. Chernova, et al. The Candidate Tumour Suppressor Protein Ing4 Regulates Brain Tumour Growth and Angiogenesis[J]. Nature, 2004, 428 (6980): 328-332.
[84] Joyce D., C. Albanese, J. Steer, et al. Nf-Kappab and Cell-Cycle Regulation: The Cyclin Connection[J]. Cytokine Growth Factor Rev, 2001, 12 (1): 73-90.
[85] Cao Y., G. Bonizzi, T. N. Seagroves, et al. Ikkalpha Provides an Essential Link between Rank Signaling and Cyclin D1 Expression During Mammary Gland Development[J].Cell, 2001, 107 (6): 763-775.
[86] Dajee M., M. Lazarov, J. Y. Zhang, et al. Nf-Kappab Blockade and Oncogenic Ras Trigger Invasive Human Epidermal Neoplasia[J]. Nature, 2003, 421 (6923): 639-643.
[87] Zhang J. Y., C. L. Green, S. Tao, et al. Nf-Kappab Rela Opposes Epidermal Proliferation Driven by Tnfr1 and Jnk[J]. Genes Dev, 2004, 18(1): 17-22.
[88] Herschman H. R. Prostaglandin Synthase 2[J]. Biochim Biophys Acta, 1996, 1299 (1): 125-140.
[89] Dubois R. N., S. B. Abramson, L. Crofford, et al. Cyclooxygenase in Biology and Disease[J].Faseb J, 1998, 12 (12): 1063-1073.
[90] Herschman H. R., W. Xie, S. Reddy. Inflammation, Reproduction, Cancer and All That.... The Regulation and Role of the Inducible Prostaglandin Synthase[J].Bioessays, 1995, 17(12): 1031-1037.
[91] Smith W. L., D. L. DeWitt, R. M. Garavito. Cyclooxygenases: Structural, Cellular, and Molecular Biology[J]. Annu Rev Biochem, 2000, 69: 145-182.
[92] Raz A., A. Wyche, N. Siegel, et al. Regulation of Fibroblast Cyclooxygenase Synthesis by Interleukin-1[J]. J Biol Chem, 1988, 263 (6): 3022-3028.
[93] Fu J. Y, J. L. Masferrer, K. Seibert, et al. The Induction and Suppression of Prostaglandin H2 Synthase (Cyclooxygenase) in Human Monocytes[J]. J Biol Chem, 1990, 265 (28): 16737-16740.
[94] Xie W. L., J. G. Chipman, D. L. Robertson, et al. Expression of a Mitogen-Responsive Gene Encoding Prostaglandin Synthase Is Regulated by Mrna Splicing[J].Proc Natl Acad Sci U S A, 1991, 88 (7): 2692-2696.
[95] Kujubu D. A., B. S. Fletcher, B. C. Varnum, et al. Tis10, a Phorbol Ester Tumor Promoter-Inducible Mrna from Swiss 3t3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologue[J]. J Biol Chem, 1991, 266 (20): 12866-12872.
[96] Smith W. L., R. M. Garavito, D. L. DeWitt. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2[J]. J Biol Chem, 1996, 271 (52): 33157-33160.
[97] Masferrer J. L., B. S. Zweifel, P. T. Manning, et al. Selective Inhibition of Inducible Cyclooxygenase 2 in Vivo Is Antiinflammatory and Nonulcerogenic[JJ. Proc Natl Acad Sci U S A, 1994, 91 (8): 3228-3232.
[98] Marnett L. J., A. S. Kalgutkar. Cyclooxygenase 2 Inhibitors: Discovery, Selectivity and the Future[J]. Trends Pharmacol Sci, 1999, 20 (11): 465-469.
[99] Laine L., S. Harper, T. Simon, et al. A Randomized Trial Comparing the Effect of Rofecoxib, a Cyclooxygenase 2-Specific Inhibitor, with That of Ibuprofen on the Gastroduodenal Mucosa of Patients with Osteoarthritis.Rofecoxib Osteoarthritis Endoscopy Study Group[J]. Gastroenterology, 1999, 117 (4): 776-783.
[100] Emery P., H. Zeidler, T. K. Kvien, et al. Celecoxib Versus Diclofenac in Long-Term Management of Rheumatoid Arthritis: Randomised Double-Blind Comparison[J]. Lancet, 1999, 354 (9196): 2106-2111.
[101] Kinzler K. W., B. Vogelstein. Landscaping the Cancer Terrain[J]. Science, 1998, 280 (5366): 1036-1037.
[102] Jung Y. J., J. S. Isaacs, S. Lee, et al. Il-1 beta-Mediated up-Regulation of Hif-1alpha Via an Nfkappab/Cox-2 Pathway Identifies Hif-1 as a Critical Link between Inflammation and Oncogenesis[J]. Faseb J,2003,17( 14):2115-2117.
[103] Majima M., M. Isono, Y. Ikeda, et al. Significant Roles of Inducible Cyclooxygenase (Cox)-2 in Angiogenesis in Rat Sponge Implants[J]. Jpn J Pharmacol, 1997, 75 (2): 305-114.
[104] Majima M., I. Hayashi, M. Muramatsu, et al. Cyclo-Oxygenase-2 Enhances Basic Fibroblast Growth Factor-Induced Angiogenesis through Induction of Vascular Endothelial Growth Factor in Rat Sponge Implants[J]. Br J Pharmacol, 2000, 130 (3): 641-649.
[105] Daniel T. O., H. Liu, J. D. Morrow, et al. Thromboxane A2 Is a Mediator of Cyclooxygenase-2-Dependent Endothelial Migration and Angiogenesis[J]. Cancer Res, 1999, 59 (18): 4574-4577.
[106] Masferrer J. L., K. M. Leahy, A. T. Koki, et al. Antiangiogenic and Antitumor Activities of Cyclooxygenase-2 Inhibitors[J]. Cancer Res, 2000, 60 (5): 1306-1311.
[107] Jones M. K., H. Wang, B. M. Peskar, et al. Inhibition of Angiogenesis by Nonsteroidal Anti-Inflammatory Drugs: Insight into Mechanisms and Implications for Cancer Growth and Ulcer Healing[J]. Nat Med, 1999, 5(12): 1418-1423.
[108] Williams C. S., M. Tsujii, J. Reese, et al. Host Cyclooxygenase-2 Modulates Carcinoma Growth[J]. J Clin Invest, 2000, 105 (11): 1589-1594.
[109] Sheng H., J. Shao, S. C. Kirkland, et al. Inhibition of Human Colon Cancer Cell Growth by Selective Inhibition of Cyclooxygenase-2[J]. J Clin Invest, 1997, 99 (9): 2254-2259.
[110] Tsujii M., R. N. DuBois. Alterations in Cellular Adhesion and Apoptosis in Epithelial Cells Overexpressing Prostaglandin Endoperoxide Synthase 2[J]. Cell, 1995, 83 (3): 493-501.
[111] Tsujii M., S. Kawano, R. N. DuBois. Cyclooxygenase-2 Expression in Human Colon Cancer Cells Increases Metastatic Potential[J]. Proc Natl Acad Sci U S A, 1997, 94 (7): 3336-3340.
[112] Tsujii M., S. Kawano, S. Tsuji, et al. Cyclooxygenase Regulates Angiogenesis Induced by Colon Cancer Cells[J]. Cell, 1998, 93 (5): 705-716.
[113] Chinery R., R. J. Coffey, R. Graves-Deal, et al. Prostaglandin J2 and 15-Deoxy-Delta12,14-Prostaglandin J2 Induce Proliferation of Cyclooxygenase-Depleted Colorectal Cancer Cells[J]. Cancer Res, 1999, 59 (11): 2739-2746.
[114] Buckman S. Y., A. Gresham, P. Hale, et al. Cox-2 Expression Is Induced by Uvb Exposure in Human Skin: Implications for the Development of Skin Cancer[J].Carcinogenesis, 1998, 19 (5): 723-729.
[115] Wolff H., K. Saukkonen, S. Anttila, et al. Expression of Cyclooxygenase-2 in Human Lung Carcinoma[J]. Cancer Res, 1998, 58 (22): 4997-5001.
[116] Hwang D., D. Scollard, J. Byrne, et al. Expression of Cyclooxygenase-1 and Cyclooxygenase-2 in Human Breast Cancer[J]. J Natl Cancer Inst, 1998, 90(6): 455-460.
[117] Gupta S., M. Srivastava, N. Ahmad, et al. Over-Expression of Cyclooxygenase-2 in Human Prostate Adenocarcinoma[J]. Prostate, 2000, 42 (1): 73-78.
[118] Mohammed S. I., D. W. Knapp, D. G. Bostwick, et al. Expression of Cyclooxygenase-2 (Cox-2) in Human Invasive Transitional Cell Carcinoma (Tcc) of the Urinary Bladder[J]. Cancer Res, 1999, 59 (22): 5647-5650.
[119] Tucker O. N., A. J. Dannenberg, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Human Pancreatic Cancer[J]. Cancer Res, 1999, 59 (5): 987-990.
[120] Chan G, J. O. Boyle, E. K. Yang, et al. Cyclooxygenase-2 Expression Is up-Regulated in Squamous Cell Carcinoma of the Head and Neck[J]. Cancer Res, 1999, 59 (5): 991-994.
[121] Grubbs C. J., R. A. Lubet, A. T. Koki, et al. Celecoxib Inhibits N-Butyl-N-(4-Hydroxybutyl)-Nitrosamine-Induced Urinary Bladder Cancers in Male B6d2f1 Mice and Female Fischer-344 Rats[J]. Cancer Res, 2000, 60 (20): 5599-5602.
[122] Fischer S. M., H. H. Lo, G. B. Gordon, et al. Chemopreventive Activity of Celecoxib, a Specific Cyclooxygenase-2 Inhibitor, and Indomethacin against Ultraviolet Light-Induced Skin Carcinogenesis[J]. Mol Carcinog, 1999, 25 (4): 231-240.
[123] Farrow D. C, T. L. Vaughan, P. D. Hansten, et al. Use of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Esophageal and Gastric Cancer[J]. Cancer Epidemiol Biomarkers Prev, 1998, 7 (2): 97-102.
[124] Coogan P. F., L. Rosenberg, J. R. Palmer, et al. Nonsteroidal Anti-Inflammatory Drugs and Risk of Digestive Cancers at Sites Other Than the Large Bowel[J]. Cancer Epidemiol Biomarkers Prev, 2000,9(1): 119-123.
[125] Sharpe C. R., J. P. Collet, M. McNutt, et al. Nested Case-Control Study of the Effects of Non-Steroidal Anti-Inflammatory Drugs on Breast Cancer Risk and Stage[J].Br J Cancer, 2000, 83 (1): 112-120.
[126] Egan K. M., M. J. Stampfer, E. Giovannucci, et al. Prospective Study of Regular Aspirin Use and the Risk of Breast Cancer[J]. J Natl Cancer Inst, 1996, 88 (14): 988-993.
[127] Norrish A. E., R. T. Jackson, C. U. McRae. Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Progression[J]. Int JCancer, 1998,77(4): 511-515.
[128] Castelao J. E., J. M. Yuan, M. Gago-Dominguez, et al. Non-Steroidal Anti-Inflammatory Drugs and Bladder Cancer Prevention[J]. Br J Cancer, 2000, 82 (7): 1364-1369.
[129] Rosenberg L., J. R. Palmer, R. S. Rao, et al. A Case-Control Study of Analgesic Use and Ovarian Cancer[J]. Cancer Epidemiol Biomarkers Prev, 2000, 9 (9): 933-937.
[130] Cramer D. W., B. L. Harlow, L. Titus-Ernstoff, et al. Over-the-Counter Analgesics and Risk of Ovarian Cancer[J]. Lancet, 1998, 351 (9096): 104-107.
[131] Dranoff G. Cytokines in Cancer Pathogenesis and Cancer Therapy[J]. Nat Rev Cancer, 2004, 4(1): 11-22.
[132] Koehne C. H., R. N. Dubois. Cox-2 Inhibition and Colorectal Cancer[J]. Semin Oncol, 2004, 31 (2 Suppl 7): 12-21.
[133] Steinbach G, P. M. Lynch, R. K. Phillips, et al. The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis[J]. N Engl J Med, 2000, 342 (26): 1946-1952.
[134] Solomon S. D., J. J. McMurray, M. A. Pfeffer, et al. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention[J].N Engl J Med, 2005, 352(11): 1071-1080.
[135] Bresalier R. S., R. S. Sandier, H. Quan, et al. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial[J].N Engl J Med, 2005, 352 (11): 1092-1102.
[136] Karin M., Y. Yamamoto, Q. M. Wang. The Ikk Nf-Kappa B System: A Treasure Trove for Drug Development[J]. Nat Rev Drug Discov, 2004, 3(1): 17-26.