RNA干扰STAT3基因对食管癌细胞放射敏感性影响的实验研究
摘要
目的:本研究通过构建STAT3基因siRNA重组质粒,转染食管癌Eca-109细胞,特异性阻断STAT3基因的表达,联合不同剂量的X线照射,观察放射合并RNA干扰对细胞增殖、细胞周期、凋亡和放射增敏性的影响,初步探讨其放射增敏机制,为寻找食管癌的放射增敏靶点、提高食管癌的放疗疗效提供实验依据。
方法:
1、免疫细胞化学法、Western blot方法检测食管癌Eca-109细胞中STAT3蛋白表达。
2、针对人STAT3基因mRNA序列,构建3个siRNA重组质粒:pRNAT-U6.1-siRNA1、pRNAT-U6.1-siRNA2、pRNAT-U6.1-siRNA3,同时构建1个阴性重组质粒:pRNAT-U6.1-negative。重组质粒测序鉴定。
3、重组质粒转染Eca-109细胞,G418筛选获得稳定表达siRNA的细胞克隆,RT-PCR、Western blot方法检测细胞STAT3 mRNA及蛋白表达。
4、MTT法、流式细胞仪分别检测STAT3-siRNA对细胞增殖、细胞周期和凋亡的影响。
5、Eca-109细胞分别接受0、2Gy、4Gy、6Gy、8Gy X线照射,MTT法、平板克隆形成实验分别计算细胞存活分数,流式细胞仪检测细胞周期和凋亡。
6、稳定表达siRNA的细胞分别接受0、2Gy、4Gy、6Gy、8Gy X线照射,MTT法、平板克隆形成实验分别计算细胞存活分数,流式细胞仪检测4Gy X线照射的细胞周期和凋亡。
结果:
1、细胞免疫化学法和Western blot方法检测证实,食管癌Eca-109细胞中有STAT3蛋白表达。
2、成功构建了3个STAT3基因siRNA重组质粒,经测序鉴定正确。
3、RT-PCR、Western blot方法分析显示,转染pRNAT-U6.1-siRNA3重组质粒可明显抑制肿瘤细胞STAT3 mRNA和蛋白的表达,而pRNAT-U6.1-siRNA1和pRNAT-U6.1-siRNA2重组质粒对STAT3基因的抑制作用不明显。
4、MTT实验证实,siRNA3治疗组肿瘤细胞生长抑制率为35.68%,明显高于对照组,差异有统计学意义(p＜0.01)。
5、流式细胞仪检测证实,siRNA3治疗组G_0/G_1期细胞占79.51%,较对照组明显增高,差异有统计学意义(p＜0.05);细胞凋亡率为13.26%,较对照组明显增加,差异有统计学意义(p＜0.01)。
6、6Gy、8Gy X线照射,Eca-109细胞存活分数分别为44.28%、16.74%,较2Gy、4Gy X线照射明显降低,差异有统计学意义(p＜0.01)。
7、4Gy、6Gy、8Gy X线照射,Eca-109细胞中G_2/M期细胞分别占11.7%、14.08%、24.27%,较0、2Gy X线照射明显增高,差异有统计学意义(p＜0.01)。不同剂量X线照射引起的细胞凋亡率差异无统计学意义(p＞0.05)。
8、不同剂量X线照射,siRNA3治疗组细胞存活分数均低于对照组,差异有统计学意义(p＜0.01)。
9、4Gy X线照射,siRNA3治疗组G_0/G_1期细胞占83.79%,较对照组明显增高,差异有统计学意义(p＜0.01);细胞凋亡率为16.42%,较对照组明显增加,差异有统计学意义(p＜0.01)。
10、经计算本研究的放射增敏比为1.334,提示RNA干扰STAT3基因对放射有增敏作用。
结论:
1、食管癌Eca-109细胞中有STAT3蛋白表达。
2、成功构建了3个STAT3基因siRNA重组质粒pRNAT-U6.1-siRNA,经测序鉴定正确。
3、pRNAT-U6.1-siRNA3重组质粒能有效地抑制肿瘤细胞STAT3 mRNA和蛋白的表达。
4、STAT3-siRNA可抑制Eca-109细胞增殖、引起细胞周期G_0/G_1期阻滞、诱导肿瘤细胞凋亡。
5、单纯照射可抑制Eca-109细胞的增殖、引起细胞周期G_2/M期阻滞,但是未诱导明显的肿瘤细胞凋亡。
6、放射合并STAT3-siRNA可明显抑制Eca-109细胞的增殖、引起细胞周期G_0/G_1期阻滞、诱导肿瘤细胞凋亡。
7、RNA干扰STAT3基因的表达对肿瘤细胞有放射增敏作用,可以提高Eca-109细胞的放射敏感性。
Objective:Construct recombinant plasmid expressing siRNA targeting STAT3, transfect it into esophageal carcinoma cell line Eca-109 to inhibit the expression of STAT3,irradiate the cells with different doses of X-rays to study the effect of cell proliferation,cell cycle,apoptosis and sensitivity of radiotherapy,explore the mechanisms of radiosensitization,provide evidence for improving radiosensitivity and radiotherapeutic effect in esophageal carcinoma.
Methods:
1.Immunocytochemistry analysis and Western blot analyses the expression of STAT3 protein in esophageal carcinoma cell line Eca-109.
2.Three short hairpin sequences targeting STAT3 were desined and three recombinant plasmids expressing STAT3 siRNA were constructed: pRNAT-U6.1-siRNA1,pRNAT-U6.1-siRNA2,pRNAT-U6.1-siRNA3,and a negative recombinant plasmid pRNAT-U6.1-negative which didn't interfere with STAT3 was constructed meanwhile.The recombinant plasmids were identified by sequencing.
3.Recombinant plasmids were transfected into Eca-109 cells,stabilized transfected cells were selected with G418.Inhibitory effect of STAT3 mRNA and protein was detected by RT-PCR and Western blot respectively.
4.Aider transfection of Eca-109 cells with STAT3 siRNA,the proliferation of cells was analysed by MTT assay,the cell cycle distribution and apoptosis were analysed with flow cytometry.
5.Irradiated with 0,2Gy,4Gy,6Gy,8Gy X-rays,the survival fraction of Eca-109 cells were ascertained by MTT and clonogenic assays,the cell cycle and apoptosis were detected by flow cytometry.
6.Stabilized transfected cells were exposed to 0,2Gy,4Gy,6Gy,8Gy X-rays respectively,the survival fraction of cells were determined by MTT and clonogenic assays,flow cytometry was applied to analyse cell cycle distribution and apoptosis at the dose of 4Gy.
Results:
1.Immunocytochemistry analysis and Western blot analyses showed that STAT3 protein expressed in esophageal carcinoma cell line Eca-109.
2.Three recombinant plasmids expressing STAT3 siRNA were constructed and identified as correct by sequencing.
3.The results from RT-PCR analysis and Western bolt analyses demonstrated that the plasmids containing pRNAT-U6.1-siRNA3 could specifically reduce the expression of STAT3 mRNA and protein.However,the other plasmids containing pRNAT-U6.1-siRNA1 and pRNAT-U6.1-siRNA2 had no inhibitory effect on STAT3.
4.MTT assay explained that the growth-inhibition rate in siRNA3 group was 35.68%,significantly higher than that of the control(p＜0.01).
5.Flow cytometry detection confirmed that the percentage of G_0/G_1 phase cell in siRNA3 group was 79.51%,significantly increased compared with the control (p＜0.05);the apoptosis rate in siRNA3 group was 13.26%,increased obviously than that of the control(p＜0.01).
6.Irradiated with 6Gy,8Gy X-rays,the survival fraction of Eca-109 cells was 44.28%and 16.74%respectively,decreased significantly compared with 2Gy and 4Gy(p＜0.01).
7.Exposed to 4Gy,6Gy,8Gy X-radiation,the percentage of G_0/G_1 phase cell in Eca-109 wasl 1.7%,14.08%and 24.27%respectively,significantly higher than that of 0 and 2Gy(p＜0.01).There were no significant differences in apoptosis rate induced by irradiation(p＞0.05).
8.Irradiated with different doses,the survival fraction in siRNA3 group was significantly lower than that of the control(p＜0.01).
9.Irradiated with 4Gy X-rays,the percentage of G_0/G_1 phase cell in siRNA3 group was 83.79%,significantly increased compared with the control(p＜0.05);the apoptosis rate in siRNA3 group was 16.42%,increased significantly than that of the control (p＜0.01).
10.The sensitization enhancement ratio(SER)in this study was 1.334,showed that RNAi on STAT3 had effect on radiosensitization.
Conclusion:
1.STAT3 protein expressed in esophageal carcinoma cell line Eca-109.
2.Three recombinant plasmids expressing STAT3-siRNA were constructed and identified as correct by sequencing.
3.The plasmids containing pRNAT-U6.1-siRNA3 could obviously reduce the expression of STAT3 mRNA and protein.
4.STAT3-siRNA can inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_0/G_1 phase and induce apoptosis.
5.Single irradiation can inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_2/M phase,but induce little apoptosis.
6.Radiotherapy combined with STAT3-siRNA can significantly inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_0/G_1 phase and induce apoptosis.
7.RNAi on STAT3 had effect on radiosensitization,it improved the radiosensitivity in Eca-109 cells.
方法:
1、免疫细胞化学法、Western blot方法检测食管癌Eca-109细胞中STAT3蛋白表达。
2、针对人STAT3基因mRNA序列,构建3个siRNA重组质粒:pRNAT-U6.1-siRNA1、pRNAT-U6.1-siRNA2、pRNAT-U6.1-siRNA3,同时构建1个阴性重组质粒:pRNAT-U6.1-negative。重组质粒测序鉴定。
3、重组质粒转染Eca-109细胞,G418筛选获得稳定表达siRNA的细胞克隆,RT-PCR、Western blot方法检测细胞STAT3 mRNA及蛋白表达。
4、MTT法、流式细胞仪分别检测STAT3-siRNA对细胞增殖、细胞周期和凋亡的影响。
5、Eca-109细胞分别接受0、2Gy、4Gy、6Gy、8Gy X线照射,MTT法、平板克隆形成实验分别计算细胞存活分数,流式细胞仪检测细胞周期和凋亡。
6、稳定表达siRNA的细胞分别接受0、2Gy、4Gy、6Gy、8Gy X线照射,MTT法、平板克隆形成实验分别计算细胞存活分数,流式细胞仪检测4Gy X线照射的细胞周期和凋亡。
结果:
1、细胞免疫化学法和Western blot方法检测证实,食管癌Eca-109细胞中有STAT3蛋白表达。
2、成功构建了3个STAT3基因siRNA重组质粒,经测序鉴定正确。
3、RT-PCR、Western blot方法分析显示,转染pRNAT-U6.1-siRNA3重组质粒可明显抑制肿瘤细胞STAT3 mRNA和蛋白的表达,而pRNAT-U6.1-siRNA1和pRNAT-U6.1-siRNA2重组质粒对STAT3基因的抑制作用不明显。
4、MTT实验证实,siRNA3治疗组肿瘤细胞生长抑制率为35.68%,明显高于对照组,差异有统计学意义(p＜0.01)。
5、流式细胞仪检测证实,siRNA3治疗组G_0/G_1期细胞占79.51%,较对照组明显增高,差异有统计学意义(p＜0.05);细胞凋亡率为13.26%,较对照组明显增加,差异有统计学意义(p＜0.01)。
6、6Gy、8Gy X线照射,Eca-109细胞存活分数分别为44.28%、16.74%,较2Gy、4Gy X线照射明显降低,差异有统计学意义(p＜0.01)。
7、4Gy、6Gy、8Gy X线照射,Eca-109细胞中G_2/M期细胞分别占11.7%、14.08%、24.27%,较0、2Gy X线照射明显增高,差异有统计学意义(p＜0.01)。不同剂量X线照射引起的细胞凋亡率差异无统计学意义(p＞0.05)。
8、不同剂量X线照射,siRNA3治疗组细胞存活分数均低于对照组,差异有统计学意义(p＜0.01)。
9、4Gy X线照射,siRNA3治疗组G_0/G_1期细胞占83.79%,较对照组明显增高,差异有统计学意义(p＜0.01);细胞凋亡率为16.42%,较对照组明显增加,差异有统计学意义(p＜0.01)。
10、经计算本研究的放射增敏比为1.334,提示RNA干扰STAT3基因对放射有增敏作用。
结论:
1、食管癌Eca-109细胞中有STAT3蛋白表达。
2、成功构建了3个STAT3基因siRNA重组质粒pRNAT-U6.1-siRNA,经测序鉴定正确。
3、pRNAT-U6.1-siRNA3重组质粒能有效地抑制肿瘤细胞STAT3 mRNA和蛋白的表达。
4、STAT3-siRNA可抑制Eca-109细胞增殖、引起细胞周期G_0/G_1期阻滞、诱导肿瘤细胞凋亡。
5、单纯照射可抑制Eca-109细胞的增殖、引起细胞周期G_2/M期阻滞,但是未诱导明显的肿瘤细胞凋亡。
6、放射合并STAT3-siRNA可明显抑制Eca-109细胞的增殖、引起细胞周期G_0/G_1期阻滞、诱导肿瘤细胞凋亡。
7、RNA干扰STAT3基因的表达对肿瘤细胞有放射增敏作用,可以提高Eca-109细胞的放射敏感性。
Objective:Construct recombinant plasmid expressing siRNA targeting STAT3, transfect it into esophageal carcinoma cell line Eca-109 to inhibit the expression of STAT3,irradiate the cells with different doses of X-rays to study the effect of cell proliferation,cell cycle,apoptosis and sensitivity of radiotherapy,explore the mechanisms of radiosensitization,provide evidence for improving radiosensitivity and radiotherapeutic effect in esophageal carcinoma.
Methods:
1.Immunocytochemistry analysis and Western blot analyses the expression of STAT3 protein in esophageal carcinoma cell line Eca-109.
2.Three short hairpin sequences targeting STAT3 were desined and three recombinant plasmids expressing STAT3 siRNA were constructed: pRNAT-U6.1-siRNA1,pRNAT-U6.1-siRNA2,pRNAT-U6.1-siRNA3,and a negative recombinant plasmid pRNAT-U6.1-negative which didn't interfere with STAT3 was constructed meanwhile.The recombinant plasmids were identified by sequencing.
3.Recombinant plasmids were transfected into Eca-109 cells,stabilized transfected cells were selected with G418.Inhibitory effect of STAT3 mRNA and protein was detected by RT-PCR and Western blot respectively.
4.Aider transfection of Eca-109 cells with STAT3 siRNA,the proliferation of cells was analysed by MTT assay,the cell cycle distribution and apoptosis were analysed with flow cytometry.
5.Irradiated with 0,2Gy,4Gy,6Gy,8Gy X-rays,the survival fraction of Eca-109 cells were ascertained by MTT and clonogenic assays,the cell cycle and apoptosis were detected by flow cytometry.
6.Stabilized transfected cells were exposed to 0,2Gy,4Gy,6Gy,8Gy X-rays respectively,the survival fraction of cells were determined by MTT and clonogenic assays,flow cytometry was applied to analyse cell cycle distribution and apoptosis at the dose of 4Gy.
Results:
1.Immunocytochemistry analysis and Western blot analyses showed that STAT3 protein expressed in esophageal carcinoma cell line Eca-109.
2.Three recombinant plasmids expressing STAT3 siRNA were constructed and identified as correct by sequencing.
3.The results from RT-PCR analysis and Western bolt analyses demonstrated that the plasmids containing pRNAT-U6.1-siRNA3 could specifically reduce the expression of STAT3 mRNA and protein.However,the other plasmids containing pRNAT-U6.1-siRNA1 and pRNAT-U6.1-siRNA2 had no inhibitory effect on STAT3.
4.MTT assay explained that the growth-inhibition rate in siRNA3 group was 35.68%,significantly higher than that of the control(p＜0.01).
5.Flow cytometry detection confirmed that the percentage of G_0/G_1 phase cell in siRNA3 group was 79.51%,significantly increased compared with the control (p＜0.05);the apoptosis rate in siRNA3 group was 13.26%,increased obviously than that of the control(p＜0.01).
6.Irradiated with 6Gy,8Gy X-rays,the survival fraction of Eca-109 cells was 44.28%and 16.74%respectively,decreased significantly compared with 2Gy and 4Gy(p＜0.01).
7.Exposed to 4Gy,6Gy,8Gy X-radiation,the percentage of G_0/G_1 phase cell in Eca-109 wasl 1.7%,14.08%and 24.27%respectively,significantly higher than that of 0 and 2Gy(p＜0.01).There were no significant differences in apoptosis rate induced by irradiation(p＞0.05).
8.Irradiated with different doses,the survival fraction in siRNA3 group was significantly lower than that of the control(p＜0.01).
9.Irradiated with 4Gy X-rays,the percentage of G_0/G_1 phase cell in siRNA3 group was 83.79%,significantly increased compared with the control(p＜0.05);the apoptosis rate in siRNA3 group was 16.42%,increased significantly than that of the control (p＜0.01).
10.The sensitization enhancement ratio(SER)in this study was 1.334,showed that RNAi on STAT3 had effect on radiosensitization.
Conclusion:
1.STAT3 protein expressed in esophageal carcinoma cell line Eca-109.
2.Three recombinant plasmids expressing STAT3-siRNA were constructed and identified as correct by sequencing.
3.The plasmids containing pRNAT-U6.1-siRNA3 could obviously reduce the expression of STAT3 mRNA and protein.
4.STAT3-siRNA can inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_0/G_1 phase and induce apoptosis.
5.Single irradiation can inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_2/M phase,but induce little apoptosis.
6.Radiotherapy combined with STAT3-siRNA can significantly inhibit the proliferation of Eca-109 cells,result in cell cycle arrest at G_0/G_1 phase and induce apoptosis.
7.RNAi on STAT3 had effect on radiosensitization,it improved the radiosensitivity in Eca-109 cells.
引文
[1]J Fearlay,F Bray,P Pisani,et al.Globocan 2000:cancer incidence,mortality and prevalence worldwide[M].Lyon France:IARC press,2001:581.
[2]Parkin DM.Global cancer statistics in the year 2000[J].Lancet Oncol,2001,2(9):533-543.
[3]邹小农.食管癌流行病学[J].中华肿瘤防治杂志,2006,13(18):18-21.
[4]韩企夏,施学辉.食管癌[A].见汤钊猷.现代肿瘤学[M].第二版.上海:上海医科大学出版社,2000:691.
[5]施学辉,吴根娣,刘新伟,等.后程加速超分割放射治疗食管癌的长期疗效.中华放射肿瘤学杂志,1997,6(1):12-15.
[6]韩春,万钧,周道安,等.100例食管癌后程加速放射治疗的研究[J].中华放射肿瘤学杂志,1997,6(1):16-18.
[7]肖泽芬,食管癌[A].见殷蔚伯,谷铣之.肿瘤放射治疗学[M].第三版.北京:中国协和医科大学出版社,2002:610.
[8]Chakraborty A,Tweardy DJ.STAT3 and G-CSF-induced myeloid differentianon [J].Leuk Lymphoma,1998,30(5-6):433-442.
[9]Bromberg J.Stat proteins and oncogenesis[J].J Clin Invest,2002,109(9):1139-1142.
[10]Bromberg J,Darnell JE Jr.The role of STATs in transcriptional control and their impact on cellular function[J].Oncogene,2000,19(21):2468-2473.
[11]Levy DE,Darnell JE Jr.Stats:transcriptional control and biological impact[J].Nat Rev Mol Cell Biol,2002,3(9):651-662.
[12]Bowman T,Garcia R,Turkson J,et al.STATs in oncogenesis[J].Oncogen,2000,19(21):2474-2488.
[13]Darnell JE Jr.STATs and gene regulation[J].Science,1997,277(5332):1630-1635.
[14]Sano S,Itami S,Takeda K et al.Keratinocyte-specific ablation of Stat3 exihibits impaired skin remodeling,but does not affect skin morphogenesis[J].EMBO J,1999,18(17):4657-4668.
[15]Turkson J,Bowman T,Garcia R et al.Stat3 activation by Src induces specific gene regulation and is required for cell transformation[J]. Mol Cell Biol, 1998,18(5):2545-2552.
[16] Tian H, Wittmack EK, Jorgensen TJ. P21~(WAF\CIPI) antisense therapy radiosensitize radiosensitizes human colon cancer by converting growth arrest to apoptosis[J]. Cancer Res, 2000,60(3):679-684.
[17] Wacheck V, Selzer E, Gunsberg P, et al. Bcl-xL antisense oligodeoxynucleotides radiosensitise colon cancer cells[J]. Br J Cancer, 2003,89(7):1352-1357.
[18] Kim KY, Seol J Y, Jeon GA, et al. The combined treatment of aspirin and radiation induces apoptosis by the regulation of bcl-2 and caspase-3 in human cervical cancer cell[J]. Cancer Lett, 2003,189(2): 157-166.
[19] Couzin J. Breakthrough of the year. Small RNAs make big splash[J]. Science, 2002,298(5602):2296-2297.
[20] Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science, 1994,264(5164):1415-1421.
[21] Hoey T, Grusby MJ. STATs as mediators of cytokine-induced responses[J]. Adv Immunol, 1999,71:145-162.
[22] Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and Stat3 in inflammation and cancer. Eur J Cancer, 2005,41(16):2502-25l2.
[23] Wegenka UM, Lutticken C, Buschmann J, et al. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (Stat) family. Mol Cell Biol, 1994,14(5):3186-3196.
[24] Lutticken C, Wegenka UM, Yuan J, et al. Association of transcription factor APRF and protein kinase Jakl with the interleukin-6 signal transducer gp130. Science, 1994,263(5143):89-92.
[25] Zhong Z, Wen Z, Darnell JE Jr. Stat3: a Stat family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 1994,264(5155):95-98.
[26] Akira S, Nishio Y, Moue M, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell, 1994,77(1):63-71.
[27] Heinrich PC, Behrmann I, Muller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J]. Biochem J, 1998,334(Pt 2):297-314.
[28] Boeuf H, Hauss C, Graeve FD, et al. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells[J]. J Cell Biol, 1997,138(6):1207-1217.
[29] Niwa H, Burdon T, Chambers I, et al. Self-renewal of pluripotent embryonic Stem cells is mediated via activation of STAT3[J]. Genes Dev, 1998,12(13):2048- 2060.
[30] Raz R, Lee CK, Cannizzaro LA, et al. Essential role of STAT3 for embryonic stem cell pluripotency[J]. Proc Natl Acad Sci USA, 1999,96(6):2846-2851.
[31] Matsuda T, Nakamura K, Nakao K, et al. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells[J]. EMBO J, 1999,18(15):4261-4269.
[32] Kisseleva T, Bhattacharya S, Braunstein J, et al. Signaling through the JAK/STAT pathway, recent advances and future challenges[J]. Gene, 2002,285(1-2): 1-24.
[33] Chung CD, Liao J, Lin B, et al. Specific inhibition of STAT3 signal transduction by PIAS3[J]. Science, 1997,278(5344): 1803-1805.
[34] Chakraborty A, Tweardy DJ. STAT3 and G-CSF-induced myeloid differentianon [J]. Leuk Lymphoma, 1998,30(5-6):433-442.
[35] Bromberg J. Stat proteins and oncogenesis[J]. J Clin Invest, 2002,109(9):1139-1142.
[36] Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular runction[J]. Oncogene, 2000,19(21):2468-2473.
[37] Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein[J]. Science, 1995,269(5520):81-83.
[38] Garcia R, Yu CL, Hudnall A, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells[J]. Cell Growth Differ,1997,8(12):1267-1276.
[39]Bromberg JF,Wrzeszczynska MH,Devgan G,et al.Stat3 as an oncogene[J].Cell,1999,98(12):295-303.
[40]Catlett-Falcone R,Landowski TH,Oshiro MM,et al.Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells[J].Immunity,1999,10(1):105-115.
[41]Grandis JR,Drenning SD.Chakraborty A,et al.Requirement of Stat3 but not Statl activation for epidermal growth factor receptor-mediated cell growth In vitro[J].J Clin Invest,1998,102(7):1385-1392.
[42]Niu G,Shain KH,Huang M,et al.Over expression of a dominant-negative signal and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest[J].Cancer Res,2001,61(8):3276-3280.
[43]Turkson J,Ryan D,Kim JS,et al.Phosphotyrosyl peptides block Stat3-mediated DNA binding activity,gene regulation and cell transformation[J].J Biol Chem,2001,276(48):45443-45455.
[44]Chen H,Ye D,Xie X,et al.VEGF,VEGFRs expressions and activated Stats in ovarian epithelial carcinoma[J].Gynecol Oncol,2004,94(3):630-635.
[45]Wang S,Evers B M.Caco-2 cell differentiation is associated with a decrease in Stat protein levels and binding[J].J Gast roentest Surg,1999,3(2):200-207.
[46]梁斌,王彬,祝学光,等.转录信号传导子和激活分子在人胃癌组织中的表达及意义[J].中华实验外科杂志,2001,18(4):313-314.
[47]杨俊波,毛志福,蔡享道.STAT3在食管鳞状细胞癌中的表达和意义[J].消化外科,2006,5(3):220-222.
[48]Oliveira C,Seruca R,Cameiro F.Genetics,pathology,and clinics of familial gastric cancer[J].Int J Surg Pathol,2006,14(1):21-33.
[49]Sijen T,Fleenor J,Simmer F,et al.On the role of RNA amplification in dsRNA-triggered gene silencing[J].Cell,2001,107(4):465-476.
[50]Vaucheret H,Beclin C,Fagard M.Post-transcriptional gene silencing in plants[J].J Cell Sci,2001,114(Pt 17):3083-3091.
[51]Parrish S,Fleenor J,Xu S,et al.Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference[J]. Mol Cell, 2000,6(5): 1077-1087.
[52] Sharp PA. RNA interference-2001[J]. Genes and development, 2001,15(5):485- 490.
[53] Zamore PD, Tuschl T, Sharp PA, et al. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals[J]. Cell, 2000,101(1) :25-33.
[54] Elbashir SM, Martinez J, Patkaniowska A, et al. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate[J]. EMBO J, 2001,20 (23) :6877-6888.
[55] Brummelkamp, T.R., Bernards, R., Agami, R. A system for stable expression of short interfering RNAs in mammalian cells[J]. Science, 2002,296(5567): 550-553.
[56] Merkle D, Douglas P, Moorhead GB, et al. The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation [J]. Biochemistry, 2002,41(42): 12706-12714.
[57] Pedroso de Lima MC, Simoes S, Pires P, et al. Cationic lipid-DNA complexes in gene delivery: from biophysics to biological applications[J]. Adv Drug Deliv Rev,2001,47(2-3):277-294.
[58] Nakanishi M, Noguchi A. Confocal and probe microscopy to study gene transfectian mediated by cationic liposomes with a cationic cholesterol derivative[J]. Adv Drug Deliv Rev, 2001,52(3):197-207.
[59] Clark PR, Hersh EM. Cationic lipid-mediated gene transfer: current concepts[J]. Curr Opin Mol Ther, 1999,1(2):158-176.
[60] Wang H, Zeng ZC, Bui TA, et al. Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group[J]. Oncogene, 2001,20(18):2212-2224.
[61] McManus M T, Haines B B, Dillon CP, et al. Small interfering RNA-mediated gene silencing in T lymphocytes[J]. J Immunol, 2002,169(10):5754-5760.
[62] Redell MS, Tweardy DJ. Targeting transcription factors for cancer therapy[J]. Curr Pharm Des, 2005,11(22):2873-2887.
[63]Bromberg J.Stat proteins and oncogenesis[J].J Clin Invest,2002,109(9):1139-1142.
[64]Buettner R,Mora LB,Jove R.Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention[J].Clin Cancer Res,2002,8(4):945-954.
[65]Niu G,Wright KL,Huang M,et al.Constitutive Stat 3 activity up-regulates VEGF expression and tumorangiogenesis[J].Oncogene,2002,21(13):2000-2008
[66]Baus D,Pfitzner E.Specific function of STAT3,SOCS1,and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma calls[J].Int J Cancer,2006,118(6):1404-1413.
[67]Konnikova L,Kotecki M,Kruger MM,et al.Knockdown of Stat3 expression by RNAi induces apoptosis in astrocytoma cells[J].BMC Cancer,2003,3:23.
[68]Ling X,Arlinghaus RB.Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice[J].Cancer Res,2005,65(7):2532-2536.
[69]Peschos D,Tsanou E,Stefanou D,et al.Expression of cyclin-dependent kinases inhibitors p21(WAF1)and p27(KIP1)in benign,premalignant and malignant laryngeal lesions.correlation with cell cycle regulatory proteins[J].In vivo,2004,18(6):719-724.
[70]Coats S,Flanagan WM,Nourse J,et al.Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle[J].Science,1996,272(5263):877-880.
[71]Elledge SJ,Winston J,Harper JW.A question of balance:the role of cyclin-kinase inhibitors in development and tumorigenesis[J].Trends Cell Biol,1996,6(10):388-392.
[72]金成一,李学峰,郭春沅.细胞周期调控的分子机制[J].延边大学农学学报,2000,22(2):147-150.
[73]Li Z,Wang C,Prendergast G,et al.Cyclin D1 Functions in Cell Migration[J].Cell Cycle,2006,5(21):2440-2442.
[74]Michalides R,van Veelen N,Hart A,et al.Overexpression of cyclin D1correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck[J].Cancer Res,1995,55(5):975-978.
[75] van Diest PJ, Michalides RJ, Jannink L, et al. Cyclin D1 expression in invasive breast cancer. Correlations and prognostic value[J]. Am J Pathol, 1997,150(2): 705-711.
[76] Zhou P, Jiang W, Zhang Y J, et al. Antisense to cyclin Dl inhibits growth and reverses the transformed phenotype of human esophageal cancer cells[J]. Oncogene, 1995,11(3):571-580.
[77] Sherr CJ. Cancer cell cycles[J]. Science, 1996,274(5293): 1672-1677.
[78] Wu W, Slomovitz BM, Soliman PT, et al. Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma[J]. Int J Gynecol Cancer, 2006,16(4): 1668-1672.
[79] Namazie A, Alavi S, Olopade OI, et al. Cyclin Dl amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors[J]. Laryngoscope, 2002,112(3):472-481.
[80] Jiang W, Kahn SM, Tomita N, et al. Amplification and expression of the human Cyclin D gene in esophageal cancer[J]. Cancer Res, 1992,52(10):2980-2983.
[81] Wang LD, Shi ST, Zhou Q, et al. Changes in p53 and Cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis[J]. Int J Cancer, 1994,59(4):514-519.
[82] Bahnassy AA, Zekri AR, El-Houssini S, et al. Cyclin A and cyclinDl as significant prognostic markers in colorectal cancer patients[J]. Gastroenterol, 2004, 4(1):22-29.
[83] Masuda M, Suzui M, Yasumalu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J]. Cancer Res, 2002,62(12):3351-3355.
[84] Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene[J]. Cell, 1999,98(3):295-303.
[85] Frank DA, Mahajan S, Ritz JB. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues[J]. J Clin Investig, 1997,100(12):3140-3148.
[86]Decker,T.,Stockinger,S.,Karaghiosoff,M.,et al.Interferons and Stats in innate immunity to microorganisms[J].J Clin Invest,2002,109(10):1271-1277.
[87]Udy GB,Tower RP,Snell RG,et al.Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression[J].Proc Natl Acad Sci U S A,1997,94(14):7239-7244.
[88]Teglund S,Mckay C,Schuetz E,et al.Stat5a and stat5b proteins have essencial and nonessential or redundant,role in cytokine responses[J].Cell,1998,93(5):841-850.
[89]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Star3 gene leads to early embryonic lethality[J].Proc Natl Acad Sci U S A,1997,94(8):3801-3804.
[90]Raz,R.,Durbin,J.E.,Levy,D.E.Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines,interferons,and growth factors[J].J Biol Chem,1994,269(39):24391-24395.
[91]Stev A,Benjamin B.Rituximab inactivates signal transducer and activation of transcription 3(STAT3)activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs[J].Cancer Re,2001,61(13):5137-5144..
[92]Gao LF,Xu DQ,Wen LJ,et al.Inhibition of STAT3 expression by siRNA suppresses groth and induces apoptosis in laryngeal cancercells[J].Acta Pharmacol Sin,2005,26(3):377-383.
[93]Boise LH,Gonzalez-Garcia M,Postema CE,et al.Bcl-x,a bcl-2 related gene that functions as a dominant regulator of apoptosis cell death[J].Cell,1993,74(4):597-608.
[94]Sierra A,Castellsague X,Coll T,et al.Expression of death-related gene and their relationship to loss of apoptosis in T1 ductal breast carcinomas[J].Br J Cancer,1998,79(2):103-110.
[95]陈燕,周剑锋,乐蓓蓓等.bcl-2基因及其家族bax,bcl-x1和Fas/APO-1,P16的检测在急性白血病中的临床意义[J].癌症,1998,17(5):352-355.
[96] Pan G,O' , Rourke K, Dixit VM, et al. Caspase-9, Bcl-xL, and Apaf-1 form a ternary complex[J]. J Biol Chem, 1998,273(10):5841-5845.
[97] Cory S, Huang DC, Adams JM. The Bcl-2 family:roles in cell survival and oncogenesis[J]. Oncogene, 2003,22(53):8590-8607.
[98] Oshiro MM, Landowski TH, Catlett Falcone R, et al. Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells[J]. Clin Cancer Res, 2001,7(12):4262-4271.
[99] Xi S, Gooding WE, Grandis JR, et al. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy[J]. Oncogene, 2005,24(6):970-979.
[100] Johnson AL. Mcl-1-just another antiapoptotic Bcl-2 Homolog[J]? Endocrinology, 1999,140(12):5465-5468.
[101] Opfeman J T, Letai A, Beard C, et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1[J]. Nature, 2003,426(6967):671-676.
[102] Michels J, O Neill JW, DallmanCL, et al. Mcl-1 is required forAkata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage[J]. Oncogene, 2004,23(28): 4818-4827.
[103] Derenne S, Monia B, DeanNM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(1) is an essential survival protein of human myeloma cells[J]. Blood, 2002,100(1):194-199.
[104] Moulding DA, Giles RV, Spiller DG, et al. A poptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells[J]. Blood, 2000,96(5):1756-1763.
[105] Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-lexpression[J]. J Clin Invest, 2001,107(3):351-362.
[106] Gritsko T, Williams A, Turkson J, et al. Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells[J]. Clin Cancer Res, 2006,12(1):11-19.
[107]Sun C,Nettesheim D,Liu Z,et al.Solution structure of human survivin and its binding interface with Smac/Diablo[J].Biochemistry,2005,44(1):11-17.
[108]Carvalho A,Carmena M,Sambade C,et al.Survivin is required for stable checkpoint activation in taxol-treatcd HeLa cells[J].J Cell Sci,2003,116(Pt 14):2987-2998.
[109]Konnikova L,Kotecki M,Kruger MM,et al.Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells[J].BMC Cancer,2003,3:23.
[110]魏康.细胞受照射后死亡的分子机理[A].见夏寿首.分子放射生物学[M].北京:原子能出版社,1992:342.
[111]Desai,Arshad,Rogers,et al.Cell biology[J].Current Opinion in Cell Biology,2002,14(6):661-671.
[112]Reis T,Edgar BA.Negative Regulation of dE2F1 by Cyclin-Dependent Kinases Controls Cell Cycle Timing[J].Cell,2004,117(2):253-264.
[113]Shireen H K,Goodffrey M.p53 and pRb prevent replication in response to microtubule inhibitors by mediating a reversible G_1 arrest[J].Cancer research,1998,58(3):396-401.
[114]Hermeking H,Lengauer C,Polyak K,et al.14-3-3 is a p53-regulated inhibitor of G_2/M progression[J].Mol Cell,1997,1(1):3-11.
[115]Fasullo M,Bennett T,AhChing P.The saccharomyces cerevisiae RAD9checkpoint reduces the DNA damage associated stimulation of directed translocation[J].Mol Cell Biol,1998,18(3):1190-2000.
[116]Biade S,Stobbe CC,Chapman JD.The instrinsic radiosensitivity of some tumor cells through their cell cycle[J].Radiation Res,1997,147(4):416-421.
[117]张孟贤,于世英.宫颈癌细胞周期阻滞和凋亡与放射敏感性的关系[J].中华放射肿瘤学杂志,2002,11(2):116-117.
[118]Hui ZG,Li YX,Yang WZ,et al.Abrogation of radiation-induced G2 arrest and radiosensitization by 7-hydroxystaurosporine(UCN-01)in human nasopharyngeal carcinoma cell line[J].Ai Zheng,2003,22(1):6-10.
[119]Bernhard EJ,McKenna WG,Muschel RJ.Cyclin expression and G2-phase delay after irradiation[J].Radiat Res,1994,138(1 Suppl):S64-67.
[120]夏景光,李文建,魏巍,等.电离辐射对不同肿瘤细胞细胞周期进程的影 响[J]. 辐射研究与辐射工艺学报, 2005, 23 (2) : 91.
[121] Logsdon MD, Meyn REJr, Besa PC, et al. Apoptosis and the bcl-2 family-patterns of expression and prognostic value in stage I and II follicular center lymphoma[J]. Int J Radiat Oncol Biol Phys, 1999,44(1) :19-29.
[122] Dubray B, Breton C, Delic J, et al. In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas[J]. Radiother Oncol, 1998,46(2):185-191.
[123] Shinomiya N. New concepts in radiation-induced apoptosis: 'premitotic apoptosis'and 'postmitotic apoptosis'[J]. J Cell Mol Med, 2001,5(3):240-253.
[124] Blank KR, Rudoltz MS, Kao GD, et al. The molecular regulation of apoptosis and implications for radiation oncology[J]. Int J Radiat Biol, 1997,71(5):455- 466.
[125] Stephens LC , Hunter NR, Ang KK, et al. Development of apoptosis in irradiated murine tumors as a function of time and dose[J]. Radiat Res, 1993,135(1):75-80.
[126] Akagi Y, Ito K, Sawada S. Radiation-induced apoptosis and necrosis in Molt-4 cells: a study of dose-effect relationships and their modification[J]. Int J Radiat Biol, 1993,64(1):47-56.
[127] Ling CC, Chen CH, Li WX. Apoptosis induced at different dose rates: implication for the shoulder region of cell survival curves[J]. Radiother Oncol, 1994,32(2): 129-136.
[128] Takahashi T, Mitsuhashi N, Furuta M, et al. Apoptosis induced by heavy ion (carbon) irradiation of two human tumours with different radiosensitivities in vivo: relative biological effectiveness (RBE) of carbon beam[J]. Anticancer Res, 1998,18(1A):253-256.
[129] Dubray B, Breton C, Delic J, et al. In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas[J]. Radiother Oncol, 1998,46(2): 185-191.
[130] Lang FF, Yung W K, Raju U , et al. Enhancement of radiosensitivity of wild-type p53 human glioma cells by Adenovirus-mediated delivery of the p53 gene [J]. J Neurosurg, 1998, 89 (1) :125-132.
[131]Olive PL,Banh JP,Durand RE.Development of apoptosis and polyploidy in human lymphoblast cells as a function of position in the cell cycle at the time of irradit ion[J].Radiat Res,1996,146(6):595-602.
[132]Chapman JD,et al.Condensed chromatin and cell inactivation by single-hit kinetics[J].Radiat Res,1999,(514):433-441.
[133]Cory S,Huang DC,Adams JM.The bcl-2 family:roles in cell survival and oncogenesis[J].Oncogene,2003,22(53):8590-8607.
[134]Rosse T,Olivier R,Monney L,et al.Bcl-2 prolongs cell survival after bax-induced release of cytochrome C[J].Nature,1998,391(6666):496-499.
[135]Findly HW,Gu L,Meager AM,et al.Expression and regulation of Bcl-2,Bcl-x1 and Bax correlate with P53 stares and sensitivity to apotosis in childhood acute lymphoblastic leukemia[J].Blood.1997.89(8):2986-2993.
[136]李惠翔,王尧河,石永刚,等.凋亡相关基因与食管鳞状细胞癌放射敏感性相关关系的研究[J].中华放射医学与防护杂志,2000,20(6):411-413.
[137]黄闻,陈茂怀,吴名耀,等.Bcl-2和bax蛋白表达与鼻咽癌放射敏感性相关关系的探讨[J].中国肿瘤临床,2004,31(18):1051-1053.
[138]宋晖,辛晓燕,肖锋,等.survivin基因RNA干涉对宫颈癌细胞凋亡和放射敏感性的影响[J].肿瘤,2006,26(8):732-737.
[139]Ikeguchi M,Yamaguchi K,Kaibara N.Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor(hOT7T175)gene expression in esophageal squamous cell carcinoma[J].Clin Cancer Res,2004,10(4):1379-1383.
[140]仇晓军,陆德炎,季斌,等.放射诱导胃癌细胞的凋亡及其相关基因的研究[J].中华放射肿瘤学杂志,2005,14(5):447-450.
[141]郑瑛,周昌龙,李旭奎,等.单次不同X线剂量照射对SACC-83细胞的放射生物学效应[J].现代肿瘤医学,2005,13(1)26-29.
[142]买世娟,宗永生,熊敏,等.胸腺癌中p53蛋白表达对癌细胞增殖和凋亡的影响[J].癌症,2000,19(9):864-867.
[143]Carmichael J,DeGraff WG,Gazdar AF,et al.Evaluation of a tetrazolium-based semiautomated colorimetric assay:assessment of chemosensitivity testing[J].Cancer Res,1987,47(4):936-942.
[144] Fertil B, Malaise EP. Intrisicradiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves[J]. Int J Radiat Oncol Bio Phys, 1985,11(9): 1699-1707.
[145] Gaussen A, Legal JD, Beron Gaillard N, et al. Radiosensitivity of human normal and tumoralthyroid cells using fluorescence in situ hybridization and clonogenic survival assay[J]. Int J Radiat Oncol Biol Phys,1999,44(3):683-691.
[146] West CML, Dvidson SE, Roberts SA, et al. The independence of intrinsic radiosensitivity as prognostic factor for patient response to radiotherapy of carcinoma of the cervix[J]. Br J Cancer, 1997,76(9): 1184-1190.
[147] Roth J A, Cristiano RJ. Gene therapy for cancer: what have we done and where are we doing?[J]. J Natl Cancer Inst, 1997, 89(1):21-39.
[1]Hoey T,Grusby MJ.STATs as mediators of cytokine-induced responses[J].Adv Immunol,1999,71:145-162.
[2]Leonard WJ.Role of Jak kinases and STATs in cytokine signal transduction[J].Int J Hematol,2001,73(3):271-277.
[3]Igaz P,Toth S,Falus A.Biological and clinical significance of the JAK-STAT pathway;lessons from knockout mice[J].Inflamm Res,2001,50(9):435-441.
[4]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality[J].Proc Natl Acad Sci USA,1997,94(8):3801-3804.
[5]Akira S,NishioY,Inoue M,et al.Molecular cloning of APRF,a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway[J].Cell,1994,77(1):63-71.
[6]Lutticken C,Wegenka UM,Yuan J,et al.Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130[J].Science,1994,263(5143):89-92.
[7]Zhong Z,Wen Z,Darnell JE.Stat3 and Stat4:members of the family of signal transducers and activators of transcription[J].Proc Natl Acad Sci USA,1994,91(11):4806-4810.
[8]Raz R,Durbin JE,Levy DE.Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines,interferons,and growth factors[J].J Biol Chem,1994,269(39):24391-24395.
[9]Takeda K,Clausen BE,Kaisho T,et al.Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils[J].Immunity,1999,10(1):39-49.
[10]Chakraborty A,Dyer KF,Cascio M,et al.Identification of a novel Stat3recruitment and activation motif within the granulocyte colony-stimulating factor receptor[J].Blood,1999,93(1):15-24.
[11]Darnell JE.STATs and gene regulation[J].Science,1997,277(5332):1630-1635.
[12]Heinrich PC,Behrmann Ⅰ,Muller-Newen G,et al.Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J].Biochem J,1998,334(Pt 2):297-314.
[13]Boeuf H,Hauss C,Graeve FD,et al.Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells[J].J Cell Biol,1997,138(6):1207-1217.
[14]Niwa H,Burdon T,Chambers I,et al.Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3[J].Genes Dev,1998,12(13):2048-2060.
[15]Raz R,Lee CK,Cannizzaro LA,et al.Essential role of STAT3 for embryonic stem cell pluripotency[J].Proc Natl Acad Sci USA,1999,96(6):2846-2851.
[16]Matsuda T,Nakamura K,Nakao K,et al.STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells[J].EMBO J,1999,18(15):4261-4269.
[17]Kisseleva T,Bhattacharya S,Braunstein J,et al.Signaling through the JAK/STAT pathway,recent advances and future challenges[J].Gene,2002,285(1-2):1-24.
[18]Ihle JN.The Stat family in cytokine signaling[J].Curr Opin Cell Biol,2001,13(2):211-217.
[19]叶中德,沈倍奋,黎燕.STAT3入核的核定位序列研究[J].生物化学与生物物理进展,2004,31(1):32-35.
[20] Chakraborty A, Tweardy DJ. STAT3 and G-CSF-induced myeloid differentianon[J]. Leuk Lymphoma, 1998,30(5-6):433-442.
[21] Bromberg J. Stat proteins and oncogenesis[J]. J Clin Invest, 2002,109(9):1139-1142.
[22] Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function[J]. Oncogene, 2000,19(21):2468-2473.
[23] Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact[J]. Nat Rev Mol Cell Biol, 2002,3(9):651-662.
[24] Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein[J]. Science, 1995,269(5520):81-83.
[25] Garcia R, Yu CL, Hudnall A, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells[J]. Cell Growth Differ, 1997,8(12): 1267-1276.
[26] Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene[J]. Cell, 1999,98(12):295-303.
[27] Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells[J]. Immunity, 1999,10(1): 105-115.
[28] Grandis JR, Drenning SD. Chakraborty A, et al. Requirement of Stat3 but not Statl activation for epidermal growth factor receptor-mediated cell growth In vitro[J]. J Clin Invest, 1998,102(7):1385-1392.
[29] Lou W, Ni Z, Dyer K, et al. Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway[J]. Prostate, 2000,42(3):239-242.
[30] Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate.cancer cells[J]. Cancer Res, 2002,62(22):6659-6666.
[31] Song JI, Grandis JR, LM. Stat signaling in head and neck cancer[J]. Oncogene, 2000,19(21):2489-2495.
[32] Cory S, Adams JM. Regulators of the cellular life-or-death switch[J]. Nat Rev Cancer, 2002,2(9):647-656.
[33] Burke WM, Jin X, Lin HJ, et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells[J]. Oncogene, 2001,20(55):7925-7934.
[34] Grandis JR., Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo[J]. Proc Natl Acad Sci USA, 2000,97(8):4227-4232.
[35] Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-lexpression[J]. J Clin Invest, 2001,107(3):351-362.
[36] Gritsko T, Williams A, Turkson J, et al. Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res, 2006,12(1): 11-19.
[37] Altieri DC. Validating survivin as a cancer therapeutic target[J]. Nat Rev Cancer, 2003,3(1):46-54.
[38] Raman V, Martensen SA, Reisman D, et al. Compromised HOXAS function can limit p53 expression in human breast tumours[J]. Nature, 2000,405(6789):974-978.
[39] Schmidt EV. The role of c-myc in regulation of translation initiation[J]. Oncogene, 2004, 23(18):3217-21.
[40] Bowman T, Broome MA, Sinibaldi D, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis[J]. Proc Natl Acad Sci, 2001,98(13):7319-7324.
[41] Kijima T, Niwa H, Steinman RA, et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo[J]. Cell Growth Differ, 2002,13(8):355-362.
[42] Masuda M, Suzui M, Yasumatu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J]. Cancer Res, 2002,62(12):3351-3355.
[43] Sinibaldi D, Wharton W, Turkson J, et al. Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated Stat3 signaling[J]. Oncogene, 2000,19(48):5419-5427.
[44] Plate KH, Breier G, Weich HA, et al. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo[J]. Nature, 1992,359(6398):845-848.
[45] Veikkola T, Karkkainen M, Claesson-Welsh L, et al. Regulation of angiogenesis via vascular endothelial growth factor receptors[J]. Cancer Res, 2000,60(2):203-212.
[46] Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis[J]. Oncogene, 2002,21(13):2000-2008.
[47] Wei LH, Kuo ML, Chen CA, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway[J]. Oncogene, 2003,22(10): 1517-1527.
[48] Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentially activates STAT3 in microvascular endothelial cells[J]. FASEB J, 2003,17(11):1562-1564.
[49] Yahata Y, Shirakata Y, Tokumaru S, et al. Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation[J]. J Biol Chem, 2003,278(41):40026-40031.
[50] Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis[J]. Oncogene, 2004,23(20):3550-3560.
[51] Wang T, Niu G Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells[J]. Nat Med, 2004,10(1):48-54.
[52] Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity[J]. Proc Natl Acad Sci USA, 2003,100(4): 1879-1884.
[53] Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses[J]. Cancer Res, 2003,63(9):2150-2157.
[54]Cheng F,Wang HW,Cuenca A,et al.A critical role for Star3 signaling in immune tolerance[J].Immunity,2003,19(3):425-436.
[55]Galderisi U,Cascino A,Giordano A,et al.Antisense oligonucleotide as therapeutic agents[J].J Cell Physiol,1999,181(2):251-257.
[56]Leong PL,Andrews GA,Johnson DE,et al.Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth[J].Proc Natl Acad Sci USA,2003,100(7):4138-4143.
[57]Huang JS,Guh JY,Hung WC,et al.Role of the Janus kinase(JAK)/signal transducters and activators of transcription(STAT)cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells[J].Biochem J,1999,342(Pt):231-238.
[58]Lee SO,Lou W,Qureshi KM,et al.RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells[J].Prostate,2004,60(4):303-309.
[59]王禹,张颖超,潘玉琢,等.应用沉默3基因促裸鼠移植瘤细胞凋亡及对/22基因表达的影响[J].中国普通外科杂志,2005,14(4):273-276.
[60]Smithgall TE,Briggs SD,Schreiner S,et al.Control of myeloid differentiation and survival by Stats[J].Oncogene,2000,19(21):2612-2618.
[61]Niu G,Shain KH,Huan M,et al.Overexpression of a dominant-negative signal transducer and activator transcription 3 variant tumor cells leads to production soluble factors that induce apoptosis and cell cycle arrest[J].Cancer Res,2001,61(8):3276-3280.
[62]Burdelya L,Catlett-Falcone R,Levitzki A,et al.Combination therapy with AG-490and interleukin 12 achieves greater antitumor effects than either agent alone[J].Mol Cancer Ther,2002,1(1):893-899.
[63]Shuai K.Modulation of STAT signaling by STAT-interacting proteins[J].Oncogene,2000,19(21):2638-2644.
[64]Valentino L,Pierre J.JAK/STAT signal transduction:regulators and implication in hematological malignancies[J].Biochem Pharmacol,2006,71(6):713-721.
[65]Woetmann A,Nielsen M,Christensen ST,et al.Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation,subcellular redistribution,and functional inhibition of STAT3[J].Proc Natl Acad Sci USA,1999,96(19):10620-10625.
[66]Yu CL,Jin YJ,Burakoff SJ.Cytosolic tyrosine dephosphorylation of STAT5.Potential role of SHP-2 in STAT5 regulation.[J].J Biol Chem,2000,275(1):599-604.
[67]Bowman T,Garcia R,Turkson J,et al.STATs in ongenesis[J].Oncogene,2000,9(21):2474-2488.
[2]Parkin DM.Global cancer statistics in the year 2000[J].Lancet Oncol,2001,2(9):533-543.
[3]邹小农.食管癌流行病学[J].中华肿瘤防治杂志,2006,13(18):18-21.
[4]韩企夏,施学辉.食管癌[A].见汤钊猷.现代肿瘤学[M].第二版.上海:上海医科大学出版社,2000:691.
[5]施学辉,吴根娣,刘新伟,等.后程加速超分割放射治疗食管癌的长期疗效.中华放射肿瘤学杂志,1997,6(1):12-15.
[6]韩春,万钧,周道安,等.100例食管癌后程加速放射治疗的研究[J].中华放射肿瘤学杂志,1997,6(1):16-18.
[7]肖泽芬,食管癌[A].见殷蔚伯,谷铣之.肿瘤放射治疗学[M].第三版.北京:中国协和医科大学出版社,2002:610.
[8]Chakraborty A,Tweardy DJ.STAT3 and G-CSF-induced myeloid differentianon [J].Leuk Lymphoma,1998,30(5-6):433-442.
[9]Bromberg J.Stat proteins and oncogenesis[J].J Clin Invest,2002,109(9):1139-1142.
[10]Bromberg J,Darnell JE Jr.The role of STATs in transcriptional control and their impact on cellular function[J].Oncogene,2000,19(21):2468-2473.
[11]Levy DE,Darnell JE Jr.Stats:transcriptional control and biological impact[J].Nat Rev Mol Cell Biol,2002,3(9):651-662.
[12]Bowman T,Garcia R,Turkson J,et al.STATs in oncogenesis[J].Oncogen,2000,19(21):2474-2488.
[13]Darnell JE Jr.STATs and gene regulation[J].Science,1997,277(5332):1630-1635.
[14]Sano S,Itami S,Takeda K et al.Keratinocyte-specific ablation of Stat3 exihibits impaired skin remodeling,but does not affect skin morphogenesis[J].EMBO J,1999,18(17):4657-4668.
[15]Turkson J,Bowman T,Garcia R et al.Stat3 activation by Src induces specific gene regulation and is required for cell transformation[J]. Mol Cell Biol, 1998,18(5):2545-2552.
[16] Tian H, Wittmack EK, Jorgensen TJ. P21~(WAF\CIPI) antisense therapy radiosensitize radiosensitizes human colon cancer by converting growth arrest to apoptosis[J]. Cancer Res, 2000,60(3):679-684.
[17] Wacheck V, Selzer E, Gunsberg P, et al. Bcl-xL antisense oligodeoxynucleotides radiosensitise colon cancer cells[J]. Br J Cancer, 2003,89(7):1352-1357.
[18] Kim KY, Seol J Y, Jeon GA, et al. The combined treatment of aspirin and radiation induces apoptosis by the regulation of bcl-2 and caspase-3 in human cervical cancer cell[J]. Cancer Lett, 2003,189(2): 157-166.
[19] Couzin J. Breakthrough of the year. Small RNAs make big splash[J]. Science, 2002,298(5602):2296-2297.
[20] Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science, 1994,264(5164):1415-1421.
[21] Hoey T, Grusby MJ. STATs as mediators of cytokine-induced responses[J]. Adv Immunol, 1999,71:145-162.
[22] Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and Stat3 in inflammation and cancer. Eur J Cancer, 2005,41(16):2502-25l2.
[23] Wegenka UM, Lutticken C, Buschmann J, et al. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (Stat) family. Mol Cell Biol, 1994,14(5):3186-3196.
[24] Lutticken C, Wegenka UM, Yuan J, et al. Association of transcription factor APRF and protein kinase Jakl with the interleukin-6 signal transducer gp130. Science, 1994,263(5143):89-92.
[25] Zhong Z, Wen Z, Darnell JE Jr. Stat3: a Stat family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 1994,264(5155):95-98.
[26] Akira S, Nishio Y, Moue M, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell, 1994,77(1):63-71.
[27] Heinrich PC, Behrmann I, Muller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J]. Biochem J, 1998,334(Pt 2):297-314.
[28] Boeuf H, Hauss C, Graeve FD, et al. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells[J]. J Cell Biol, 1997,138(6):1207-1217.
[29] Niwa H, Burdon T, Chambers I, et al. Self-renewal of pluripotent embryonic Stem cells is mediated via activation of STAT3[J]. Genes Dev, 1998,12(13):2048- 2060.
[30] Raz R, Lee CK, Cannizzaro LA, et al. Essential role of STAT3 for embryonic stem cell pluripotency[J]. Proc Natl Acad Sci USA, 1999,96(6):2846-2851.
[31] Matsuda T, Nakamura K, Nakao K, et al. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells[J]. EMBO J, 1999,18(15):4261-4269.
[32] Kisseleva T, Bhattacharya S, Braunstein J, et al. Signaling through the JAK/STAT pathway, recent advances and future challenges[J]. Gene, 2002,285(1-2): 1-24.
[33] Chung CD, Liao J, Lin B, et al. Specific inhibition of STAT3 signal transduction by PIAS3[J]. Science, 1997,278(5344): 1803-1805.
[34] Chakraborty A, Tweardy DJ. STAT3 and G-CSF-induced myeloid differentianon [J]. Leuk Lymphoma, 1998,30(5-6):433-442.
[35] Bromberg J. Stat proteins and oncogenesis[J]. J Clin Invest, 2002,109(9):1139-1142.
[36] Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular runction[J]. Oncogene, 2000,19(21):2468-2473.
[37] Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein[J]. Science, 1995,269(5520):81-83.
[38] Garcia R, Yu CL, Hudnall A, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells[J]. Cell Growth Differ,1997,8(12):1267-1276.
[39]Bromberg JF,Wrzeszczynska MH,Devgan G,et al.Stat3 as an oncogene[J].Cell,1999,98(12):295-303.
[40]Catlett-Falcone R,Landowski TH,Oshiro MM,et al.Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells[J].Immunity,1999,10(1):105-115.
[41]Grandis JR,Drenning SD.Chakraborty A,et al.Requirement of Stat3 but not Statl activation for epidermal growth factor receptor-mediated cell growth In vitro[J].J Clin Invest,1998,102(7):1385-1392.
[42]Niu G,Shain KH,Huang M,et al.Over expression of a dominant-negative signal and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest[J].Cancer Res,2001,61(8):3276-3280.
[43]Turkson J,Ryan D,Kim JS,et al.Phosphotyrosyl peptides block Stat3-mediated DNA binding activity,gene regulation and cell transformation[J].J Biol Chem,2001,276(48):45443-45455.
[44]Chen H,Ye D,Xie X,et al.VEGF,VEGFRs expressions and activated Stats in ovarian epithelial carcinoma[J].Gynecol Oncol,2004,94(3):630-635.
[45]Wang S,Evers B M.Caco-2 cell differentiation is associated with a decrease in Stat protein levels and binding[J].J Gast roentest Surg,1999,3(2):200-207.
[46]梁斌,王彬,祝学光,等.转录信号传导子和激活分子在人胃癌组织中的表达及意义[J].中华实验外科杂志,2001,18(4):313-314.
[47]杨俊波,毛志福,蔡享道.STAT3在食管鳞状细胞癌中的表达和意义[J].消化外科,2006,5(3):220-222.
[48]Oliveira C,Seruca R,Cameiro F.Genetics,pathology,and clinics of familial gastric cancer[J].Int J Surg Pathol,2006,14(1):21-33.
[49]Sijen T,Fleenor J,Simmer F,et al.On the role of RNA amplification in dsRNA-triggered gene silencing[J].Cell,2001,107(4):465-476.
[50]Vaucheret H,Beclin C,Fagard M.Post-transcriptional gene silencing in plants[J].J Cell Sci,2001,114(Pt 17):3083-3091.
[51]Parrish S,Fleenor J,Xu S,et al.Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference[J]. Mol Cell, 2000,6(5): 1077-1087.
[52] Sharp PA. RNA interference-2001[J]. Genes and development, 2001,15(5):485- 490.
[53] Zamore PD, Tuschl T, Sharp PA, et al. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals[J]. Cell, 2000,101(1) :25-33.
[54] Elbashir SM, Martinez J, Patkaniowska A, et al. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate[J]. EMBO J, 2001,20 (23) :6877-6888.
[55] Brummelkamp, T.R., Bernards, R., Agami, R. A system for stable expression of short interfering RNAs in mammalian cells[J]. Science, 2002,296(5567): 550-553.
[56] Merkle D, Douglas P, Moorhead GB, et al. The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation [J]. Biochemistry, 2002,41(42): 12706-12714.
[57] Pedroso de Lima MC, Simoes S, Pires P, et al. Cationic lipid-DNA complexes in gene delivery: from biophysics to biological applications[J]. Adv Drug Deliv Rev,2001,47(2-3):277-294.
[58] Nakanishi M, Noguchi A. Confocal and probe microscopy to study gene transfectian mediated by cationic liposomes with a cationic cholesterol derivative[J]. Adv Drug Deliv Rev, 2001,52(3):197-207.
[59] Clark PR, Hersh EM. Cationic lipid-mediated gene transfer: current concepts[J]. Curr Opin Mol Ther, 1999,1(2):158-176.
[60] Wang H, Zeng ZC, Bui TA, et al. Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group[J]. Oncogene, 2001,20(18):2212-2224.
[61] McManus M T, Haines B B, Dillon CP, et al. Small interfering RNA-mediated gene silencing in T lymphocytes[J]. J Immunol, 2002,169(10):5754-5760.
[62] Redell MS, Tweardy DJ. Targeting transcription factors for cancer therapy[J]. Curr Pharm Des, 2005,11(22):2873-2887.
[63]Bromberg J.Stat proteins and oncogenesis[J].J Clin Invest,2002,109(9):1139-1142.
[64]Buettner R,Mora LB,Jove R.Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention[J].Clin Cancer Res,2002,8(4):945-954.
[65]Niu G,Wright KL,Huang M,et al.Constitutive Stat 3 activity up-regulates VEGF expression and tumorangiogenesis[J].Oncogene,2002,21(13):2000-2008
[66]Baus D,Pfitzner E.Specific function of STAT3,SOCS1,and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma calls[J].Int J Cancer,2006,118(6):1404-1413.
[67]Konnikova L,Kotecki M,Kruger MM,et al.Knockdown of Stat3 expression by RNAi induces apoptosis in astrocytoma cells[J].BMC Cancer,2003,3:23.
[68]Ling X,Arlinghaus RB.Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice[J].Cancer Res,2005,65(7):2532-2536.
[69]Peschos D,Tsanou E,Stefanou D,et al.Expression of cyclin-dependent kinases inhibitors p21(WAF1)and p27(KIP1)in benign,premalignant and malignant laryngeal lesions.correlation with cell cycle regulatory proteins[J].In vivo,2004,18(6):719-724.
[70]Coats S,Flanagan WM,Nourse J,et al.Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle[J].Science,1996,272(5263):877-880.
[71]Elledge SJ,Winston J,Harper JW.A question of balance:the role of cyclin-kinase inhibitors in development and tumorigenesis[J].Trends Cell Biol,1996,6(10):388-392.
[72]金成一,李学峰,郭春沅.细胞周期调控的分子机制[J].延边大学农学学报,2000,22(2):147-150.
[73]Li Z,Wang C,Prendergast G,et al.Cyclin D1 Functions in Cell Migration[J].Cell Cycle,2006,5(21):2440-2442.
[74]Michalides R,van Veelen N,Hart A,et al.Overexpression of cyclin D1correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck[J].Cancer Res,1995,55(5):975-978.
[75] van Diest PJ, Michalides RJ, Jannink L, et al. Cyclin D1 expression in invasive breast cancer. Correlations and prognostic value[J]. Am J Pathol, 1997,150(2): 705-711.
[76] Zhou P, Jiang W, Zhang Y J, et al. Antisense to cyclin Dl inhibits growth and reverses the transformed phenotype of human esophageal cancer cells[J]. Oncogene, 1995,11(3):571-580.
[77] Sherr CJ. Cancer cell cycles[J]. Science, 1996,274(5293): 1672-1677.
[78] Wu W, Slomovitz BM, Soliman PT, et al. Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma[J]. Int J Gynecol Cancer, 2006,16(4): 1668-1672.
[79] Namazie A, Alavi S, Olopade OI, et al. Cyclin Dl amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors[J]. Laryngoscope, 2002,112(3):472-481.
[80] Jiang W, Kahn SM, Tomita N, et al. Amplification and expression of the human Cyclin D gene in esophageal cancer[J]. Cancer Res, 1992,52(10):2980-2983.
[81] Wang LD, Shi ST, Zhou Q, et al. Changes in p53 and Cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis[J]. Int J Cancer, 1994,59(4):514-519.
[82] Bahnassy AA, Zekri AR, El-Houssini S, et al. Cyclin A and cyclinDl as significant prognostic markers in colorectal cancer patients[J]. Gastroenterol, 2004, 4(1):22-29.
[83] Masuda M, Suzui M, Yasumalu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J]. Cancer Res, 2002,62(12):3351-3355.
[84] Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene[J]. Cell, 1999,98(3):295-303.
[85] Frank DA, Mahajan S, Ritz JB. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues[J]. J Clin Investig, 1997,100(12):3140-3148.
[86]Decker,T.,Stockinger,S.,Karaghiosoff,M.,et al.Interferons and Stats in innate immunity to microorganisms[J].J Clin Invest,2002,109(10):1271-1277.
[87]Udy GB,Tower RP,Snell RG,et al.Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression[J].Proc Natl Acad Sci U S A,1997,94(14):7239-7244.
[88]Teglund S,Mckay C,Schuetz E,et al.Stat5a and stat5b proteins have essencial and nonessential or redundant,role in cytokine responses[J].Cell,1998,93(5):841-850.
[89]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Star3 gene leads to early embryonic lethality[J].Proc Natl Acad Sci U S A,1997,94(8):3801-3804.
[90]Raz,R.,Durbin,J.E.,Levy,D.E.Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines,interferons,and growth factors[J].J Biol Chem,1994,269(39):24391-24395.
[91]Stev A,Benjamin B.Rituximab inactivates signal transducer and activation of transcription 3(STAT3)activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs[J].Cancer Re,2001,61(13):5137-5144..
[92]Gao LF,Xu DQ,Wen LJ,et al.Inhibition of STAT3 expression by siRNA suppresses groth and induces apoptosis in laryngeal cancercells[J].Acta Pharmacol Sin,2005,26(3):377-383.
[93]Boise LH,Gonzalez-Garcia M,Postema CE,et al.Bcl-x,a bcl-2 related gene that functions as a dominant regulator of apoptosis cell death[J].Cell,1993,74(4):597-608.
[94]Sierra A,Castellsague X,Coll T,et al.Expression of death-related gene and their relationship to loss of apoptosis in T1 ductal breast carcinomas[J].Br J Cancer,1998,79(2):103-110.
[95]陈燕,周剑锋,乐蓓蓓等.bcl-2基因及其家族bax,bcl-x1和Fas/APO-1,P16的检测在急性白血病中的临床意义[J].癌症,1998,17(5):352-355.
[96] Pan G,O' , Rourke K, Dixit VM, et al. Caspase-9, Bcl-xL, and Apaf-1 form a ternary complex[J]. J Biol Chem, 1998,273(10):5841-5845.
[97] Cory S, Huang DC, Adams JM. The Bcl-2 family:roles in cell survival and oncogenesis[J]. Oncogene, 2003,22(53):8590-8607.
[98] Oshiro MM, Landowski TH, Catlett Falcone R, et al. Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells[J]. Clin Cancer Res, 2001,7(12):4262-4271.
[99] Xi S, Gooding WE, Grandis JR, et al. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy[J]. Oncogene, 2005,24(6):970-979.
[100] Johnson AL. Mcl-1-just another antiapoptotic Bcl-2 Homolog[J]? Endocrinology, 1999,140(12):5465-5468.
[101] Opfeman J T, Letai A, Beard C, et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1[J]. Nature, 2003,426(6967):671-676.
[102] Michels J, O Neill JW, DallmanCL, et al. Mcl-1 is required forAkata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage[J]. Oncogene, 2004,23(28): 4818-4827.
[103] Derenne S, Monia B, DeanNM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(1) is an essential survival protein of human myeloma cells[J]. Blood, 2002,100(1):194-199.
[104] Moulding DA, Giles RV, Spiller DG, et al. A poptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells[J]. Blood, 2000,96(5):1756-1763.
[105] Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-lexpression[J]. J Clin Invest, 2001,107(3):351-362.
[106] Gritsko T, Williams A, Turkson J, et al. Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells[J]. Clin Cancer Res, 2006,12(1):11-19.
[107]Sun C,Nettesheim D,Liu Z,et al.Solution structure of human survivin and its binding interface with Smac/Diablo[J].Biochemistry,2005,44(1):11-17.
[108]Carvalho A,Carmena M,Sambade C,et al.Survivin is required for stable checkpoint activation in taxol-treatcd HeLa cells[J].J Cell Sci,2003,116(Pt 14):2987-2998.
[109]Konnikova L,Kotecki M,Kruger MM,et al.Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells[J].BMC Cancer,2003,3:23.
[110]魏康.细胞受照射后死亡的分子机理[A].见夏寿首.分子放射生物学[M].北京:原子能出版社,1992:342.
[111]Desai,Arshad,Rogers,et al.Cell biology[J].Current Opinion in Cell Biology,2002,14(6):661-671.
[112]Reis T,Edgar BA.Negative Regulation of dE2F1 by Cyclin-Dependent Kinases Controls Cell Cycle Timing[J].Cell,2004,117(2):253-264.
[113]Shireen H K,Goodffrey M.p53 and pRb prevent replication in response to microtubule inhibitors by mediating a reversible G_1 arrest[J].Cancer research,1998,58(3):396-401.
[114]Hermeking H,Lengauer C,Polyak K,et al.14-3-3 is a p53-regulated inhibitor of G_2/M progression[J].Mol Cell,1997,1(1):3-11.
[115]Fasullo M,Bennett T,AhChing P.The saccharomyces cerevisiae RAD9checkpoint reduces the DNA damage associated stimulation of directed translocation[J].Mol Cell Biol,1998,18(3):1190-2000.
[116]Biade S,Stobbe CC,Chapman JD.The instrinsic radiosensitivity of some tumor cells through their cell cycle[J].Radiation Res,1997,147(4):416-421.
[117]张孟贤,于世英.宫颈癌细胞周期阻滞和凋亡与放射敏感性的关系[J].中华放射肿瘤学杂志,2002,11(2):116-117.
[118]Hui ZG,Li YX,Yang WZ,et al.Abrogation of radiation-induced G2 arrest and radiosensitization by 7-hydroxystaurosporine(UCN-01)in human nasopharyngeal carcinoma cell line[J].Ai Zheng,2003,22(1):6-10.
[119]Bernhard EJ,McKenna WG,Muschel RJ.Cyclin expression and G2-phase delay after irradiation[J].Radiat Res,1994,138(1 Suppl):S64-67.
[120]夏景光,李文建,魏巍,等.电离辐射对不同肿瘤细胞细胞周期进程的影 响[J]. 辐射研究与辐射工艺学报, 2005, 23 (2) : 91.
[121] Logsdon MD, Meyn REJr, Besa PC, et al. Apoptosis and the bcl-2 family-patterns of expression and prognostic value in stage I and II follicular center lymphoma[J]. Int J Radiat Oncol Biol Phys, 1999,44(1) :19-29.
[122] Dubray B, Breton C, Delic J, et al. In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas[J]. Radiother Oncol, 1998,46(2):185-191.
[123] Shinomiya N. New concepts in radiation-induced apoptosis: 'premitotic apoptosis'and 'postmitotic apoptosis'[J]. J Cell Mol Med, 2001,5(3):240-253.
[124] Blank KR, Rudoltz MS, Kao GD, et al. The molecular regulation of apoptosis and implications for radiation oncology[J]. Int J Radiat Biol, 1997,71(5):455- 466.
[125] Stephens LC , Hunter NR, Ang KK, et al. Development of apoptosis in irradiated murine tumors as a function of time and dose[J]. Radiat Res, 1993,135(1):75-80.
[126] Akagi Y, Ito K, Sawada S. Radiation-induced apoptosis and necrosis in Molt-4 cells: a study of dose-effect relationships and their modification[J]. Int J Radiat Biol, 1993,64(1):47-56.
[127] Ling CC, Chen CH, Li WX. Apoptosis induced at different dose rates: implication for the shoulder region of cell survival curves[J]. Radiother Oncol, 1994,32(2): 129-136.
[128] Takahashi T, Mitsuhashi N, Furuta M, et al. Apoptosis induced by heavy ion (carbon) irradiation of two human tumours with different radiosensitivities in vivo: relative biological effectiveness (RBE) of carbon beam[J]. Anticancer Res, 1998,18(1A):253-256.
[129] Dubray B, Breton C, Delic J, et al. In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas[J]. Radiother Oncol, 1998,46(2): 185-191.
[130] Lang FF, Yung W K, Raju U , et al. Enhancement of radiosensitivity of wild-type p53 human glioma cells by Adenovirus-mediated delivery of the p53 gene [J]. J Neurosurg, 1998, 89 (1) :125-132.
[131]Olive PL,Banh JP,Durand RE.Development of apoptosis and polyploidy in human lymphoblast cells as a function of position in the cell cycle at the time of irradit ion[J].Radiat Res,1996,146(6):595-602.
[132]Chapman JD,et al.Condensed chromatin and cell inactivation by single-hit kinetics[J].Radiat Res,1999,(514):433-441.
[133]Cory S,Huang DC,Adams JM.The bcl-2 family:roles in cell survival and oncogenesis[J].Oncogene,2003,22(53):8590-8607.
[134]Rosse T,Olivier R,Monney L,et al.Bcl-2 prolongs cell survival after bax-induced release of cytochrome C[J].Nature,1998,391(6666):496-499.
[135]Findly HW,Gu L,Meager AM,et al.Expression and regulation of Bcl-2,Bcl-x1 and Bax correlate with P53 stares and sensitivity to apotosis in childhood acute lymphoblastic leukemia[J].Blood.1997.89(8):2986-2993.
[136]李惠翔,王尧河,石永刚,等.凋亡相关基因与食管鳞状细胞癌放射敏感性相关关系的研究[J].中华放射医学与防护杂志,2000,20(6):411-413.
[137]黄闻,陈茂怀,吴名耀,等.Bcl-2和bax蛋白表达与鼻咽癌放射敏感性相关关系的探讨[J].中国肿瘤临床,2004,31(18):1051-1053.
[138]宋晖,辛晓燕,肖锋,等.survivin基因RNA干涉对宫颈癌细胞凋亡和放射敏感性的影响[J].肿瘤,2006,26(8):732-737.
[139]Ikeguchi M,Yamaguchi K,Kaibara N.Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor(hOT7T175)gene expression in esophageal squamous cell carcinoma[J].Clin Cancer Res,2004,10(4):1379-1383.
[140]仇晓军,陆德炎,季斌,等.放射诱导胃癌细胞的凋亡及其相关基因的研究[J].中华放射肿瘤学杂志,2005,14(5):447-450.
[141]郑瑛,周昌龙,李旭奎,等.单次不同X线剂量照射对SACC-83细胞的放射生物学效应[J].现代肿瘤医学,2005,13(1)26-29.
[142]买世娟,宗永生,熊敏,等.胸腺癌中p53蛋白表达对癌细胞增殖和凋亡的影响[J].癌症,2000,19(9):864-867.
[143]Carmichael J,DeGraff WG,Gazdar AF,et al.Evaluation of a tetrazolium-based semiautomated colorimetric assay:assessment of chemosensitivity testing[J].Cancer Res,1987,47(4):936-942.
[144] Fertil B, Malaise EP. Intrisicradiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves[J]. Int J Radiat Oncol Bio Phys, 1985,11(9): 1699-1707.
[145] Gaussen A, Legal JD, Beron Gaillard N, et al. Radiosensitivity of human normal and tumoralthyroid cells using fluorescence in situ hybridization and clonogenic survival assay[J]. Int J Radiat Oncol Biol Phys,1999,44(3):683-691.
[146] West CML, Dvidson SE, Roberts SA, et al. The independence of intrinsic radiosensitivity as prognostic factor for patient response to radiotherapy of carcinoma of the cervix[J]. Br J Cancer, 1997,76(9): 1184-1190.
[147] Roth J A, Cristiano RJ. Gene therapy for cancer: what have we done and where are we doing?[J]. J Natl Cancer Inst, 1997, 89(1):21-39.
[1]Hoey T,Grusby MJ.STATs as mediators of cytokine-induced responses[J].Adv Immunol,1999,71:145-162.
[2]Leonard WJ.Role of Jak kinases and STATs in cytokine signal transduction[J].Int J Hematol,2001,73(3):271-277.
[3]Igaz P,Toth S,Falus A.Biological and clinical significance of the JAK-STAT pathway;lessons from knockout mice[J].Inflamm Res,2001,50(9):435-441.
[4]Takeda K,Noguchi K,Shi W,et al.Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality[J].Proc Natl Acad Sci USA,1997,94(8):3801-3804.
[5]Akira S,NishioY,Inoue M,et al.Molecular cloning of APRF,a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway[J].Cell,1994,77(1):63-71.
[6]Lutticken C,Wegenka UM,Yuan J,et al.Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130[J].Science,1994,263(5143):89-92.
[7]Zhong Z,Wen Z,Darnell JE.Stat3 and Stat4:members of the family of signal transducers and activators of transcription[J].Proc Natl Acad Sci USA,1994,91(11):4806-4810.
[8]Raz R,Durbin JE,Levy DE.Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines,interferons,and growth factors[J].J Biol Chem,1994,269(39):24391-24395.
[9]Takeda K,Clausen BE,Kaisho T,et al.Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils[J].Immunity,1999,10(1):39-49.
[10]Chakraborty A,Dyer KF,Cascio M,et al.Identification of a novel Stat3recruitment and activation motif within the granulocyte colony-stimulating factor receptor[J].Blood,1999,93(1):15-24.
[11]Darnell JE.STATs and gene regulation[J].Science,1997,277(5332):1630-1635.
[12]Heinrich PC,Behrmann Ⅰ,Muller-Newen G,et al.Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J].Biochem J,1998,334(Pt 2):297-314.
[13]Boeuf H,Hauss C,Graeve FD,et al.Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells[J].J Cell Biol,1997,138(6):1207-1217.
[14]Niwa H,Burdon T,Chambers I,et al.Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3[J].Genes Dev,1998,12(13):2048-2060.
[15]Raz R,Lee CK,Cannizzaro LA,et al.Essential role of STAT3 for embryonic stem cell pluripotency[J].Proc Natl Acad Sci USA,1999,96(6):2846-2851.
[16]Matsuda T,Nakamura K,Nakao K,et al.STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells[J].EMBO J,1999,18(15):4261-4269.
[17]Kisseleva T,Bhattacharya S,Braunstein J,et al.Signaling through the JAK/STAT pathway,recent advances and future challenges[J].Gene,2002,285(1-2):1-24.
[18]Ihle JN.The Stat family in cytokine signaling[J].Curr Opin Cell Biol,2001,13(2):211-217.
[19]叶中德,沈倍奋,黎燕.STAT3入核的核定位序列研究[J].生物化学与生物物理进展,2004,31(1):32-35.
[20] Chakraborty A, Tweardy DJ. STAT3 and G-CSF-induced myeloid differentianon[J]. Leuk Lymphoma, 1998,30(5-6):433-442.
[21] Bromberg J. Stat proteins and oncogenesis[J]. J Clin Invest, 2002,109(9):1139-1142.
[22] Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function[J]. Oncogene, 2000,19(21):2468-2473.
[23] Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact[J]. Nat Rev Mol Cell Biol, 2002,3(9):651-662.
[24] Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein[J]. Science, 1995,269(5520):81-83.
[25] Garcia R, Yu CL, Hudnall A, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells[J]. Cell Growth Differ, 1997,8(12): 1267-1276.
[26] Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene[J]. Cell, 1999,98(12):295-303.
[27] Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells[J]. Immunity, 1999,10(1): 105-115.
[28] Grandis JR, Drenning SD. Chakraborty A, et al. Requirement of Stat3 but not Statl activation for epidermal growth factor receptor-mediated cell growth In vitro[J]. J Clin Invest, 1998,102(7):1385-1392.
[29] Lou W, Ni Z, Dyer K, et al. Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway[J]. Prostate, 2000,42(3):239-242.
[30] Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate.cancer cells[J]. Cancer Res, 2002,62(22):6659-6666.
[31] Song JI, Grandis JR, LM. Stat signaling in head and neck cancer[J]. Oncogene, 2000,19(21):2489-2495.
[32] Cory S, Adams JM. Regulators of the cellular life-or-death switch[J]. Nat Rev Cancer, 2002,2(9):647-656.
[33] Burke WM, Jin X, Lin HJ, et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells[J]. Oncogene, 2001,20(55):7925-7934.
[34] Grandis JR., Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo[J]. Proc Natl Acad Sci USA, 2000,97(8):4227-4232.
[35] Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-lexpression[J]. J Clin Invest, 2001,107(3):351-362.
[36] Gritsko T, Williams A, Turkson J, et al. Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res, 2006,12(1): 11-19.
[37] Altieri DC. Validating survivin as a cancer therapeutic target[J]. Nat Rev Cancer, 2003,3(1):46-54.
[38] Raman V, Martensen SA, Reisman D, et al. Compromised HOXAS function can limit p53 expression in human breast tumours[J]. Nature, 2000,405(6789):974-978.
[39] Schmidt EV. The role of c-myc in regulation of translation initiation[J]. Oncogene, 2004, 23(18):3217-21.
[40] Bowman T, Broome MA, Sinibaldi D, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis[J]. Proc Natl Acad Sci, 2001,98(13):7319-7324.
[41] Kijima T, Niwa H, Steinman RA, et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo[J]. Cell Growth Differ, 2002,13(8):355-362.
[42] Masuda M, Suzui M, Yasumatu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma[J]. Cancer Res, 2002,62(12):3351-3355.
[43] Sinibaldi D, Wharton W, Turkson J, et al. Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated Stat3 signaling[J]. Oncogene, 2000,19(48):5419-5427.
[44] Plate KH, Breier G, Weich HA, et al. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo[J]. Nature, 1992,359(6398):845-848.
[45] Veikkola T, Karkkainen M, Claesson-Welsh L, et al. Regulation of angiogenesis via vascular endothelial growth factor receptors[J]. Cancer Res, 2000,60(2):203-212.
[46] Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis[J]. Oncogene, 2002,21(13):2000-2008.
[47] Wei LH, Kuo ML, Chen CA, et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway[J]. Oncogene, 2003,22(10): 1517-1527.
[48] Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentially activates STAT3 in microvascular endothelial cells[J]. FASEB J, 2003,17(11):1562-1564.
[49] Yahata Y, Shirakata Y, Tokumaru S, et al. Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation[J]. J Biol Chem, 2003,278(41):40026-40031.
[50] Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis[J]. Oncogene, 2004,23(20):3550-3560.
[51] Wang T, Niu G Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells[J]. Nat Med, 2004,10(1):48-54.
[52] Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity[J]. Proc Natl Acad Sci USA, 2003,100(4): 1879-1884.
[53] Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses[J]. Cancer Res, 2003,63(9):2150-2157.
[54]Cheng F,Wang HW,Cuenca A,et al.A critical role for Star3 signaling in immune tolerance[J].Immunity,2003,19(3):425-436.
[55]Galderisi U,Cascino A,Giordano A,et al.Antisense oligonucleotide as therapeutic agents[J].J Cell Physiol,1999,181(2):251-257.
[56]Leong PL,Andrews GA,Johnson DE,et al.Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth[J].Proc Natl Acad Sci USA,2003,100(7):4138-4143.
[57]Huang JS,Guh JY,Hung WC,et al.Role of the Janus kinase(JAK)/signal transducters and activators of transcription(STAT)cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells[J].Biochem J,1999,342(Pt):231-238.
[58]Lee SO,Lou W,Qureshi KM,et al.RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells[J].Prostate,2004,60(4):303-309.
[59]王禹,张颖超,潘玉琢,等.应用沉默3基因促裸鼠移植瘤细胞凋亡及对/22基因表达的影响[J].中国普通外科杂志,2005,14(4):273-276.
[60]Smithgall TE,Briggs SD,Schreiner S,et al.Control of myeloid differentiation and survival by Stats[J].Oncogene,2000,19(21):2612-2618.
[61]Niu G,Shain KH,Huan M,et al.Overexpression of a dominant-negative signal transducer and activator transcription 3 variant tumor cells leads to production soluble factors that induce apoptosis and cell cycle arrest[J].Cancer Res,2001,61(8):3276-3280.
[62]Burdelya L,Catlett-Falcone R,Levitzki A,et al.Combination therapy with AG-490and interleukin 12 achieves greater antitumor effects than either agent alone[J].Mol Cancer Ther,2002,1(1):893-899.
[63]Shuai K.Modulation of STAT signaling by STAT-interacting proteins[J].Oncogene,2000,19(21):2638-2644.
[64]Valentino L,Pierre J.JAK/STAT signal transduction:regulators and implication in hematological malignancies[J].Biochem Pharmacol,2006,71(6):713-721.
[65]Woetmann A,Nielsen M,Christensen ST,et al.Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation,subcellular redistribution,and functional inhibition of STAT3[J].Proc Natl Acad Sci USA,1999,96(19):10620-10625.
[66]Yu CL,Jin YJ,Burakoff SJ.Cytosolic tyrosine dephosphorylation of STAT5.Potential role of SHP-2 in STAT5 regulation.[J].J Biol Chem,2000,275(1):599-604.
[67]Bowman T,Garcia R,Turkson J,et al.STATs in ongenesis[J].Oncogene,2000,9(21):2474-2488.