干扰XIAP基因联合5-FU对人胆管癌裸鼠移植瘤的影响及增强化疗敏感性的研究
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摘要
目的：通过把X连锁凋亡抑制蛋白(X-chromosome-linked inhibitor of apoptosis,XIAP)基因的反义寡核苷酸(Antisense Oligodeoxynucleotide,ASODN)转染入人胆管癌QBC939裸鼠移植瘤细胞中,探讨ASODN对人胆管癌裸鼠移植瘤细胞中XIAP基因的抑制作用及对癌细胞增殖及凋亡的影响；观察反义寡核苷酸抑制XIAP基因表达后胆管癌细胞对化疗药物氟尿嘧啶(5-FU)敏感性的影响。方法：将处于对数期的QBC939细胞种植于裸鼠左前肢腋下,每只0.2m1(4×107).待模型建立(5mm×5mm)以后随机分为5组：Control组、Lip组、5-FU组、ASODN/Lip组和ASODN/Lip-5FU组分别给予瘤周或瘤体直接注射细胞转染液(无血清无抗生素)600u1、浓度为10g/ml的Lip100μ1加细胞转染液至600u1、细胞转染液600u1、终浓度为1μM的ASODN和浓度为10μg/ml的Lip100μ1加转染液至600μ1与终浓度为1μM的ASODN和浓度为10μg/ml的Lip100μ1加转染液至600μ1进行转染,以后每周1次,共4次。转染后的第1、3、5天开始给予相关组腹腔注射5-FU10mg/Kg,其他组腹腔注射等量的生理盐水。观察肿瘤体积的变化及裸鼠体重变化,计算抑瘤率。4周后处死裸鼠,取肿瘤组织行RT-PCR检测XIAP基因mRNA表达情况,取肿瘤组织制成的细胞悬液行流式细胞术(FCM)检测细胞周期及凋亡情况,其余肿瘤组织行病理确认、免疫组织化学检测XIAP、PCNA蛋白表达及TUNEL原位凋亡检测,并计算细胞增殖指数及凋亡指数。
结果：成功的建立了人胆管癌裸鼠皮下移植瘤模型。采用阳离子脂质体转染技术成功将ASODN转染入裸鼠体内QBC939细胞中。大体标本显示ASODN-Lip组及ASODN/Lip-5FU组的肿瘤生长受到抑制,体积较小,抑瘤率达54.55%和65.00%明显高于其他三组,差异有显著性(P<0.05)；而Control组、Lip组和5-FU组肿瘤体积逐渐增加；各组瘤体组织重量亦有显著差异((P<0.05),ASODN/Lip-5FU组及ASODN/Lip组重量抑瘤率分别为60.60%、39.02%,差异有显著性(P<0.05)；各组裸鼠体重变化无统计学意义。RT-PCR结果示ASODN/Lip组及ASODN/Lip-5FU组肿瘤的XIAP mRNA表达较其他组明显降低,差异有统计学意义(P<0.05)。流式细胞术表明ASODN/Lip组和ASODN/Lip-5FU组瘤体细胞均出现了代表凋亡的亚G_1峰(15.11±2.25)%、(60.36±2.17)%,且Go/G1期细胞均高于对照组,差异有统计学意义(P<0.05)。免疫组化结果示转染ASODN后ASODN/Lip-5FU组与ASODN/Lip组XIAP蛋白阳性表达率为(27.83±4.97)%、(31.62±6.85)%明显低于对照组(62.54±8.32)%,差异有统计学意义(P<0.05)。PCNA免疫组化显示联合化疗组增殖指数明显低于对照组,差异有统计学意义(P<0.05)。TUNEL结果示ASODN/Lip-5FU组、ASODN/Lip组与5-FU组凋亡指数分别为(18.93±0.21)%、(10.19±0.24)%、(10.22±0.18)%,与对照组比较差异有统计学意义(P<0.05),ASODN/Lip-5FU组与5-FU组间也有统计学意义(P<0.05)。
结论：转染ASODN能有效下调人胆管癌QBC939裸鼠移植瘤细胞XIAP基因表达,通过ASODN干扰XIAP基因关键区域能有效抑制胆管癌细胞的增殖并诱导其凋亡,从而抑制肿瘤瘤体生长；同时抑制XIAP基因的表达能显著增强胆管癌细胞对化疗药物5-FU的敏感性,可能为胆管癌基因治疗提供新途径。
Objective:Through transfected antisense oligonucleotide of x linked inhibitor of apoptosis protein into transplanted human cholangiocarcinoma QBC939 cells in nude mice by cationic liposomes, to explore the effect of ASODN on human cholangiocarcinoma cells inhibition of XIAP gene in nude mice, proliferation and induced apoptosis of cancer cells;To observate the sensitivity of cholangiocarcinoma cells to chemotherapeutical drugs fluorouracil(5-FU) after the expression of antisense oligonucleotides inhibit XIAP gene.
Methods:planted the cells of the proliferative logarithmic phase of QBC939 into the area of left forlimb armpit of nude mice,each 0.2m1(4 X 10~7). after 10 days constructed tumor model(5mm X 5mm),the mice were divided into 5 groups randomly:control group、liposomes (lip) group、5-FU group、ASODN/lip group and ASODN/lip5-FU group. Each group were injected transfer dye liquid 600μl (serum without antibiotics)、Lip 10μg/ml 100μl add transfer liquid to 600μl、transfer dye liquid 600μl、ASODN/Lip final concentration 1μM+Lipfectin 10μg/ml 100μl add transfer liquid to 600μl and ASODN/Lip final concentration 1μM+Lipfectin lOμg/ml 100μl add transfer liquid to 600μl into the tumor or around the tumor, respectively.4 times injections were given,one time per week. Each related group injected 5-FU 1Omg/Kg on the first、third、fifth day after transferred,the other group were injected normal saline. mice were killed after 4 weeks.The expression of XIAP mRNA was determined by RT-PCR; Apoptosis and cells cycle changes were determined by flow cytometry.Immunohistochemical SP staining method were used to detect the expression of XIAP and PCNA protein, TUNEL in situ apoptosis. Cell proliferation index and apoptosis index.were calculated.
Results:The subcutaneous tumor model in nude mice was successfully established. Using cationic liposome transfected ASODN into nude mice successfully. Gross specimen shows the tumor volume of ASODN/Lip and ASODN/Lip-5FU decreased during treatment, the rate of tumor suppression reached 54.55% and 65.00%,which were significantly increased in the group of ASODN/Lip and ASODN/Lip-5FU compared with other 3 groups(p< 0.05);while the tumor volume of the other three groups increase.The weight of tumor were significantly different in each group(p< 0.05). The inhibition rates of tumor weight were 60.60%、39.02% in the group of ASODN/Lip-5FU and ASODN/Lip respectively, the different was significant(p< 0.05).There are no statistical difference among the groups in body weight changes of 5 groups mice. RT-PCR results show that the expression of XIAP mRNA decreased significangtly in ASODN/Lip and ASODN/Lip-5FU than other groups(P<0.05). Flow cytometry showed that ASODN/Lip group and ASODN/Lip-5FU group QBC939 cells were found to represent the sub-G_1 apoptotic peak (15.11±2.25)%, (60.36±2.17)%, and the Go/G_1 phase cells was higher than control group, the difference was significant (P<0.05). Immunohistochemical results showed after transfection ASODN, ASODN/Lip-5FU group and ASODN/Lip group XIAP protein expression was (27.83±4.97)%、(31.62±6.85)%, significantly lower than the control group (62.54±8.32)%.The difference was statistically significant (P <0.05). PCNA immunohistochemistry showed the proliferation index of the transfection ASODN and combined 5-FU group was significantly lower than the control group, the difference was statistically significant (P<0.05). TUNEL results showed that the apoptosis index of ASODN/Lip-5FU group, ASODN/Lip group and 5-FU group were (18.93±0.21)%、(10.19±0.24)%、(10.22±0.18)%, compared with the control group the differences were statistically significant (P <0.05),ASODN/Lip-5FU group and 5-FU group were statistically. significant(P <0.05).
Conlusion:The liposomal transfection of ASODN can down-regulate the expression of XIAP gene,Which can inhibit cells growth and induce apoptosis of transplanted cholangiocarcinoma QBC939 cells in nude mice, and increase the chemotherapeutic sensitivity of transplanted cholangiocarcinoma cells of QBC939 after XIAP inhibition. So it may be the new target for gene therapy in cholangiocarcinoma.
结果：成功的建立了人胆管癌裸鼠皮下移植瘤模型。采用阳离子脂质体转染技术成功将ASODN转染入裸鼠体内QBC939细胞中。大体标本显示ASODN-Lip组及ASODN/Lip-5FU组的肿瘤生长受到抑制,体积较小,抑瘤率达54.55%和65.00%明显高于其他三组,差异有显著性(P<0.05)；而Control组、Lip组和5-FU组肿瘤体积逐渐增加；各组瘤体组织重量亦有显著差异((P<0.05),ASODN/Lip-5FU组及ASODN/Lip组重量抑瘤率分别为60.60%、39.02%,差异有显著性(P<0.05)；各组裸鼠体重变化无统计学意义。RT-PCR结果示ASODN/Lip组及ASODN/Lip-5FU组肿瘤的XIAP mRNA表达较其他组明显降低,差异有统计学意义(P<0.05)。流式细胞术表明ASODN/Lip组和ASODN/Lip-5FU组瘤体细胞均出现了代表凋亡的亚G_1峰(15.11±2.25)%、(60.36±2.17)%,且Go/G1期细胞均高于对照组,差异有统计学意义(P<0.05)。免疫组化结果示转染ASODN后ASODN/Lip-5FU组与ASODN/Lip组XIAP蛋白阳性表达率为(27.83±4.97)%、(31.62±6.85)%明显低于对照组(62.54±8.32)%,差异有统计学意义(P<0.05)。PCNA免疫组化显示联合化疗组增殖指数明显低于对照组,差异有统计学意义(P<0.05)。TUNEL结果示ASODN/Lip-5FU组、ASODN/Lip组与5-FU组凋亡指数分别为(18.93±0.21)%、(10.19±0.24)%、(10.22±0.18)%,与对照组比较差异有统计学意义(P<0.05),ASODN/Lip-5FU组与5-FU组间也有统计学意义(P<0.05)。
结论：转染ASODN能有效下调人胆管癌QBC939裸鼠移植瘤细胞XIAP基因表达,通过ASODN干扰XIAP基因关键区域能有效抑制胆管癌细胞的增殖并诱导其凋亡,从而抑制肿瘤瘤体生长；同时抑制XIAP基因的表达能显著增强胆管癌细胞对化疗药物5-FU的敏感性,可能为胆管癌基因治疗提供新途径。
Objective:Through transfected antisense oligonucleotide of x linked inhibitor of apoptosis protein into transplanted human cholangiocarcinoma QBC939 cells in nude mice by cationic liposomes, to explore the effect of ASODN on human cholangiocarcinoma cells inhibition of XIAP gene in nude mice, proliferation and induced apoptosis of cancer cells;To observate the sensitivity of cholangiocarcinoma cells to chemotherapeutical drugs fluorouracil(5-FU) after the expression of antisense oligonucleotides inhibit XIAP gene.
Methods:planted the cells of the proliferative logarithmic phase of QBC939 into the area of left forlimb armpit of nude mice,each 0.2m1(4 X 10~7). after 10 days constructed tumor model(5mm X 5mm),the mice were divided into 5 groups randomly:control group、liposomes (lip) group、5-FU group、ASODN/lip group and ASODN/lip5-FU group. Each group were injected transfer dye liquid 600μl (serum without antibiotics)、Lip 10μg/ml 100μl add transfer liquid to 600μl、transfer dye liquid 600μl、ASODN/Lip final concentration 1μM+Lipfectin 10μg/ml 100μl add transfer liquid to 600μl and ASODN/Lip final concentration 1μM+Lipfectin lOμg/ml 100μl add transfer liquid to 600μl into the tumor or around the tumor, respectively.4 times injections were given,one time per week. Each related group injected 5-FU 1Omg/Kg on the first、third、fifth day after transferred,the other group were injected normal saline. mice were killed after 4 weeks.The expression of XIAP mRNA was determined by RT-PCR; Apoptosis and cells cycle changes were determined by flow cytometry.Immunohistochemical SP staining method were used to detect the expression of XIAP and PCNA protein, TUNEL in situ apoptosis. Cell proliferation index and apoptosis index.were calculated.
Results:The subcutaneous tumor model in nude mice was successfully established. Using cationic liposome transfected ASODN into nude mice successfully. Gross specimen shows the tumor volume of ASODN/Lip and ASODN/Lip-5FU decreased during treatment, the rate of tumor suppression reached 54.55% and 65.00%,which were significantly increased in the group of ASODN/Lip and ASODN/Lip-5FU compared with other 3 groups(p< 0.05);while the tumor volume of the other three groups increase.The weight of tumor were significantly different in each group(p< 0.05). The inhibition rates of tumor weight were 60.60%、39.02% in the group of ASODN/Lip-5FU and ASODN/Lip respectively, the different was significant(p< 0.05).There are no statistical difference among the groups in body weight changes of 5 groups mice. RT-PCR results show that the expression of XIAP mRNA decreased significangtly in ASODN/Lip and ASODN/Lip-5FU than other groups(P<0.05). Flow cytometry showed that ASODN/Lip group and ASODN/Lip-5FU group QBC939 cells were found to represent the sub-G_1 apoptotic peak (15.11±2.25)%, (60.36±2.17)%, and the Go/G_1 phase cells was higher than control group, the difference was significant (P<0.05). Immunohistochemical results showed after transfection ASODN, ASODN/Lip-5FU group and ASODN/Lip group XIAP protein expression was (27.83±4.97)%、(31.62±6.85)%, significantly lower than the control group (62.54±8.32)%.The difference was statistically significant (P <0.05). PCNA immunohistochemistry showed the proliferation index of the transfection ASODN and combined 5-FU group was significantly lower than the control group, the difference was statistically significant (P<0.05). TUNEL results showed that the apoptosis index of ASODN/Lip-5FU group, ASODN/Lip group and 5-FU group were (18.93±0.21)%、(10.19±0.24)%、(10.22±0.18)%, compared with the control group the differences were statistically significant (P <0.05),ASODN/Lip-5FU group and 5-FU group were statistically. significant(P <0.05).
Conlusion:The liposomal transfection of ASODN can down-regulate the expression of XIAP gene,Which can inhibit cells growth and induce apoptosis of transplanted cholangiocarcinoma QBC939 cells in nude mice, and increase the chemotherapeutic sensitivity of transplanted cholangiocarcinoma cells of QBC939 after XIAP inhibition. So it may be the new target for gene therapy in cholangiocarcinoma.
引文
【1】周永昌,郭万学主编,超声医学第二版,北京科学技术出版社,1994,6.
【2】 Menias CO,Surabhi VR,Prasad SR,et al. Mimics of cholangiocarcinoma:spectrum of disease [J]. Radiographics.2008,(28)4:1115-1129.
【3】 Malhi H, Gores GJ. Cholangiocarcinoma:modern advances in understanding a deadly old disease [J]. J Hepatol,2006,45(6):856-867.
【4】 Chaudhary PM, Roninson IB. Activation of MDRI (P-glycoprotein) gene expression in human cells by protein kinase C agonists[J]. Oncol Res,1992,4(7):281-290.
【5】 Gores GJ.Cholangiocarcinoma:current concepts and insights [J].Hepatology,2003,37(28): 961-969.
【6】 Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma:consensus document [J]. Gut,2002,51(6):V11-V19.
【7】 Hezel AF,Zhu AX. Systemic therapy for biliary tract cancers [J]. Oncologist,2008, 13(4):415-423.
【8】 Fischerl U,Schulze-osthoff K. Apoptosis-based therapies and drug targets [J].Cell Death Differ,2005,12 (1):942-961.
【9】 Schimmer AD, Dalilil S, Batey RA,et al.Targeting XIAP for the treatment of malignancy [J]. Cell Death Differ,2006,13(2):179-188.
【10】 Gore ME,Colins MK.Gene therapy for cancer[J].Eru J Cancer,1994,30A(8):1047-1049.
【11】 Tsuruta Y,Mandai M,Konishi I,et al.Combination effect of adenovirus-mediated pro-apoptotic bax gene transfer with cisplatin or paclitaxel treatment in ovarian cancer cell lines[J].Eur J Cancer,2001,37(4):531-541
【12】 Alberts SR, Schroeder M, Erlichman C,et al.Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma:a North Central Cancer Treatment Group phase II trial[J].J Clin Oncol,2004,22(34):4944-4950.
【13】 Shen M, Feng Y, Ge B, et al.Liposome-C-erbB2 antisense oligodoxynucleotides in human ovarian cancer cells[J].Chin Med J(Engl),2001,114(7):735-737
【14】 Kronenwett R,Hass R.Antisense strategies for the treatment of hematological malignancies and solid tumors[J].Ann Hematol,1998,77(1-2):1-12
【15】马立东.XIAP在人类胆管癌中的表达及临床意义[D].沈阳：中国医科大学,2006：10-14.
【16】李鹏,崔平,贾俊琴等.转染反义寡核苷酸对人胆管癌QBC939细胞XIAP基因表达及细胞周期作用的实验研究[J].昆明医学院学报,2009，(3)57-62.
【17】 Hu Y, Cherton-Horvat G, Dragowska V,et al. Antisense Oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J]. Clin Cancer Res.2003,9 (7):2826-2836.
【18】 Tasaki K, Yoshida Y, Miyauchi M,et al. Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts[J]. Cancer Gene Ther,2000,7(2):255-261.
【19】王小华,张平,李国亮等.PCNA反义寡核苷酸对小鼠LA795肺腺癌皮下移植瘤生长的影响[J].临床和实验医学杂志,2008,7(11)：3、6.
【20】Patel T. Worldwide trends in mortality from biliary tractmalignancies[J]. BMC Cancer,2002, 2:10.
【21】 Jemal A,Thomas A,Murray T,et al.Cancer Statistics 2002[J].CA Cancer J Clin,2002, 52(1):23-47.
【22】 Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas [J]. Cancer,1995; 75(1 Suppl.):171-190.
【23】 Kim, R, Tanabe, K, Emi, M, et al.Potential roles of antisense therapy in the molecular targeting of genes involved in cancer [J]. Int J Oncol,2004,24(1):5-17.
【24】 Clark RE.Antisense therapeutics in chronic myeloid leukaemia:the promise, the progress and the problems [J]. Leukemia,2000,14(3):347-355.
【25】 Bertram J,Killian M,Brysch W,et al.Reduction of erbB2 gene product in mamma carcinoma cell lines by erbB2 mRNA-specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides.Biochem[J].Biochem Biophys Res Commun, 1994:200(1):661-667.
【26】 Summerton J.Morpholino antisense oligomers:the case for an RNase H-independent structural type[J]. Biochim BioPhys Acta,1999,1489(1):141-158.
【27】 Nielsen PE, Egholm M.An introduction to Peptide nucleic acid[J].Curr Issues Mol Biol,1999,(1-2):89-104.
【28】 Braasch DA, Corey DR.Locked nucleic acid(LNA):fine-tuning the recognition of DNA and RNA[J]. Chem Biol,2001,8(1):1-7.
【29】 Pirollo KF, Rait A,Sleer LS,et al.Antisense therapeutics:from theory to clinical practice[J]. Pharmacol Ther,2003,99(1):55-77.
【30】 Kurreck J.Antisense technologics.Improvement through novel chemical modifications [J]. Eur J Biochem,2003,270(8):1628-1644.
【31】 Turano B,Humphreys T.Quantitative determination of phosphorothioate-modified oligodeoxyribonucleotide Persistence[J]. Biotechniques,1994,17(2):266-267.
【32】 Sands H,Gorey-Feret LJ,Cocuzza AJ,et al.Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I.Comparison of a phosphodiester and a phosphorothioate[J].Mol Pharmacol,1994,45(5):932-943.
【33】 Wu-Pong S.Calcium-dependent oligonucleotide cellular uptake[J].Biochimie,
1996;78(1):33-38.
【34】 Zobel HP,Junghans M,Maienschein V,et al.Enhaneed antisense efficacy of oligonucleotides adsorbed to monomethylaminoethylmeththacrylate methylmethacrylate copolymer nanoparticles[J].Eur J Pharm Biopharm,2000,49(3):203-210.
【35】 Quattrone A,Papucci L,Morganti M,et al.Inhibition of MDR1 gene expression by antimessenger oligonucleotides lowers multiple drug resistance[J].Oncol Res,1994, 6(7):311-20.
【36】 Jansen B,Zangemeister-Wittke U.Antisense therapy for cancer the time of truth[J]. Lancet Oncol,2002,3(1 1):672-676.
【37】 Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins:why XIAP is the black sheep of the family[J]. EMBO Rep,2006,7(10):988-994.
【38】 Tamm I. Antisense therapy in clinical oncology:preclinical and clinical experiences [J]. Methods Mol Med,2005,106,113-134.
【39】 Konishib T,Teruya M,Kawahara M,et al.Chemotherapy of gastric cancer[J].Gan To Kagaku Ryoho,1998,25(4):504-515.
【40】Tsutsumi M,Noguchi O,Okita S,et al.Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxoprolyl)amine in hamsters[J]. Carcinogenesis,1995,16(3):457-459.
【41】 Okino H,Maeyama R,Manabe T,et al.Trans-tissue,sustained release of gemcitabine from photocured gelatin gel inhibits the growth of heterotopic human pancreatic tumor in nude mice[J].Clin Cancer Res,2003,9(15):5786-5793.
【42】 Cardillo TM,Karacay H,Goldenberg DM,et al.Improved targeting of pancreatic cancenexperimental studies of a new bispecific antibody,pretargeting enhancement system for immunoscintigraphy[J]. Clin Cancer Res,2004,10(10):3552-3561.
【43】 Fukasawa M,Korc M.Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines[J].Clin Cancer Res,2004,10(10):3327-3332.
【44】 Hwang RF,Yokoi K,Bucana CD,et al.Inhibition of platelet-derived growth factor receptor phosphorylation by STI571(Gleevec)reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model[J].Clin Cancer Res,2003,9(17):6534-6544.
【45】 Zervos EE,Norman JG,Gower WR,et al.Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo[J].J Surg Res,1997,69(2):367-371.
【46】 Jacob D,Davis J, Zhu H,et al.Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter[J].Clin Cancer Res,2004,10(10):3535-3541.
【47】 Orr RM,Dorr FA.Clinical studies of antisense oligonucleotides for cancer therapy[J]. Methods Mol Med,2005,106,85-111.
【48】 Webb A, Cunningham D, Cotter F,etal. Bcl-2 antisense therapy in patients with non-Hodgkin lymphoma[J]. Lancet,1997,349:(9059):1137-1141.
【49】 Ziegler A, Simoes-Wuest AP, Zangemeister-Wittke U. Optimizing efficacy of antisense oligodeoxynucleotides targeting inhibitors of apoptosis[J].Methods Enzymol,2000,314: 477-490.
【50】 Holcik M, Yeh C, Korneluk RG, et al.Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death[J]. Oncogene,2000, 19(36):4174-4177.
【51】 Bilim V, Kasahara T, Hara N, et al. Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistance TCC in vitro[J]. Int J Cancer,2003,103(1):29-37.
【52】 Sasaki H, Sheng Y, Kotsuji F,et al.Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells[J]. Cancer Res, 2000,60(20):5659-5666.
【53】 Astudillo H,Lopez T,Cstillo S,et al.p53, Bcl-2, PCNA expression,and apoptotic rates during cervical tumorigenesis[J].Ann NY Acad Sci,2003,1010:771-774.
【54】 Taftachi R,Ayhan A,Ekici S,et al.Proliferating-cell nuclear antigen (PCNA)as an independent prognostic marker in patients after prostatectomy:a cormparison of PCNA and Ki-67[J].BJU Int,2005,95(4):650-654.
【55】 Kontopidis G,Wu SY, Zheleva DI.Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design[J].Proc Natl Acad Sci,2005,102(6):1871-1876.
【1】 Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol 1993;67 (4):2168-2174.
【2】 Deng Y,Lin Y,Wu X.TRAIL-induced apoptosis requires Bxa-dependent mitochondrial release of smac/DIABLO[J].Genes Dev,2002,16:33-45.
【3】 Hannun YA.Apoptosis and dilemma of cancer chemotherapy[J].Blood,1997,89 (6):1845-1853.
【4】 Liston P, Roy N, Tamai K, et al. Suppression of apoptosis in mammalian cells by NAIP and a related gamily of IAP genes[J]. Nature,1996,379 (6563):349-353.
【5】 Rajcan-Separovic E,Liston P,Lefebvre C,et al. Assignment of human inhibitor of apoptosis protein(IAP)genes xiap, hiaP-1, and hiap-2 to chromosomes Xg25 and 11q22-q23 by fluorescence in situ hybridization[J].Genomics.1996;37(3):404-6
【6】 Wright ME,Han DK,Hockenbery DM.Caspase-3 and inhibitor of apoptosis protein(s) interactions in Saccharomyces cerevisiae and mammatian cells[J].FEBS Lett,2000, 481(1):13-18.
【7】 Holcik M,Gibson H,Korneluk RG,et al. XIAP:apoptotic brake and promising therapeutic target [J]. Apoptosis,2001,6(4):253-261.
【8】 Yamagiwa Y, Marienfeld C, Meng F, etal. Translational regulation of x-linked inhibitor of apoptosis protein by interleukin-6:a novel mechanism of tumor cell survival [J]. Cancer Res,2004,64 (4):1293-1298.
【9】 Zou T,Rao JN,Guo X,et al.NF-kappaB mediated IAp expression induces resistance of intestinal epithelial cells to apoptosis after Polyamine deleption[J].AmJ Physiol cell Physiol,2004,286(5):1009-1018
【10】 Byun DS,Cho K,Ryu BK,et al.Hypermethylation of XIAP-associated factor 1,a putative tumor suppressor gene from the 17p 13.2 locus,in human gastric adenocarcinomas[J].CancerRes,2003;63(21):7068-7075.
【11】 Liston P,Fong WG,Kelly NL,et al.Identification of XAF1 as antagonist of XIAP anti-caspase activity[J].Nat Cell Biol,2001,3(2):128-133.
【12】 Ng CP,BonavidaB. X-linked inhibitor of apoptosis(XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation:sensitization by overexpression of second mitochondrial-derived activator of caspase/direct IAP-binding protein with low pl(Smac/DIABLO)[J].Mol Cancer Ther,2002;1(12):1051-1058.
【13】 Chai J,Du C,Wu JW,et al. Structural and biochemical basis of apoptotic activation by Smac/DIABLO [J]. Nature,2000,406(6798):855-862.
【14】 Shiozaki EN,Shi Y. Caspases, IAPs and Smac/DIABLO:Mechanisms from structural biology [J].Trends Biochem Sci,2004,29(9):486-494.
【15】 Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins:why XIAP is the black sheep of the family [J]. EMBO Rep,2006,7(10):988-994.
【16】 Duckett C, Nava VE, Gedrich RW, et al.A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors [J]. EMBO J,1996,15(11): 2685-2689.
【17】 Deveraux QL, Roy N, Stennicke HR, 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.
【18】 Deveraux QL, Leo E, Stennicke HR, et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases[J]. EMBO J,1999,18(19):5242-5251.
【19】 Devereaux QL,Takahashi R,Salvesen GS,et al.X-linked IAP is a direct inhibitor of cell-death Proteases[J].Nature,1997,388(6639):300-304.
【20】 Takahashi R,Deveraux Q,Tamm I,et al.A single BIR domain of XIAP sufficient for inhibiting caspases[J]. Biol Chem,1998,273(14):7787-7790.
【21】 Scott FL,Denault JB,Riedl SJ,et al.XIAP inhibits caspase-3and-7 using two binding sites: evolutionarily conserved mechanism of IAPs [J].EMBO J,2005,24(3):645-655.
【22】 Sun C,Cai M,Meadow RP,et al.NMR structure and mutagenesis of the third BIR domain of the inhibitor of apoptosis protein XIAP[J].J BiolChem,2000,275(43): 33777-33781.
【23】 Riedl SJ,Renatus M,Zhou Q,et al.Structural basis for the inhibition of caspase-3 by XIAP[J].Cell,2001,104(5):791-800.
【24】 Shiozaki EN,Chai J,Rigotti DJ,et al.Mechanism of XIAP-mediated inhibition of caspase-9[J].Mol Cell,2003, 11(2):519-527
【25】 Srinivasula SM,Hegde R,SalehA,et al.A conserved XIAp-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis[J].Nature,2001 410(6824):112-116
【26】 Shin H,Okada K,Wilkinson JC,et al.Identification of ubiquitionation site on the X-linked inhlbitior of apoptosis Protein[J].Biochem J,2003,373(pt3):965-971.
【27】 Morizane Y,Honda R,Fukami K,et al.X-linked inhibitor of apoptosis functions as ubiquitin ligase toward matuse caspase-9 and cytosolic Smac/DIABLO[J].J Biochem, 2005,137(2):125-132.
【28】 Suzuki Y,Nakabayashi Y,Takahashi R,et al.Ubiquitin-Protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of Caspase-3 and enhances its anti-apoptotic effete in Fas-induced cell death[J].Proc Natl Acad Sci U.S.A.2001,98(15):8662-8667.
【29】 Hida A,Kawakami A,Nakashima T,et al.Nuclear factor-kappaB and caspases co-operatively regulate the activation and apoptosis of human macrophages[J].Immunology,2000,99(4):553-560
【30】 Stehlik C,de Martin R,Kumabashiri I,et al.Nuclear factor(NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis[J].J Exp Med,1998,188(1):211-216
【31】 Kaur S,Wang F,Venkatraman M,et al.X-linked inhibitor of apoptosis(XIAP) inhlibits c-Jun N-terminal kinase 1(JNKI) activation by transforming growth factor betal(TGF-betal) through ubiquitin-mediated proteosomal degradation of the TGF-betal-activated kinase-1(TAK1) [J].J BiolChem,2005,280(46):38599-38608
【32】 Varghese J,Khandre NS,Sarin A.Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line[J].Apoptosis,2003,8(4):363-370
【33】 Ottonello L,Bertolotto M,Montecucco F,et al.Dexamethasone-induced apoptosis of humnan monocytes exposed to immune complexes.Intervention of CD95-and XIAP-dependent Pathways[J].Int J Immunopathol Pharmacol,2005,18(3):403-415
【34】 Liu X,Shi Y,Giranda VL,et al.Inhibition of the phosphatidylinositol 3-kinase/Akt Pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis [J].Mol Cancer Ther,2006,5(3):494-501
【35】 Levkau B,Garton KJ, Ferri N, et al.XIAP induces cell-cycle arrest and activates nuclear factor-kappaB:new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells[J].Circ Res2001;88(3):282-290.
【36】 Li CQ,Trudel LJ,Wogan GN.Nitric oxide-induced genotoxicity,mitochondrial damage,and apoptosis in human lymphoblastoid cells expressing wild type and mutant p53[J].Proc Natl Acad Sci U S A,2002,99(16):10364-10369.
【37】 Sasaki H,Sheng Y,Kotsuji F, et al.Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells[J].Cancer Res,2000,60(20):5659-5666.
【38】 Fraser M,Leung BM,Yan X,et al.p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells[J].Cancer Res,2003,63(21):7081-7088.
【39】 Roa WH,Chen H,Fulton D,et al.X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells[J].Clin Invest Med,2003,26(5): 231-242.
【40】 Schimmer AD,Dalili S,Batery RA,etal.Targeting XIAP for treatment of malignancy [J]. Cell Death Differ,2006,13(2):179-188.
【41】 Lin MT, Chang CC, Chen ST, et al. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF- kappaB- dependent XIAP up-regulation[J]. J Biol Chem,2004,279 (23):24015-24023.
【42】 Bilim V, Kasahara T, Hara N, et al.Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro[J]. Int J Cancer,2003,103(1):29-37.
【43】 Mansouri A, Zhang Q, Ridgway LD, et al. Cisplatin resistance in an ovarian carcinoma is associated with a defect in programmed cell death control through XIAP regulation[J]. Oncol Res,2003,13(6-10):399-404.
【44】 Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance [J]. Oncogene,2003, 22(20):3138-3151.
【45】 Katedra i Klinika Hematologii, etal. The role of the inhibitor of apoptosis protein (LAP) family in hematological malignancies [J].Postepy Hig Med Dosw.(online),2008; 62: 55-63.
【46】李鹏.干扰XIAP基因对人胆管癌QBC939细胞增殖的抑制作用及化疗敏感性影响的研究[D].昆明：昆明医学院,2009,34.
【47】 Xu D,Bureau Y,Mclntyre DC,et al.Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus[J].J Neurosci.1999 Jun15:19(12):5026-503
【48】 Schimmer AD,Welsh K,Pinilla C,et al.Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity[J].Cancer Cell.2004Jan;5(1):25-35.
【49】 Holcik M,Yeh C,Korneluk RG,et al.Translational upregulation of X-linked inhibitor of apoptosis(XIAP)increases resistance to radiation induced cell death[J].Oncogene 2000, 19(36):4174-4177.
【50】 Zhang HG,Huang N,Liu D,et al.Gene therapy that inhibits nuclear translocation of nuclear factor kappaB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts[J].Arthritis Rheum.2000May:43(5):1094-1105.
【51】 Tong QS,Zheng LD,Wang L,et al.Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells[J].Cancer Gene Ther.2005May; 12(5):509-514.
【52】 Hu Y, Cherton-Horvat G,Dragowska V, et al.Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J].Clin Cancer Res.2003Jul:9(7):2826-2836.
【53】 Lima RT, Martins LM, Guimaraes JE, et al.Specific downregulation of bcl-2 and XIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells[J].CancerGene Ther.2004, May:11 (5):309-316.
【54】 McManus DC, Lefebvre CA, Cherton-Horvat G,et al.Loss of XIAP protein expression by RNAi and antisense approaches sensitize cancer cells to functionally diverse chemotherapeutics[J].Oncogene,2004Oct21;23(49):8105-8117.
【55】 Vucic D,Kaiser WJ,Miller LK,et al.Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM[J]. Mol cell Biol.1998,18(6):3300-3309.
【56】 Jia L,Patwari Y,Kelsey SM et al.Role of Smac in human leukaemic cell apoptosis and proliferation[J].Oncogene,2003,22(11):1589-1599.
【57】 Gottfried Y,Rotem A,Lotan R,et al.The mitochondrial ARTS protein promotes apoptosis through targeting XIAP[J].EMBO J.2004APr7:23(7):1627-1635.
【58】 Verhagen AM,Silke J,Ekert PG,et al.HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins [J].J Biol Chem,2002 Jan4;277(1):445-455.
【2】 Menias CO,Surabhi VR,Prasad SR,et al. Mimics of cholangiocarcinoma:spectrum of disease [J]. Radiographics.2008,(28)4:1115-1129.
【3】 Malhi H, Gores GJ. Cholangiocarcinoma:modern advances in understanding a deadly old disease [J]. J Hepatol,2006,45(6):856-867.
【4】 Chaudhary PM, Roninson IB. Activation of MDRI (P-glycoprotein) gene expression in human cells by protein kinase C agonists[J]. Oncol Res,1992,4(7):281-290.
【5】 Gores GJ.Cholangiocarcinoma:current concepts and insights [J].Hepatology,2003,37(28): 961-969.
【6】 Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma:consensus document [J]. Gut,2002,51(6):V11-V19.
【7】 Hezel AF,Zhu AX. Systemic therapy for biliary tract cancers [J]. Oncologist,2008, 13(4):415-423.
【8】 Fischerl U,Schulze-osthoff K. Apoptosis-based therapies and drug targets [J].Cell Death Differ,2005,12 (1):942-961.
【9】 Schimmer AD, Dalilil S, Batey RA,et al.Targeting XIAP for the treatment of malignancy [J]. Cell Death Differ,2006,13(2):179-188.
【10】 Gore ME,Colins MK.Gene therapy for cancer[J].Eru J Cancer,1994,30A(8):1047-1049.
【11】 Tsuruta Y,Mandai M,Konishi I,et al.Combination effect of adenovirus-mediated pro-apoptotic bax gene transfer with cisplatin or paclitaxel treatment in ovarian cancer cell lines[J].Eur J Cancer,2001,37(4):531-541
【12】 Alberts SR, Schroeder M, Erlichman C,et al.Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma:a North Central Cancer Treatment Group phase II trial[J].J Clin Oncol,2004,22(34):4944-4950.
【13】 Shen M, Feng Y, Ge B, et al.Liposome-C-erbB2 antisense oligodoxynucleotides in human ovarian cancer cells[J].Chin Med J(Engl),2001,114(7):735-737
【14】 Kronenwett R,Hass R.Antisense strategies for the treatment of hematological malignancies and solid tumors[J].Ann Hematol,1998,77(1-2):1-12
【15】马立东.XIAP在人类胆管癌中的表达及临床意义[D].沈阳：中国医科大学,2006：10-14.
【16】李鹏,崔平,贾俊琴等.转染反义寡核苷酸对人胆管癌QBC939细胞XIAP基因表达及细胞周期作用的实验研究[J].昆明医学院学报,2009，(3)57-62.
【17】 Hu Y, Cherton-Horvat G, Dragowska V,et al. Antisense Oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J]. Clin Cancer Res.2003,9 (7):2826-2836.
【18】 Tasaki K, Yoshida Y, Miyauchi M,et al. Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts[J]. Cancer Gene Ther,2000,7(2):255-261.
【19】王小华,张平,李国亮等.PCNA反义寡核苷酸对小鼠LA795肺腺癌皮下移植瘤生长的影响[J].临床和实验医学杂志,2008,7(11)：3、6.
【20】Patel T. Worldwide trends in mortality from biliary tractmalignancies[J]. BMC Cancer,2002, 2:10.
【21】 Jemal A,Thomas A,Murray T,et al.Cancer Statistics 2002[J].CA Cancer J Clin,2002, 52(1):23-47.
【22】 Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas [J]. Cancer,1995; 75(1 Suppl.):171-190.
【23】 Kim, R, Tanabe, K, Emi, M, et al.Potential roles of antisense therapy in the molecular targeting of genes involved in cancer [J]. Int J Oncol,2004,24(1):5-17.
【24】 Clark RE.Antisense therapeutics in chronic myeloid leukaemia:the promise, the progress and the problems [J]. Leukemia,2000,14(3):347-355.
【25】 Bertram J,Killian M,Brysch W,et al.Reduction of erbB2 gene product in mamma carcinoma cell lines by erbB2 mRNA-specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides.Biochem[J].Biochem Biophys Res Commun, 1994:200(1):661-667.
【26】 Summerton J.Morpholino antisense oligomers:the case for an RNase H-independent structural type[J]. Biochim BioPhys Acta,1999,1489(1):141-158.
【27】 Nielsen PE, Egholm M.An introduction to Peptide nucleic acid[J].Curr Issues Mol Biol,1999,(1-2):89-104.
【28】 Braasch DA, Corey DR.Locked nucleic acid(LNA):fine-tuning the recognition of DNA and RNA[J]. Chem Biol,2001,8(1):1-7.
【29】 Pirollo KF, Rait A,Sleer LS,et al.Antisense therapeutics:from theory to clinical practice[J]. Pharmacol Ther,2003,99(1):55-77.
【30】 Kurreck J.Antisense technologics.Improvement through novel chemical modifications [J]. Eur J Biochem,2003,270(8):1628-1644.
【31】 Turano B,Humphreys T.Quantitative determination of phosphorothioate-modified oligodeoxyribonucleotide Persistence[J]. Biotechniques,1994,17(2):266-267.
【32】 Sands H,Gorey-Feret LJ,Cocuzza AJ,et al.Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I.Comparison of a phosphodiester and a phosphorothioate[J].Mol Pharmacol,1994,45(5):932-943.
【33】 Wu-Pong S.Calcium-dependent oligonucleotide cellular uptake[J].Biochimie,
1996;78(1):33-38.
【34】 Zobel HP,Junghans M,Maienschein V,et al.Enhaneed antisense efficacy of oligonucleotides adsorbed to monomethylaminoethylmeththacrylate methylmethacrylate copolymer nanoparticles[J].Eur J Pharm Biopharm,2000,49(3):203-210.
【35】 Quattrone A,Papucci L,Morganti M,et al.Inhibition of MDR1 gene expression by antimessenger oligonucleotides lowers multiple drug resistance[J].Oncol Res,1994, 6(7):311-20.
【36】 Jansen B,Zangemeister-Wittke U.Antisense therapy for cancer the time of truth[J]. Lancet Oncol,2002,3(1 1):672-676.
【37】 Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins:why XIAP is the black sheep of the family[J]. EMBO Rep,2006,7(10):988-994.
【38】 Tamm I. Antisense therapy in clinical oncology:preclinical and clinical experiences [J]. Methods Mol Med,2005,106,113-134.
【39】 Konishib T,Teruya M,Kawahara M,et al.Chemotherapy of gastric cancer[J].Gan To Kagaku Ryoho,1998,25(4):504-515.
【40】Tsutsumi M,Noguchi O,Okita S,et al.Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxoprolyl)amine in hamsters[J]. Carcinogenesis,1995,16(3):457-459.
【41】 Okino H,Maeyama R,Manabe T,et al.Trans-tissue,sustained release of gemcitabine from photocured gelatin gel inhibits the growth of heterotopic human pancreatic tumor in nude mice[J].Clin Cancer Res,2003,9(15):5786-5793.
【42】 Cardillo TM,Karacay H,Goldenberg DM,et al.Improved targeting of pancreatic cancenexperimental studies of a new bispecific antibody,pretargeting enhancement system for immunoscintigraphy[J]. Clin Cancer Res,2004,10(10):3552-3561.
【43】 Fukasawa M,Korc M.Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines[J].Clin Cancer Res,2004,10(10):3327-3332.
【44】 Hwang RF,Yokoi K,Bucana CD,et al.Inhibition of platelet-derived growth factor receptor phosphorylation by STI571(Gleevec)reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model[J].Clin Cancer Res,2003,9(17):6534-6544.
【45】 Zervos EE,Norman JG,Gower WR,et al.Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo[J].J Surg Res,1997,69(2):367-371.
【46】 Jacob D,Davis J, Zhu H,et al.Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter[J].Clin Cancer Res,2004,10(10):3535-3541.
【47】 Orr RM,Dorr FA.Clinical studies of antisense oligonucleotides for cancer therapy[J]. Methods Mol Med,2005,106,85-111.
【48】 Webb A, Cunningham D, Cotter F,etal. Bcl-2 antisense therapy in patients with non-Hodgkin lymphoma[J]. Lancet,1997,349:(9059):1137-1141.
【49】 Ziegler A, Simoes-Wuest AP, Zangemeister-Wittke U. Optimizing efficacy of antisense oligodeoxynucleotides targeting inhibitors of apoptosis[J].Methods Enzymol,2000,314: 477-490.
【50】 Holcik M, Yeh C, Korneluk RG, et al.Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death[J]. Oncogene,2000, 19(36):4174-4177.
【51】 Bilim V, Kasahara T, Hara N, et al. Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistance TCC in vitro[J]. Int J Cancer,2003,103(1):29-37.
【52】 Sasaki H, Sheng Y, Kotsuji F,et al.Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells[J]. Cancer Res, 2000,60(20):5659-5666.
【53】 Astudillo H,Lopez T,Cstillo S,et al.p53, Bcl-2, PCNA expression,and apoptotic rates during cervical tumorigenesis[J].Ann NY Acad Sci,2003,1010:771-774.
【54】 Taftachi R,Ayhan A,Ekici S,et al.Proliferating-cell nuclear antigen (PCNA)as an independent prognostic marker in patients after prostatectomy:a cormparison of PCNA and Ki-67[J].BJU Int,2005,95(4):650-654.
【55】 Kontopidis G,Wu SY, Zheleva DI.Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design[J].Proc Natl Acad Sci,2005,102(6):1871-1876.
【1】 Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol 1993;67 (4):2168-2174.
【2】 Deng Y,Lin Y,Wu X.TRAIL-induced apoptosis requires Bxa-dependent mitochondrial release of smac/DIABLO[J].Genes Dev,2002,16:33-45.
【3】 Hannun YA.Apoptosis and dilemma of cancer chemotherapy[J].Blood,1997,89 (6):1845-1853.
【4】 Liston P, Roy N, Tamai K, et al. Suppression of apoptosis in mammalian cells by NAIP and a related gamily of IAP genes[J]. Nature,1996,379 (6563):349-353.
【5】 Rajcan-Separovic E,Liston P,Lefebvre C,et al. Assignment of human inhibitor of apoptosis protein(IAP)genes xiap, hiaP-1, and hiap-2 to chromosomes Xg25 and 11q22-q23 by fluorescence in situ hybridization[J].Genomics.1996;37(3):404-6
【6】 Wright ME,Han DK,Hockenbery DM.Caspase-3 and inhibitor of apoptosis protein(s) interactions in Saccharomyces cerevisiae and mammatian cells[J].FEBS Lett,2000, 481(1):13-18.
【7】 Holcik M,Gibson H,Korneluk RG,et al. XIAP:apoptotic brake and promising therapeutic target [J]. Apoptosis,2001,6(4):253-261.
【8】 Yamagiwa Y, Marienfeld C, Meng F, etal. Translational regulation of x-linked inhibitor of apoptosis protein by interleukin-6:a novel mechanism of tumor cell survival [J]. Cancer Res,2004,64 (4):1293-1298.
【9】 Zou T,Rao JN,Guo X,et al.NF-kappaB mediated IAp expression induces resistance of intestinal epithelial cells to apoptosis after Polyamine deleption[J].AmJ Physiol cell Physiol,2004,286(5):1009-1018
【10】 Byun DS,Cho K,Ryu BK,et al.Hypermethylation of XIAP-associated factor 1,a putative tumor suppressor gene from the 17p 13.2 locus,in human gastric adenocarcinomas[J].CancerRes,2003;63(21):7068-7075.
【11】 Liston P,Fong WG,Kelly NL,et al.Identification of XAF1 as antagonist of XIAP anti-caspase activity[J].Nat Cell Biol,2001,3(2):128-133.
【12】 Ng CP,BonavidaB. X-linked inhibitor of apoptosis(XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation:sensitization by overexpression of second mitochondrial-derived activator of caspase/direct IAP-binding protein with low pl(Smac/DIABLO)[J].Mol Cancer Ther,2002;1(12):1051-1058.
【13】 Chai J,Du C,Wu JW,et al. Structural and biochemical basis of apoptotic activation by Smac/DIABLO [J]. Nature,2000,406(6798):855-862.
【14】 Shiozaki EN,Shi Y. Caspases, IAPs and Smac/DIABLO:Mechanisms from structural biology [J].Trends Biochem Sci,2004,29(9):486-494.
【15】 Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins:why XIAP is the black sheep of the family [J]. EMBO Rep,2006,7(10):988-994.
【16】 Duckett C, Nava VE, Gedrich RW, et al.A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors [J]. EMBO J,1996,15(11): 2685-2689.
【17】 Deveraux QL, Roy N, Stennicke HR, 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.
【18】 Deveraux QL, Leo E, Stennicke HR, et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases[J]. EMBO J,1999,18(19):5242-5251.
【19】 Devereaux QL,Takahashi R,Salvesen GS,et al.X-linked IAP is a direct inhibitor of cell-death Proteases[J].Nature,1997,388(6639):300-304.
【20】 Takahashi R,Deveraux Q,Tamm I,et al.A single BIR domain of XIAP sufficient for inhibiting caspases[J]. Biol Chem,1998,273(14):7787-7790.
【21】 Scott FL,Denault JB,Riedl SJ,et al.XIAP inhibits caspase-3and-7 using two binding sites: evolutionarily conserved mechanism of IAPs [J].EMBO J,2005,24(3):645-655.
【22】 Sun C,Cai M,Meadow RP,et al.NMR structure and mutagenesis of the third BIR domain of the inhibitor of apoptosis protein XIAP[J].J BiolChem,2000,275(43): 33777-33781.
【23】 Riedl SJ,Renatus M,Zhou Q,et al.Structural basis for the inhibition of caspase-3 by XIAP[J].Cell,2001,104(5):791-800.
【24】 Shiozaki EN,Chai J,Rigotti DJ,et al.Mechanism of XIAP-mediated inhibition of caspase-9[J].Mol Cell,2003, 11(2):519-527
【25】 Srinivasula SM,Hegde R,SalehA,et al.A conserved XIAp-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis[J].Nature,2001 410(6824):112-116
【26】 Shin H,Okada K,Wilkinson JC,et al.Identification of ubiquitionation site on the X-linked inhlbitior of apoptosis Protein[J].Biochem J,2003,373(pt3):965-971.
【27】 Morizane Y,Honda R,Fukami K,et al.X-linked inhibitor of apoptosis functions as ubiquitin ligase toward matuse caspase-9 and cytosolic Smac/DIABLO[J].J Biochem, 2005,137(2):125-132.
【28】 Suzuki Y,Nakabayashi Y,Takahashi R,et al.Ubiquitin-Protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of Caspase-3 and enhances its anti-apoptotic effete in Fas-induced cell death[J].Proc Natl Acad Sci U.S.A.2001,98(15):8662-8667.
【29】 Hida A,Kawakami A,Nakashima T,et al.Nuclear factor-kappaB and caspases co-operatively regulate the activation and apoptosis of human macrophages[J].Immunology,2000,99(4):553-560
【30】 Stehlik C,de Martin R,Kumabashiri I,et al.Nuclear factor(NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis[J].J Exp Med,1998,188(1):211-216
【31】 Kaur S,Wang F,Venkatraman M,et al.X-linked inhibitor of apoptosis(XIAP) inhlibits c-Jun N-terminal kinase 1(JNKI) activation by transforming growth factor betal(TGF-betal) through ubiquitin-mediated proteosomal degradation of the TGF-betal-activated kinase-1(TAK1) [J].J BiolChem,2005,280(46):38599-38608
【32】 Varghese J,Khandre NS,Sarin A.Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line[J].Apoptosis,2003,8(4):363-370
【33】 Ottonello L,Bertolotto M,Montecucco F,et al.Dexamethasone-induced apoptosis of humnan monocytes exposed to immune complexes.Intervention of CD95-and XIAP-dependent Pathways[J].Int J Immunopathol Pharmacol,2005,18(3):403-415
【34】 Liu X,Shi Y,Giranda VL,et al.Inhibition of the phosphatidylinositol 3-kinase/Akt Pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis [J].Mol Cancer Ther,2006,5(3):494-501
【35】 Levkau B,Garton KJ, Ferri N, et al.XIAP induces cell-cycle arrest and activates nuclear factor-kappaB:new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells[J].Circ Res2001;88(3):282-290.
【36】 Li CQ,Trudel LJ,Wogan GN.Nitric oxide-induced genotoxicity,mitochondrial damage,and apoptosis in human lymphoblastoid cells expressing wild type and mutant p53[J].Proc Natl Acad Sci U S A,2002,99(16):10364-10369.
【37】 Sasaki H,Sheng Y,Kotsuji F, et al.Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells[J].Cancer Res,2000,60(20):5659-5666.
【38】 Fraser M,Leung BM,Yan X,et al.p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells[J].Cancer Res,2003,63(21):7081-7088.
【39】 Roa WH,Chen H,Fulton D,et al.X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells[J].Clin Invest Med,2003,26(5): 231-242.
【40】 Schimmer AD,Dalili S,Batery RA,etal.Targeting XIAP for treatment of malignancy [J]. Cell Death Differ,2006,13(2):179-188.
【41】 Lin MT, Chang CC, Chen ST, et al. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF- kappaB- dependent XIAP up-regulation[J]. J Biol Chem,2004,279 (23):24015-24023.
【42】 Bilim V, Kasahara T, Hara N, et al.Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro[J]. Int J Cancer,2003,103(1):29-37.
【43】 Mansouri A, Zhang Q, Ridgway LD, et al. Cisplatin resistance in an ovarian carcinoma is associated with a defect in programmed cell death control through XIAP regulation[J]. Oncol Res,2003,13(6-10):399-404.
【44】 Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance [J]. Oncogene,2003, 22(20):3138-3151.
【45】 Katedra i Klinika Hematologii, etal. The role of the inhibitor of apoptosis protein (LAP) family in hematological malignancies [J].Postepy Hig Med Dosw.(online),2008; 62: 55-63.
【46】李鹏.干扰XIAP基因对人胆管癌QBC939细胞增殖的抑制作用及化疗敏感性影响的研究[D].昆明：昆明医学院,2009,34.
【47】 Xu D,Bureau Y,Mclntyre DC,et al.Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus[J].J Neurosci.1999 Jun15:19(12):5026-503
【48】 Schimmer AD,Welsh K,Pinilla C,et al.Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity[J].Cancer Cell.2004Jan;5(1):25-35.
【49】 Holcik M,Yeh C,Korneluk RG,et al.Translational upregulation of X-linked inhibitor of apoptosis(XIAP)increases resistance to radiation induced cell death[J].Oncogene 2000, 19(36):4174-4177.
【50】 Zhang HG,Huang N,Liu D,et al.Gene therapy that inhibits nuclear translocation of nuclear factor kappaB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts[J].Arthritis Rheum.2000May:43(5):1094-1105.
【51】 Tong QS,Zheng LD,Wang L,et al.Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells[J].Cancer Gene Ther.2005May; 12(5):509-514.
【52】 Hu Y, Cherton-Horvat G,Dragowska V, et al.Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J].Clin Cancer Res.2003Jul:9(7):2826-2836.
【53】 Lima RT, Martins LM, Guimaraes JE, et al.Specific downregulation of bcl-2 and XIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells[J].CancerGene Ther.2004, May:11 (5):309-316.
【54】 McManus DC, Lefebvre CA, Cherton-Horvat G,et al.Loss of XIAP protein expression by RNAi and antisense approaches sensitize cancer cells to functionally diverse chemotherapeutics[J].Oncogene,2004Oct21;23(49):8105-8117.
【55】 Vucic D,Kaiser WJ,Miller LK,et al.Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM[J]. Mol cell Biol.1998,18(6):3300-3309.
【56】 Jia L,Patwari Y,Kelsey SM et al.Role of Smac in human leukaemic cell apoptosis and proliferation[J].Oncogene,2003,22(11):1589-1599.
【57】 Gottfried Y,Rotem A,Lotan R,et al.The mitochondrial ARTS protein promotes apoptosis through targeting XIAP[J].EMBO J.2004APr7:23(7):1627-1635.
【58】 Verhagen AM,Silke J,Ekert PG,et al.HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins [J].J Biol Chem,2002 Jan4;277(1):445-455.