胰腺癌中survivin的表达意义及RNAi对PANC-1细胞凋亡和化疗敏感性影响的研究
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摘要
[目的]胰腺癌对绝大部分化疗药物耐药。存活素(survivin)基因是凋亡抑制蛋白家族成员中抑制凋亡作用最强的一种,在大部分恶性肿瘤组织和细胞中高表达,是肿瘤增殖和化疗耐药的重要因子。本研究的主要目的有:(1)探讨survivin在胰腺癌组织中的表达及其与临床病理的关系。(2)观察胰腺癌细胞株PANC-1中survivin的表达及其在化疗药物吉西他滨作用后的变化。(3)运用RNAi载体抑制survivin的表达对诱导PANC-1细胞凋亡的影响。(4) RNAi抑制survivin的表达对增加化疗药物吉西他滨化疗敏感性的影响。为探索胰腺癌新的治疗方法奠定实验基础。
[方法](1)运用免疫组化法检测35例胰腺癌手术切除标本和10例癌旁胰腺组织,分析survivin的表达和临床病理特征的关系。(2)培养胰腺癌细胞PANC-1,加入吉西他滨,运用RT-PCR和Western blot检测survivin的表达。(3)构建以U6为启动子的RNAi载体并转染PANC-1,运用RT-PCR和Western blot检测survivin的表达,FCM检测凋亡指数和Hoechest 33258检测凋亡形态。(4) MTT、FCM和Hoechest 33258检测PANC-1对化疗药物吉西他滨的敏感性。
[结果](1)免疫组化显示胰腺癌组织中有survivin的阳性表达,而癌旁组织中无survivin的表达。胰腺癌组织中其表达的阳性率(26/35,74.29%)明显高于癌旁组织(0/10,0%),差异有统计学意义(P＜0.05)。survivin在胰腺癌组织中的阳性率与肿瘤的临床分期和病理分级有关;两病理因素分组间差异有统计学意义(P＜0.05),而与肿瘤的远处转移无明显关系;远处转移分组间差异无统计学意义(P＞0.05)。(2)用1μg/ml及10μg/ml浓度的吉西他滨作用胰腺癌细胞株24h和48h,survivin mRNA水平分别上升了(1.34±0.12)倍、(2.40±0.17)倍和(3.33±0.20)倍、(4.41±0.18)倍,蛋白水平分别上升了(1.20±0.07)倍、(1.48±0.19)倍和(2.90±0.04)倍、(4.50±0.20)倍,差异有统计学意义(p＜0.05)。(3)转染survivin的RNAi载体后24h、48h,survivin mRNA和蛋白的瞬时抑制率分别为52.67%±3.51%、75.33%±3.06%和58.00%±3.61%、76.67%±4.73%;流式细胞仪检测的凋亡指数分别为9.33%±1.53%和14.57%±1.50%;Hoechst33258染色发现,PANC-1细胞出现核皱缩、浓染和碎裂等典型的凋亡形态。(4) Survivin抑制后,PANC-1对吉西他滨的敏感性增加,流式细胞仪检测转染后48h凋亡指数由15.67%±1.16%增加到35.67%±1.53%,差异有统计学意义(p＜0.05),吉西他滨的IC_(50)由1.24±0.11μg/ml下降到0.39±0.07μg/ml,差异有统计学意义(p＜0.05)。
[结论](1)Survivin在胰腺癌组织中的阳性率高于癌旁组织,其与病理分级和临床分期的关系表明survivin可能在胰腺癌的增殖和预后中起重要作用。(2)胰腺癌细胞株的化疗耐药可能通过吉西他滨诱导survivin的表达上调而增强。(3)以U6为启动子的survivin的RNAi载体,能有效地抑制胰腺癌细胞株PANC-1中survivin的表达,并且诱导细胞凋亡。(4)胰腺癌细胞株PANC-1对吉西他滨的化疗敏感性能够通过运用RNAi技术抑制survivin的表达而增强。
[Objective]Pancreatic carcinoma is resist to most of all chemotherapeutical drugs.Survivin,as the most potent one of inhibitor of apoptosis(IAP) families,up-regulating in many cancer tissues and cells, is thought an important factor contributed to carcinoma proliferation and chemoresistance.The main aims of this study are as follows.(1) To discuss the expression of survivin in the pancreatic carcinoma tissue and the relationship between it's expression and the clinicopathologic parameters.(2) To observe the change of the expression of survivin in the pancreatic carcinoma cell line PANC-1 induced by chemotherapeutical drug gemcitabine.(3) To investigate survivin inhibited by RNA interference(RNAi) vectors,and induce apoptosis.(4) To investigate the sensitivity to chemotherapeutical drug gemcitabine enhanced after survivin inhibited by RNAi.Lay an experimental foundation for further exploration of new therapy of pancreatic carcinoma.
[Method](1) 35 samples of resected pancreatic carcinoma tissues and 10 normal tissues from the carcinoma besides examined by immunohistochemistry and the relationship of survivin expression to the clinicopathologic parameters analyzed.(2) The pancreatic carcinoma cell line PANC-1 cultured with the gemcitabine,and survivin expression examined by RT-PCR and Western blot.(3) RNA interference vectors with U6 promoter against survivin constructed and transfected into the pancreatic carcinoma cell line PANC-1,the expression of survivin examined by RT-PCR and Western blot,FCM employed to examine the apoptosis index of PANC-1 and apoptotic morphology was examined by Hoechst 33258.(4) The sensitivity of PANC-1 to chemotherapeutical drug gemcitabine further examined by MTT,FCM and Hoechst 33258.
[Result](1) Survivin expressed in pancreatic carcinoma tissues, and none of carcinoma besides tissues;the survivin expression rate of carcinoma tissues(26/35,74.29%) higher than the carcinoma besides normal tissues(0/10,0%),and the difference between them was statistically significant(P＜0.05).The rate was related to the pathological grade and the clinical stage(P＜0.05),not related to the metastasis (P＞0.05).(2) 24 and 48 hours after cultured by gemcitabine with the concentration of 1μg/ml and 10μg/ml,survivin mRNA level was increased(1.34±0.12)、(2.40±0.17)、(3.33±0.20) and(4.41±0.18) folds,and the protein expression was enhanced(1.20±0.07)、(1.48±0.19)、(2.90±0.04) and(4.50±0.20) folds respectively,and the difference between them was statistically significant(P＜0.05).(3) RNAi vectors against survivin could inhibite the survivin mRNA and protein expression level of 52.67%±3.51%、75.33%±3.06%and 58.00%±3.61%、76.67%±4.73%at 24h and 48h instantaneous effectively.The apoptosis index examined by FCM is 9.33%±1.53%and 14.57%±1.50%. The typical apoptotic morphology of condensed,shrinked and reptured nucleoli of PANC-1 found by Hoechst33258 stained.(4) The sensitivity of PANC-1 to gemcitabine increased after survivin was inhibited,the apoptosis index examined by FCM apparent increased from 15.67%±1.16%to 35.67%±1.53%by the action of gemcitabine(P＜0.05), with the IC_(50) to gemcitabine decreased greatly from 1.24±0.11μg/ml to 0.39±0.07μg/ml,and the difference between them was statistically significant(P＜0.05).
[Conclusion](1) The positive rate of survivin higher than the carcinoma besides normal tissues,and which related to the differentiation and the clinical stage of pancreatic carcinoma indicate survivin is thought of an important factor contributed to carcinoma proliferation and prognosis.(2) The capacity of pancreatic carcinoma cell line chemoresistance could be enhanced by gemcitabine cultured with the survivin expression up-regulated.(3) The RNAi vectors with U6 promoter could effective suppress the expression of survivin in pancreatic carcionoma cell line PANC-1,and induce the PANC-1 apoptosis.(4) The chemosensitivity of gemcitabine in pancreatic carcinoma cell line PANC-1 could be enhanced by suppress the expression of survivin through RNAi technology.
[方法](1)运用免疫组化法检测35例胰腺癌手术切除标本和10例癌旁胰腺组织,分析survivin的表达和临床病理特征的关系。(2)培养胰腺癌细胞PANC-1,加入吉西他滨,运用RT-PCR和Western blot检测survivin的表达。(3)构建以U6为启动子的RNAi载体并转染PANC-1,运用RT-PCR和Western blot检测survivin的表达,FCM检测凋亡指数和Hoechest 33258检测凋亡形态。(4) MTT、FCM和Hoechest 33258检测PANC-1对化疗药物吉西他滨的敏感性。
[结果](1)免疫组化显示胰腺癌组织中有survivin的阳性表达,而癌旁组织中无survivin的表达。胰腺癌组织中其表达的阳性率(26/35,74.29%)明显高于癌旁组织(0/10,0%),差异有统计学意义(P＜0.05)。survivin在胰腺癌组织中的阳性率与肿瘤的临床分期和病理分级有关;两病理因素分组间差异有统计学意义(P＜0.05),而与肿瘤的远处转移无明显关系;远处转移分组间差异无统计学意义(P＞0.05)。(2)用1μg/ml及10μg/ml浓度的吉西他滨作用胰腺癌细胞株24h和48h,survivin mRNA水平分别上升了(1.34±0.12)倍、(2.40±0.17)倍和(3.33±0.20)倍、(4.41±0.18)倍,蛋白水平分别上升了(1.20±0.07)倍、(1.48±0.19)倍和(2.90±0.04)倍、(4.50±0.20)倍,差异有统计学意义(p＜0.05)。(3)转染survivin的RNAi载体后24h、48h,survivin mRNA和蛋白的瞬时抑制率分别为52.67%±3.51%、75.33%±3.06%和58.00%±3.61%、76.67%±4.73%;流式细胞仪检测的凋亡指数分别为9.33%±1.53%和14.57%±1.50%;Hoechst33258染色发现,PANC-1细胞出现核皱缩、浓染和碎裂等典型的凋亡形态。(4) Survivin抑制后,PANC-1对吉西他滨的敏感性增加,流式细胞仪检测转染后48h凋亡指数由15.67%±1.16%增加到35.67%±1.53%,差异有统计学意义(p＜0.05),吉西他滨的IC_(50)由1.24±0.11μg/ml下降到0.39±0.07μg/ml,差异有统计学意义(p＜0.05)。
[结论](1)Survivin在胰腺癌组织中的阳性率高于癌旁组织,其与病理分级和临床分期的关系表明survivin可能在胰腺癌的增殖和预后中起重要作用。(2)胰腺癌细胞株的化疗耐药可能通过吉西他滨诱导survivin的表达上调而增强。(3)以U6为启动子的survivin的RNAi载体,能有效地抑制胰腺癌细胞株PANC-1中survivin的表达,并且诱导细胞凋亡。(4)胰腺癌细胞株PANC-1对吉西他滨的化疗敏感性能够通过运用RNAi技术抑制survivin的表达而增强。
[Objective]Pancreatic carcinoma is resist to most of all chemotherapeutical drugs.Survivin,as the most potent one of inhibitor of apoptosis(IAP) families,up-regulating in many cancer tissues and cells, is thought an important factor contributed to carcinoma proliferation and chemoresistance.The main aims of this study are as follows.(1) To discuss the expression of survivin in the pancreatic carcinoma tissue and the relationship between it's expression and the clinicopathologic parameters.(2) To observe the change of the expression of survivin in the pancreatic carcinoma cell line PANC-1 induced by chemotherapeutical drug gemcitabine.(3) To investigate survivin inhibited by RNA interference(RNAi) vectors,and induce apoptosis.(4) To investigate the sensitivity to chemotherapeutical drug gemcitabine enhanced after survivin inhibited by RNAi.Lay an experimental foundation for further exploration of new therapy of pancreatic carcinoma.
[Method](1) 35 samples of resected pancreatic carcinoma tissues and 10 normal tissues from the carcinoma besides examined by immunohistochemistry and the relationship of survivin expression to the clinicopathologic parameters analyzed.(2) The pancreatic carcinoma cell line PANC-1 cultured with the gemcitabine,and survivin expression examined by RT-PCR and Western blot.(3) RNA interference vectors with U6 promoter against survivin constructed and transfected into the pancreatic carcinoma cell line PANC-1,the expression of survivin examined by RT-PCR and Western blot,FCM employed to examine the apoptosis index of PANC-1 and apoptotic morphology was examined by Hoechst 33258.(4) The sensitivity of PANC-1 to chemotherapeutical drug gemcitabine further examined by MTT,FCM and Hoechst 33258.
[Result](1) Survivin expressed in pancreatic carcinoma tissues, and none of carcinoma besides tissues;the survivin expression rate of carcinoma tissues(26/35,74.29%) higher than the carcinoma besides normal tissues(0/10,0%),and the difference between them was statistically significant(P＜0.05).The rate was related to the pathological grade and the clinical stage(P＜0.05),not related to the metastasis (P＞0.05).(2) 24 and 48 hours after cultured by gemcitabine with the concentration of 1μg/ml and 10μg/ml,survivin mRNA level was increased(1.34±0.12)、(2.40±0.17)、(3.33±0.20) and(4.41±0.18) folds,and the protein expression was enhanced(1.20±0.07)、(1.48±0.19)、(2.90±0.04) and(4.50±0.20) folds respectively,and the difference between them was statistically significant(P＜0.05).(3) RNAi vectors against survivin could inhibite the survivin mRNA and protein expression level of 52.67%±3.51%、75.33%±3.06%and 58.00%±3.61%、76.67%±4.73%at 24h and 48h instantaneous effectively.The apoptosis index examined by FCM is 9.33%±1.53%and 14.57%±1.50%. The typical apoptotic morphology of condensed,shrinked and reptured nucleoli of PANC-1 found by Hoechst33258 stained.(4) The sensitivity of PANC-1 to gemcitabine increased after survivin was inhibited,the apoptosis index examined by FCM apparent increased from 15.67%±1.16%to 35.67%±1.53%by the action of gemcitabine(P＜0.05), with the IC_(50) to gemcitabine decreased greatly from 1.24±0.11μg/ml to 0.39±0.07μg/ml,and the difference between them was statistically significant(P＜0.05).
[Conclusion](1) The positive rate of survivin higher than the carcinoma besides normal tissues,and which related to the differentiation and the clinical stage of pancreatic carcinoma indicate survivin is thought of an important factor contributed to carcinoma proliferation and prognosis.(2) The capacity of pancreatic carcinoma cell line chemoresistance could be enhanced by gemcitabine cultured with the survivin expression up-regulated.(3) The RNAi vectors with U6 promoter could effective suppress the expression of survivin in pancreatic carcionoma cell line PANC-1,and induce the PANC-1 apoptosis.(4) The chemosensitivity of gemcitabine in pancreatic carcinoma cell line PANC-1 could be enhanced by suppress the expression of survivin through RNAi technology.
引文
[1]Ahmedin J,Rebecca S,Elizabeth W,et al.Cancer Statistics,2007[J].CA Cancer J Clin,2007;57:43-66.
[2]李新建.上海市胰腺癌的流行现状和趋势研究[J].外科理论与实践.2002;7(5):342-345.
[3]Aristu J,Canon R,Pardo F,et al.Surgical resection after preoperative chemo radiotherapy benefits selected patients with unresectable pancreatic cancer[J].Am J Clin Oncol,2003;26(1):30-36.
[4]Breslin TM,Hess KR,Harbison DB,et al.Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas:treatment variables and survival duration [J].Ann Surg Oncol,2001;8:123-132.
[5]Perona R,Sanchez-Perez I.Control of oncogenesis and cancer therapy resistance [J].Br J Cancer,2004;90(3):573-7.
[6]Thompson CB.Apoptosis in the pathogenesis and treatment of disease[J].Science,1995;267:1456-62.
[7]Nicholson DW.From bench to clinic with apoptosis-based therapeutic agents [J].Nature.2000;407:810-816.
[8]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol.1993;67:2168-74.
[9]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001;40(4),1117-1123.
[10]Ambrosini G,Adida C,Altieri DC.A novel anti-apoptosis gene,survivin,expressed in cancer and lymphoma[J].Nature Med,1997;3(8):917-921.
[11]Hauser HP,Bardroff M,Pyrowolakis G,Jentsch S.A Giant Ubiquitin-conjugating Enzyme Related to IAP Apoptosis Inhibitiors[J].J Cell Biol,1998;141:1415-1422.
[12]Caldas H,Jiang Y,Holloway MP,et al.Survivin splice variants regulate the balance between proliferation and cell death[J].Oncogene.2005;1:1-14.
[13]Satoh K,Kaneko K,Hirota M,et al.Expression of survivin is correlated with cancer cell apoptosis and is involved in the developed in the development of human pancreatic duct cell tumors[J].Cancer.2001;92:271-278.
[14]Liu JW,Li KZ,Dou KF,et al.Survivin antisense oligonucleotide induces apoptosis and sensitizes pancreatic cancer cells to Gemcitabine [J]. Chin J Gen Surg, 2004, 19(7): 401-3
[15] Kojima H, Iida M, Yaguchi Y, et al. Enhancement of Cisplatin sensitivity in squamous cell carcinoma of the head and neck transfected with a survivin antisense gene [J]. Arch Otolaryngol Head Neck Surg. 2006 Jun; 132(6):682-5.
[16] Carl D, Novina, Phillip A.Sharp the RNAi revolution. Nature. 2004; 430: 161-4. [17] Matzke MA, Birchler JA. RNAi-mediated pathways in the nucleus [J].Nature Reviews Genetics.2005; 6:24-35.
[18] Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy [J]. Cancer Gene Therapy. 2005; 12:217-227.
[19] Westphal S, Kalthoff H. Apoptosis: targets in pancreatic cancer [J]. Mol Cancer, 2003, 2(1): 6.
[20] Takahashi R, Deveraux Q, Trmm I, et al. A single BIR domain of XIAP sufficient for inhibiting caspases [J].J Biol Chem, 1998; 273, 7787-7790.
[21] Ambrosini G Adida C, Sirugo G, et al. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting[J].J Biol Chem, 1998,273(18): 11177-11182.
[22] LaCasse EC, Baird S, Korneluk RG, et al. The inhibitors of apoptosis and their emerging role in cancer [J].Oncogene, 1998, 17(25): 3247-3259.
[23] Hirohashi Y, Torgoe T, Maeda A, et al.HLA-A24-restricted cytotoxic T lymphocyte epitope of a tumor-associated protein, survivin [J]. Clin Cancer Res, 2002,8(6): 1731-1739.
[24] Grossman D,Meniff JM,U FZ,et al. Expression and targeting of the apoptosis inhibitor, survivin in human melanoma[J].J Invest Dermatol. 1999, 113(6): 1076-1082.
[25] Lu CD, Altieri DC, Tanigawa N, et al. Expression of a novel anti-apoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas[J].Cancer Res, 1998,58(22): 1802-1812.
[26] Kawasaki, Altieri DC, Lu CD, et al. Inhibition of apoptosis by survivin predicts short survival rates in colorectal cancer[J].Cancer Res, 1998, 58 (22): 5071- 5074.
[27] Kennedy SM, Driscoll O, Purcell R, et al. Prognostic importance of survivin in breast cancer[J].Br J Cancer, 2003, 88: 1077-1083.
[28] Monzo M, Roseu R, Felip E, et al. A novel anti-apoptosis gene: Re expression of survivin messenger RNA as a prognosis marker in non small cell lung cancer [J].J Clin Oncol,1999,17(7):2100-2106.
[29]Kami K,Doi R,Koizumi M,et al.Survivin expression is a prognostic marker in pancreatic cancer patients[J].Surgery 2004;136:443-448.
[30]Pennati M,Folini M,Zaffaroni N.Targeting survivin in cancer therapy[J].Expert Opin Ther Targets,2008,12(4):463-476.
[31]Leber R,Enomoto T,McGregor JA,et al.Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcmoma[J].Acta Obstet Gynecol Scand,2002,81(2):162-167.
[32]Jinfeng M,Kimura W,Sakurai F,et al.Histopathological study of intraductal papillary mucinous tumor of the pancreas:special reference to the roles of survivin and p53 in tumorigenesis of IPMT[J].Int J Gastrointest Cancer,2002,32(2-3):73-81.V[33]Qiao JG,Zhang YQ,Yin YC,et al.Expression of survivin in pancreatic cancer and its correlation to expression of Bcl-2[J].World J Gastroenterol,2004,10(18):2759-2761.
[34]梁智勇,刘彤华,罗玉凤,等.存活素在胰腺癌组织中的表达[J].中华病理学杂志,2005;34(2):67-70.
[35]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001,40(4),1117-1123.
[36]Suzuki A,Ito T,Kawano H,et al.survivin initiates procaspase-3/p21 complex formation as a result of interaction with CDK4 to resist Fas mediated cell death [J].Oncoge.2000,19(10):1346-1353.
[37]Andrade F,Roy S,Nicholson D,et al.Granzyme B directly and efficiently cleaves several downstream caspase substrate:implications for CTL-induced apoptosis[J].Immunity,1998,8(4):451-460.
[38]O'Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by endothelial cells[J].Am J Pathol,2000,156(2):393-398.
[39]Suzuki A,Hayashida M,Ito T,et al.Survivin initiates cell cycle entry by the competitive interaction with CDK4(P16(INK4a)and CDK2/cyclin E complex activation[J].Oncogene,2000,19(29):3225-3234.
[40]Mesri M,Wall NR,Li J,et al.Cancer gene therapy using a survivin mutant adenovirus[J].J Clin Invest,2001,108(7):981-990.
[41]Uchida H,Tanaka T,Sasaki K,et al.Adenovirus mediated transfer of siRNA against survivin induced apoptosis and at tenuated tumor cell growth in vitro and in vivo[J].Mol Ther,2004,10(1):162-171.
[42]Asanuma K,Moriai R,Yajima T,et al.Survivin as a radio resistance factor in pancreatic cancer[J].Jpn J Cancer Res,2000,91(11):1204-1209.
[43]Liu JW,Li KZ,Dou KF,et al.Survivin antisense oligonucleotide induces apoptosis and sensitizes pancreatic cancer cells to Gemcitabine[J].Chin J Gen Surg,2004,19(7):401-3.
[44]IkeguchiM,Liu J,Kaibara N.Expression of survivin mRNA and protein in gastric cancer cell line(MKN-45) during cisplatin treatment[J].Apoptosis,2002,7(1):23-29.
[45]Kappler M,BaeheM,Baterl F,et al.Knock down of survivin expression by small interfering RNA reduce the clonogenic survival of human sarcoma cell lines independently of p53[J].Cancer Gene Ther,2004,11(3):186-93.
[46]Napoli C,Lemieux C,and Jorgensen R.Introduction of a chalcone synthase gene into Petunia results in reversible co-suppression of homologous genes in trans[J].Plant Cell 2,1990:279-289.
[47]Guo S,Kemphues KJ.par-l,a gene required for establishing polarity in C.legans embryos,encodes a putative Ser/ Thr kinase that is asymmetrically distributed[J].Cell,1995,81(4):611-620.
[48]Fire A,Xu S,Montgomery MK,et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J].Nature,1998,391(6669):806-811.
[49]Paddison PJ,Caudy AA,Hanoon GJ,et al.Short hairpin RNAs(shRNAs)indue sequence specific silencing in mammalian cell[J].Genes Dev,2002,16(8):948-958.
[50]Zamore PD.RNA interference:listening to the sound of silence[J].Nat Struct Boil,2001,8(9):746-750
[51]卢听,郑启昌,熊俊,等.siRNA抑制肝癌细胞株HepG2 survivin基因表达的研究[J].华中科技大学学报(医学版),2004,33(6):696-9.
[52]Elbashir SM,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J].Nature,2001, 411(6836): 494-498.
[53] Shin S, Sung BJ, ChoYS, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and- 7 [J]. Biochemistry, 2001, 40 (4):1117-1123.
[54] O'Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin [J]. Proc Natl Acad Sci USA, 2000, 97(24): 13103-13107.
[55] Suzuki A, Ito T, Kawano H, et al. Survivin initiates procaspase-3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death [J].Oncogene,2000,19(10): 1346-1353
[56] Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/pl6(INK4a) and Cdk2/cyclinE complex activation [J].Oncogene,2000,19(29):3225-3234.
[57] Miller VM, Xia H, Marrs GL,et al. Allele-specific silencing of dominant disease genes[J]. Proc Natl Acad Sci USA, 2003, 100(12): 7195-7200.
[58] Bertrand JR, PottierM,VekrisA, et al. Comarison ofantisense oligonucleotides and siRNAs in cell culture andin vivo [J]. Biochem Biophys Res Commun, 2002, 296(4): 1000-1004.
[59] IornsE, Lord CJ, TurnerN, et al.Utilizing RNA interference to enhance cancerdrug discovery [J]. Nat Rev Drug Discov, 2007, 6(7): 556-568.
[60] Gan HZ, Zhang GZ, Zhao JS, et al.Reversal ofMDRl gene dependent multidrug resistance using shorthairpin RNA expression vector [J]. Chin Med J (Engl), 2005, 118(11): 893-902.
[61] Shin S, Sung BJ, ChoY S, et al. An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and-7 [J]. Biochemistry, 2001, 40(4): 1117-1123.
[62] HoffmanWH, Biade S, Zilfou JT,et al.Transcriptional repression of the anti-apoptotic survivin gene by wild type p53 [J]. Biol Chem, 2002, 277(5): 3247-3257.
[63] CaldasH, JiangY, HollowayMP, et al. Survivin splice variants regulate the balance between proliferation and cell death [J]. Oncogene, 2005, 24(12): 1994-2007.
[64] Trojan J, Kim SZ, Engels K, et al. In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer [J]. Anticancer Drugs. 2005, Jan; 16(1):87-91
[65] Grivicich I, Regner A, da Rocha AB, et al. The irinotecan/5-fluorouracil combination induces apoptosis and enhances manganese superoxide dismutase activity in HT-29 human colon carcinoma cells [J]. Chemotherapy. 2005, May; 51(2-3):93-102.
[66] Yokoi K, Kim SJ, Thaker P, et al. Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice [J]. Neoplasia. 2005, Jul; 7(7):696-704.
[67] Kanda T, Tada M, Imazeki F, et al. 5-aza-2'-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines [J]. Oncol Rep. 2005, Oct; 14(4):975-979.
[68] Cecconi D, Donadelli M, Scarpa A, et al. Proteomic Analysis of Pancreatic Ductal Carcinoma Cells after Combined Treatment with Gemcitabine and Trichostatin A. J Proteome Res [J]. 2005, Dec 12; 4(6): 1909-1916.
[69] Nomura T, Yamasaki M, Nomura Y, et al. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells [J]. Oncol Rep, 2005, 14(4): 993-997.
[70] Wang L, Zhang GM, Feng ZH. Down-regulation of survivin expression reversed multidrug resistance in adriamycin-resistant HL-60/ADR cell line [J]. Aeta Pharmacol Sin, 2003, 24(12): 1235-1240.
[71] Tarnawski A, Pai R, Chiou SK, et al. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B [J]. Biochem Biophys Res Commun, 2005, 334(1): 207-212.
[72] Zhang M, Mukherjee N, Bermudez RS, et al. Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo [J]. Prostate, 2005, 64(3): 293-302.
[73] IkeguchiM, Liu J, Kaibara N. Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment [J].Apoptosis, 2002, 7(1): 23-29.
[74] Jiang X,Wilford,Duensing S,et al. Participation of survivin in mitotic and apoptotic activities of normal and tumor-derived cells [J].Cell Biochem, 2001, 83(2): 342-354.
[75] Guan HT, Xue XH, Dai ZJ, et al. Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity [J]. World J Gastroenterol. 2006 May 14; 12(18):2901-7.
[76] Chandler NM, Canete JJ, Callery MP. Caspase-3 drives apoptosis in pancreatic cancer cells after treatment with gemcitabine [J]. J Gastrointest Surg. 2004, Dec; 8(8): 1072-1078.
[77] Nabhan C, Gajria D, Krett NL, et al. Caspase activation is required for gemcitabine activity in multiple myeloma cell lines [J]. Mol Cancer Ther. 2002, Nov; 1(13):1221-1227.
[78] Zhang S, Ding F, Luo A, et al. XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics [J]. Cancer Biol Ther. 2007 Jun; 6(6):973-80. Epub 2007 Mar 26.
[79] Lopes RB, Gangeswaran R, Mc Neish IA, et al. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy [J]. Int J Cancer. 2007 Jun 1; 120(11):2344-52.
[1]Ahmedin J,Rebecca S,Elizabeth W,et al.Cancer Statistics,2007[J].CA Cancer J Clin 2007;57:43-66.
[2]李新建.上海市胰腺癌的流行现状和趋势研究.外科理论与实践[J].2002;7(5):342-345.
[3]Aristu J,Canon R,Pardo F,et al.Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer[J].Am J Clin Oncol,2003;26(1):30-36.
[4]Breslin TM,Hess KR,Harbison DB,et al.Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas:treatment variables and survival duration[J].Ann Surg Oncol.2001;8:123-132.
[5]Perona R,Sanchez-Perez I.Control ofoncogenesis and cancer therapy resistance [J].Br J Cancer.2004;90(3):573-7.
[6]Nicholson DW.From bench to clinic with apoptosis-based therapeutic agents[J].Nature.2000;407:810-816.
[7]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol.1993;67:2168-74.
[8]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001;40(4),1117-1123.
[9]Burris HA,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial[J].J Clin Oncol.1997;15:2403-2413.
[10]Regine WF,Winter KW,Abrams R,et al.RTOG 9704 a phase Ⅲ study of adjuvant pre and post chemoradiation(CRT) 5-FU vs.gemcitabine(G) for resected pancreatic adenocarcinoma[J].J Clin Oncol.2006;24:4007.
[11]Neoptolemos JP,Dunn JA,Stocken DD,et al.Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer:a randomised controlled trial[J].Lancet.2001;358:1576-1585.
[12]Oettle H,Post S,Neuhaus P,et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer:a randomized controlled trial[J].JAMA.2007;297:267-277.
[13] ESPAC-3(v2) Phase Ⅲ Adjuvant Trial in Pancreatic Cancer Comparing 5FU and D-L-Folinic Acid vs. Gemcitabine [J]. National Cancer Research Network Trials Portfolio, 2004. (ISRCTN 37494643)
[14] Neoptolemos JP, StockenDD, FriessH, eta.l A randomized trial of chemoradio- therapy and chemotherapy after resection of pancreatic cancer [J]. N Engl JMed, 2004, 350(12): 1200-1210.
[15] Mornex F, Andre T, Louvet C, et al. Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: a multicenter phase Ⅱ study [J]. Proc Am Soc Clin Oncol. 2007; 25: 18s. Abstract 4520.
[16] Kim R, Saif MW. Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer? [J]. J Pancreas (Online), 2007; 8:279-288.
[17] Chauffert B, Mornex F, Bonnetain F, et al. Phase Ⅲ trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study [J]. J Clin Oncol. 2006; 24:4008.
[18] Posner M, Chang KJ, Rosemurgy A, et al. Multi-center phase Ⅱ/Ⅲ randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC) [J]. Proc Am Soc Clin Oncol. 2007; 25: 18s. Abstract 4518.
[19] Farrow B, Evers BM. Inflammation and the development of pancreatic cancer[J]. Surg Oncol. 2002; 10.153-169.
[20] Rasmussen H, Rasmussen C, Lempicki M, et al. TNFerade biologic: preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene [J]. Cancer Gene Ther. 2002; 9:951-957.
[21] BurrisHA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial [J]. J Clin Oncol, 1997; 15(6): 2403-2413.
[22] Prost P, Ychou M, Azria D. Gemcitabine and pancreatic cancer [J]. Bull Cancer, 2002; 89(1): 91-95.
[23] StathopouiosGP, SyrigosK, AravantinosG, eta.l Amulticenter phaseⅢtrial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patientswith locally advanced ormetastatic pancreatic cancer [J]. Br J Cancer, 2006; 95(5): 587-592.
[24] Saif MW. Pancreatic cancer: is this bleak landscape finally changing? Highlights from the '43rd ASCO Annual Meeting'. Chicago, IL, USA. June 1-5, 2008 [J]. J Pancreas (Online), 2007; 8:365-373.
[25] Cunningham D, Chau I, Stocken C, et al. Phase Ⅲ randomized comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer [J]. Eur J Cancer Suppl. 2005;3: 12. Abstract PS11.
[26] Song HS, Do YR, Chang HM, et al. A phase Ⅱ study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer [J]. Cancer Chemother Pharmacol. 2008 Jan 3; Epub ahead of print.
[27] Ore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group [J]. J Clin Oncol. 2007; Epub ahead of print.
[28] Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase Ⅲ study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study [J]. Proc Am Soc Clin Oncol 2007; 25:18s. Abstract LBA4509.
[29] Suwa H, Ohshio G, Arao S, et al. Immunohistochemical localization of P-glycoprotein and expression of the multidrug resistance-1 gene in human pancreatic cancer: relevance to indicator of better prognosis [J]. Jpn J Cancer Res 1996; 87(6): 641- 649.
[30] Miller DW, Fontain M, Kolar C, et al. The expression of multidrug resistance- associated protein (MRP) in pancreatic adenocarcinoma cell lines [J]. Cancer Lett 1996; 107(2): 301-306.
[31] Izquierdo MA, Scheffer GL, Flens MJ,et al. Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors [J]. Am J Pathol 1996; 148(3):871-877.
[32] Pallares-Trujillo J, Lopez-Soriano FJ, Argiles JM. Lipids: A key role in multidrug resistance? (Review) [J]. Int J Oncol 2000; 16(4): 783-798.
[33] Collier JD, Bennett MK, Hall A, et al. Expression of glutathione S-transferases in normal and malignant pancreas, an immunohistochemical study [J].Gut 1994; 35(2): 266-269.
[34] Nio Y, Dong M, Uegaki K, et al. p53 expression affects the efficacy of adjuvant chemotherapy after resection of invasive ductal carcinoma of the pancreas [J]. Anticancer Res 1998; 18(5B): 3773-3779.
[35] Shoemaker RH.Genetic and epigenetic factors in anticancer drug resistance [J]. J Natl Cancer Inst. 2000; 92(l):4-5.
[36] De Cesare M, Perego P, Rigbetti SC, et al. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts [J]. Eur J Cancer, 2005,41(8): 1213-1222.
[37] Kim R, Emi M, Tanabe K, et al. Therapeutic potential of antisense Bcl-2 as a chemosensitizer for cancer therapy [J]. Cancer, 2004, 101(11):2491-2502.
[38] Kim R, Tanabe K, Emi M, et al. Modulation of tamoxifen sensitivity antisense Bcl-2 and trastuzumab in breast carcinoma cells [J]. Cancer, 2005, 103(10): 2199-2207.
[39] Itob M, Noutomi T, Chiba H, et al. Bcl-xL antisense treatment sensitizes Bcl-xL-overexpressing squamous cell carcinoma cells to carboplatin [J]. Oral Oncol, 2002, 38 (8):752-756.
[40] Hopkins Donaldson S, Cathomas R, et al. Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bel-xL antisense treatment [J]. Int J Cancer, 2003,106 (2): 160-166.
[41] Simoes Wust AP, Schurpf T, Hall J, et al. Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. Breast Cancer Res Treat, 2002, 76 (2):157-166.
[42] Okouoyo S, Herzer K, Ucur E, et al. Rescue of death receptor and mitochondrial apoptosis signaling in resistant human NSCLC in vivo [J]. Int J Cancer, 2004, 108(4)580-587.
[43] Notarbartolo M, Cervello M, Poma P, et al. Expression of the IAPs in multidrug resistant tumor cells [J]. Oncol Rep,2004, 11( I): 133-136.
[44] Miller DW, Batrakova EV, Kabanov AV.et al. Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers [J]. Pharm Res 1999; 16(3): 396-401.
[45] Grunicke H, Hofmann J, Utz I, et al. Role of protein kinases in antitumor drug resistance [J]. Ann Hematol 1994; 69(Suppl l):Sl-6.
[46]Stein U,Walther W,Shoemaker RH,et al.Modulation of mdrl expression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance[J].Br J Cancer 1996;74(9):1384-1391.
[47]Wstanabe N,Tsuji N,Tsuji Y,et al.Endogenous Tumor Necrosis Factor Inhibits the Cytotoxicity of Exogenous Tumor Necrosis Factor and Adriamycin in Pancreatic Carcinoma Cells[J].Pancreas 1996;13(4):395-400.
[48]Holm PS,Scanlon KJ,Dietel M.Reversion of multidrug resistance in the P-glycoprotein-positive human pancreatic cell line(EPP85-181RDB) by introduction of a hammerhead ribozyme[J].Br J Cancer 1994;70(2):239-243.
[49]Kommann M,Danenberg KD,Arber N,et al.Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes[J].Cancer Res 1999;59(14):3505-3511.
[50]Stromskaya TP,Rybalkina EY,Shtil AA,et al.Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines[J].Br J Cancer 1998;71(11):1718-1725.
[51]MichaelisM,Kotchetkov R,Voge JU,et al.Cytomegalovirus infection blocks apoptosis in cancer cells[J].CMLS,Cell Mol Life Sci,2004,61(11):1307-1316.
[52]Asselin E,Mills GB,Tsang BK.XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells[J].Cancer Res,2001,61(5):1862-1868.
[53]夏曙,于世英.抑制PI3K/Akt信号转导通路提高化疗效果的实验研究[J].肿瘤,2006,26(4):311-313.
[54]Amy S.Clark,KipWest,Samantha Streicher,et al.Constitutive and Inducible Akt Activity PromotesResistance to Chemotherapy,Trastu-zumab,or Tamoxifen in Breast Cancer Cells[J].Molecular Cancer Therapeutics,2002,1(9):707-717.
[55]Mee Joo,JeG Chi,Hyucksang Lee.Expressions of HSP70 and HSP27 in Hepato- cellular Carcinoma[J].Korean Med Sci,2005,20(5):829-834.
[56]Kaur J,Kaur J,Ralhan R.Induction of apoptosis by abrogation of HSP70expression in human oral cancer cells[J].Int J Cancer,2000,85(1):1-5.
[57]Nylandsted J,RohdeM,Brand K,et al.Selective depletion of heat shock protein 70(Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2[J].Proc Natl Acad SciUSA,2000,97(14):7871-7876.
[58]Roussel E,Belanger M M,Couet J.G2 /M blockade by paclitaxel induces caveolin-1 expression inA549 lung cancer cells:caveolin-1 as amarker of cytotoxicity[J].Anticancer Drugs,2004,15(10):961-967.
[59]王立忠,贺兼斌,李杰平,等槲皮素联合顺铂对肺腺癌小鼠移植瘤及NF-κB和HIF-1a表达的影响[J].中国现代医学杂志,2006,16(9):1349-1357.
[60]Nadia Zaffaroni,Marzia Pennat,i Maria Grazia Daidone.Survivin as a target for new anticancer interventions[J].J.Cel.1 Mo.1 Med.,2005,9(2):360-372.
[61]Shin S,Sung BJ,ChoYS,et al.An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and-7[J].Biochemistry,2001,40(4):1117-1123.
[62]HoffmanWH,Biade S,Zilfou JT,et al.Transcriptional repression of the anti-apoptotic survivin gene by wild type p53[J].Biol Chem,2002,277(5):3247-3257.
[63]CaldasH,JiangY,HollowayMP,et al.Survivin splice variants regulate the balance between proliferation and cell death[J].Oncogene,2005,24(12):1994-2007.
[64]IkeguchiM,Liu J,Kaibara N.Expression of survivin mRNA and protein in gastric cancer cell line(MKN-45) during cisplatin treatment[J].Apoptosis,2002,7(1):23-29.
[65]JiangX,W ilford,Duensing S,et al.Participation of survivin in mitotic and apoptotic activities ofnormal and tumor-derived cells[J].Cell Biochem,2001,83(2):342-354.
[66]吴耀辉,邹萍,刘芳,等.多种化疗药对凋亡抑制蛋白Survivin在HL-60细胞中表达的影响[J].中国实验血液学杂志,2006,14(2):347-350.
[67]Lopes EC,Garcia MG,Vellon L,et al.Correlation between decreased apoptosis and multidrug resistance(MDR) in murine leukemic T cell lines[J].Leuk Lymphoma,2001,42(4):775-787.
[68]Palissot V,Belhoussine R,Carpentier Y,et al.Resistance to apoptosis induced by topoisomerase I inhibitors in multi-drug-resistant HL60 leukemic cells[J].Biochem Biophys Res Commun,1998,245(3):918-922.
[69]Robinson LJ,Roberts WK,Ling TT,et al.Human MDR 1 protein overexpression delays the aooototic cascade in Chinese hamster ovary fibroblasts [J]. Biochemistry, 1997, 36(37): 11169-11178.
[70] StrobelT, TaiYT, Korsmeyer S,et al. BAD partly reverses paclitaxel resistance in human ovarian cancer cells [J].Oncogene, 1998, 17(19): 2419-2427.
[71] Naijie Jing, Yidong Li,Weijun Xiong, et al.G-Quartet Oligonucleotides: A New Class of Signal Transducer andActivator of Transcription 3 Inhibitors That Suppresses Growth of Prostate and Breast Tumors through Induction of Apoptosis [J]. Cancer Research, 2004, 64(18): 6603-6609.
[72] Malay Mandal, Christine Borowsk,i Teresa Palomero,et al. The BCL2A1 gene as a pre-T cell receptor-induced regulatorof thymocyte survival [J]. JEM, 2005, 201(4): 603-614.
[73] Simone Fulda, Klaus-Michael Debatin. Sensitization forAnticancer Drug-Induced Apoptosis by Betulinic Acid [J]. Neoplasia, 2005, 7(2): 162-170.
[74] CarlosA Lopez, Eric TKimchi, Helena JMauceri, et al. Chemoinducible gene therapy: A strategy to enhance doxorubicin antitumor activity [J].Molecular Cancer Therapeutics, 2004, 3 (9): 1167-1175.
[75] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans [J]. Nature, 1998, 391 (6669): 806-811.
[76] Paddison PJ, Caudy AA, Hanoon GJ, et al. Short hairpin RNAs (shRNAs) indue sequence-specific silencing in mammalian cell [J].Genes Dev, 2002, 16(8): 948- 958.
[77] Bartel, DP. MicroRNAs: genomics, biogenesis, mechanism, and function [J]. Cell, 2004, 116(2): 281-297.
[78] Ramaswamy G, Slack FJ.SiRNA:A guide for RNA silencing [J]. Chem Biol, 2002,9(10): 1053-1055
[79] Zhang H, Kolb FA, Jaskiewicz L, et al. Single processing center models for human Dicer and bacterial RNase Ⅲ [J]. Cell, 2004, 118(1): 57-68.
[80] Zeng Y, Yi R, Cullen BR. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha [J]. EMBO J, 2005, 24(1): 138-148.
[81] Rivas FV, Tolia NH, Song JJ, et al. Purified Argonaute2 and an siRNA form recombinant human RISC [J]. Nat Struct MolBiol, 2005, 12(4): 340-349.
[82] Lingel A, Izaurralde E. RNAi: Finding the elusive endonuclease [J]. RNA, 2004, 10(11):1675-1679
[83] Schwarz DS, Hutvagner G, Du T, et al. Asymmetry in the assembly of the RNAi enzyme complex [J]. Cell, 2003, 115(2): 199-208.
[84] Song JJ, Smith SK, Hannon GJ, et al. Crystal structure of Argonaute and its implications for RISC slicer activity. Science, 2004, 305(5689): 1434-1437.
[85] Zeng Y, Cullen BR. Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences [J]. Biol Chem, 2005, 280(30): 27595-27603
[86] Pham JW, Pellino JL, Lee YS, et al. A Dicer-2-dependent 80s complex cleaves targeted mRNAs during RNAi in Drosophila [J]. Cell, 2004, 117(1): 83-94.
[87] Preall JB, Sontheimer EJ. RNAi: RISC Gets Loaded [J]. Cell, 2005, 123(4):543- 545.
[88] Hammond M. Dicing and slicing: the core machinery of the RNA interference pathway [J]. FEBS Lett, 2005, 579(26): 5822-5829.
[89] Winston WM, Molodowitch C, Hunter CP. Systemic RNAi in Celegans requires the putative transmembrane protein SED-1 [J]. Science, 2002, 295(5564): 2456- 2459.
[90] Kawasaki H, Taira K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells [J]. Nature, 2004, 431(7005): 211-217.
[91] Morris KV, Chan SW L, Jacobsen SE, et al. Small interfering RNA-induced transcriptional gene silencing in human cells [J]. Science, 2004, 305(5688): 1289-1292
[92] Grishok A, Pasqulnelli AE, Conte JM, et al. Genes and mechanisms related to RNA interference regulate expression of small temporal RNAs that control C. elegants developmental timing [J]. Cell, 2001, 106(1): 23-24.
[93] Pillai RS, Bhattacharyya SN, Artus CG, et al. Inhibition of translational Initiation by let-7 microRNA in human cells [J]. Science,2005, 309(5740): 1573-1576
[94] 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. [95] Lieberman J, Song E, Lee SK, et al. Interfering with disease: opportunities and roadb locks to harnessing RNA interference [J]. Trends Mol Med, 2003, 9(9): 397-403. [96] Jacque JM, Triques K, Srevenson M.Modulation of HIV- 1replication by RNA interference [J]. Nature, 2002, 418(13):435-438.
[97] Lee NS, Dohhjima T, Baner G, at al. Ex-pression of small inteference RNAs targeted against HIV-1rev transcriptions in human cells [J]. Nat Biotechool, 2002, 20 (19):500-505.
[98] Novina CD, Murray MF, Dykxhoorn DM, et al. siRNA-directed inhibition of HIV-linfection [J]. Nat Med, 2002, 8(15):681-686.
[99] Kapadia SB, Brideau-Andersen A, Chisari FV. Interference of hepatitis C virus RNA replication by short interfering RNAs [J]. Proc Natl Acad Sci USA,2003, 100 (4):2014-2018.
[100] McCaffrey AP, Nakai H, Pandey K, et al. Huang ZInhibition of hepatitis B virus in mice by RNA interference [J]. Nat Bioechnol, 2003, 21(6):639-644.
[101]Dector MA, Romero P, Lopez S, et al. Rotavirus gene silencing by small interfering RNAs [J]. EMBO Rep, 2002, 3(12):1175-1180.
[102] Gitlin L, Karekskg S, Andino R. short interfering RMA confers intracellular antiviral immunity in human cells [J]. Nature, 2002, 418:430-434.
[103]Lichner Z, Silhavy D, Burgyan J. Double-stranded RNA-binding proteins could suppress RNA interference-mediated anti-viral defences [J]. Gen Virol, 2003 84(pt4):975-980.
[104]Brumme lkamp TR, Bernards R, Afami R. Stable suppression of tummor orige-icity by virus-mediated RNA interference[J]. Cancer Cell,2002,2(3): 243- 247.
[105]Scherr M, Battmer K, Winkler T, et al. specific inhibition of bcr-abl gene expression by small interfering RNA[J]. Blood, 2003, 101(4):1556-1559.
[106]Heidenreich O, Krauter J. Riehle HAML/MTG8oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells [J]. Blood, 2003, 101(8):3157-3163.
[107]Bergamaschi D, Samuels V.0 'Neil NJiASPP oncoprotein is a key inhibitor of p53 conserved from worm to human [J]. Nat Genet, 2003, 33(2): 162-167.
[108] Ambrosini G, Adida C, Altieri DC.A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma [J]. Nature Med, 1997, 3(8): 917-921.
[109]Takahashi R, Deveraux Q, Tamm I, et al. A single BIR domain of XIAP sufficient for inhibiting caspase [J].J Biol Chem, 1998, 273(14):7787.
[110]Badran A,yoshida A,Ishikawa K,et al,Identification of anovel splice variant of the human anti-apoptopsis gene surviving[J].Biochem Biophys Res Commum, 2004; 314(3): 902.
[111] Ambrosini G, Adida C, Sirugo G,et al, Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting [J]. J Biol Chem, 1998,273(18): 11177-11182.
[112] Uren A G, Wang 1, Pakusch M, et al.Survivin and the inner cen-tromere protein INCENP show similar cell-cycle localization andgene knockout phenotype[J]. Curr Biol, 2002; 10(21):1319.
[113]Chakravarti A, Noll E, Black PM, et al. Quantitatively delennined survivin expression levels are of prognostic value in human gliomas [J]. J Clin Oncol, 2002, 20(4): 1063-1068.
[114] Deveraux QL, Reed JC.IAP family proteins-suppressors of apoptosis [J]. Genes, 1999; 13(3):239-252.
[115] Li F, Ambrosini G,,Chu EY,et al. Control of apoptosis and mitotic spindle checkpoint by surviving [J]. Nature, 1998, 396(6711):580.
[116] Skoufias DA, Mollinari C, Lacroix FB, et al.Human survivin is a kinetochore- associated passenger protein[J].J Cell Biol,2000,15( 7): 1575.
[117] Zhao J, Tenev T, Martins, et al. The ubiquitin-protrasone pathway regulates survivin degradation in a cell cycle-dependent manner [J].J Cell Sci, 2000,113 (23): 4363.
[118] Suzuki A, Hayashida M, Ito T, et al, survivin initiates cell cycle entry by the complex activation with CDK4/pl6(INK4a) and CDK2,cyclinE complex activation[J]. Oncogene, 2000; 19(29):3225-3234.
[119] Suzuki A,Ito T,Kawano H,et al. Survivin initiates procaspase/P21 complex formation as a result of interaction with CDK4 to resist FAS-mediated cell death [J].Oncogene, 2000; 19(10): 1346-1353.
[120]Wheatley SP, Kandels L, Adams RR, et al. INCENP binds directly to tubulin, and requires dynamic microtubules to target to the cleavage furrow [J].Exp, Cell Res, 2001b.262.122-127.
[121] O'Connor D S, Schechner J S, Adida C, et al.Control of apoptosis during angiogenesis by Survivin expression in endothelial cells[J].Am J Pathol,2000; 156(2):393-398.
[122]Papapetropoulos A, Fulton D, Mubboubi K, et al. Angiopioetin-1 inhibits endothelial cell [J].J Biol Chem, 2000; 275(13):9102.
[123]Harfouche R, Hassessian HM, Guo Y, et al. Mechanisms which mediate the antapoptotic effects of angiopoietin-1 on endothelial cells [J].Microvase Res, 2002, 64(1): 135-147.
[124] Alticri DC.Validating surviving as a cancer therapeutic target [J]. Nat. Rev. Cancer, 2003; 3:46-54.
[125] Tamm I, Wang Y, Sausville E, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs [J]. CancerRes, 1998, 58 (23): 5315-5320.
[126] Lu CD, Altieri DC.Tanigawa N.Expression of a novel anti-apoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas [J].Cancer Res,1998;58(9):1808.
[127]Endoh A,Asanuma K,Moriai R,et al.Expression of surviving mRNA in CD34-positive cells[J].Clin Chim AcTa,2001;306:149-151.
[128] Kawasaki H, Altieri DC, Lu CD,et al.Unhibition of apoptosis by survivin predicts Shorter survivin rates in colorectal cancer[J]. Cancer Res, 1998; 56(22):5071.
[129] Swana HS, Grossman D, Anthony JN, et al.Tumor content of the anti-apoptosis molecule survivin and recurrence of bladder cancer [J]. N Engl J Med, 1999; 341:452-453.
[130]ZHang Xiang-yang,Zeng Qiang,QI Fan,et al.Expression of survivin protein in prostate cancer and its clinical sign ificance[J].China Journl Of Modern Medicine,2006; 16:1060-1062.
[131] Mono M,Rosell R,Felip E,et al.A novel anti-apoptosis gene Rexpression of survivin messenger RNA as a prognosis marker in nonsmall-cell lung cancers[J].J Clin Oncol,1999;17:2100-2104.
[132] Satoh K, Kaneko K, Hirota M, et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct carcinoma[J].Cancer,2001,92(2):271-278.
[133] Smith SD,Wheeler MA,Plescia J,et al.Urine detection of survivin and diagnosis of bladder cancer[J].JAMA,2001;17;285(3):324-328.
[134]Kishi H, Igawa M, Kikuno N, et al. Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis [J]. J Urol, 2004, 171(5): 1855.
[135] Kren L, Brazdil J, Hermanova M, et al. Prognostic significance of anti-apoptosis proteins surviving and bcl-2 in non-small cell lung carcinomas: a clinicopathologic study of 102 cases [J]. App Immunohistochem Mol Morphol, 2004, 12(1):44.
[136]Nakamura M,Tsuji N,Asanuma K,et al. Survivin as a predictor of cis- diamminedichloroplatinum sensitivity in gastric cancer patients[J].Cancer Sci, 2004, 95(1):44-51.
[137]Kato l.Kuwababa Y, Mitani M,et al.Expression of surviving in esophageal cancer: correlation with the prognosis and response to chemotherapy[J]. lnt J Cancer, 2001,95 (2):92-95.
[138]Olie RA, Simoes-Wust AP, Banmann B,et al.Anovel antisense oligonucleotide targeting surviving expression induces apoptosis and sensitizes lung cancer cells to chemotherapy [J]. Cancer Res, 2000, 60(11):2805-2809.
[139]Newcomb EW. Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity [J]. Anticancer Drugs, 2004.15(5):411-419.
[140] Tu SP,Cui JT,Liston P, et al. Gene therapy for colon cancer by adeno-associated viral vector-mediated transfer of survivin Cys84Ala mutant[J] Gastroenterology, 2005, 128(2): 361-375.
[141]Fonaro M,Plescia J,Chheng S,et al.Fibronectin protects prostate cancer cells from tumor mecrosisi factor-alpha induced apoptosisi via the AKT/surviving pathway[J].J boil chem,2003;278(50):50402-50411.
[142] Ansell SM, Arendt BK, Grote DM.Inhibition of surviving expression suppresses the growth of aggressive non-hodgkin's lymphoma [J]. Leukemia, 2004;18(3). 616-623.
[143]Marzia P,Mara B,Micheiandrea DC.Ribozyme-mediated down-regulation of surviving expression sensitizes human melanoma cells to potecan in vitro and in invo[J].Carcinogenesis,2004;10(5):1093.
[144] Choi KS, Lee TH, Jung MH. Ribozyme-mediated cleavage of the human survivin mRNA and inhibition of antiapoptotic function of survivin in MCF-7 cells [J]. Cancer Gene Then 2003; 10(2):87-95.
[145] Fire A, Xu S, Montgomery MK, et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J]. Nature, 1998; 391(6669): 806-811.
[146]Kappler M,Bache M,Bartel F,et al.Knockdown of survivin expression by small interfering RNA reduces the clonogenic surviving of human sarcoma cell lines independently of p53[J].Cancer Gene Ther, 2004;11(3): 186-193.
[147] Schmitz M, Diestelkoetter P, Weigle B , et al . Generalion of survivin-specific CD8+T effector cells by dendritic cells pulsed with protein or selected peptides [J]. Cancer Res, 2000, 60:4845-4849.
[148]Wobser M, Keikavoussi P, Kunzmann V, et al. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin [J]. Cancer Immunol Immunother. 2006; 55(10): 1294-8.
[149] Nomura T, Yamasaki M, Nomura Y, et al. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells [J]. Oncol Rep, 2005, 14(4):993-997.
[150] Wang L, Zhang GM, Feng ZH. Down-regulation of survivin expression reversed multidrug resistance in adriamycin-resistant HL-60/ADR cell line [J]. Aeta Pharmacol Sin, 2003, 24(12): 1235-1240.
[151] Tarnawski A, Pai R, Chiou SK, et al. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B [J]. Biochem Biophys Res Commun, 2005, 334(1): 207-212.
[152] Zhang M, Mukherjee N, Bermudez RS, et al. Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo [J]. Prostate, 2005, 64(3):293-302.
[2]李新建.上海市胰腺癌的流行现状和趋势研究[J].外科理论与实践.2002;7(5):342-345.
[3]Aristu J,Canon R,Pardo F,et al.Surgical resection after preoperative chemo radiotherapy benefits selected patients with unresectable pancreatic cancer[J].Am J Clin Oncol,2003;26(1):30-36.
[4]Breslin TM,Hess KR,Harbison DB,et al.Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas:treatment variables and survival duration [J].Ann Surg Oncol,2001;8:123-132.
[5]Perona R,Sanchez-Perez I.Control of oncogenesis and cancer therapy resistance [J].Br J Cancer,2004;90(3):573-7.
[6]Thompson CB.Apoptosis in the pathogenesis and treatment of disease[J].Science,1995;267:1456-62.
[7]Nicholson DW.From bench to clinic with apoptosis-based therapeutic agents [J].Nature.2000;407:810-816.
[8]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol.1993;67:2168-74.
[9]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001;40(4),1117-1123.
[10]Ambrosini G,Adida C,Altieri DC.A novel anti-apoptosis gene,survivin,expressed in cancer and lymphoma[J].Nature Med,1997;3(8):917-921.
[11]Hauser HP,Bardroff M,Pyrowolakis G,Jentsch S.A Giant Ubiquitin-conjugating Enzyme Related to IAP Apoptosis Inhibitiors[J].J Cell Biol,1998;141:1415-1422.
[12]Caldas H,Jiang Y,Holloway MP,et al.Survivin splice variants regulate the balance between proliferation and cell death[J].Oncogene.2005;1:1-14.
[13]Satoh K,Kaneko K,Hirota M,et al.Expression of survivin is correlated with cancer cell apoptosis and is involved in the developed in the development of human pancreatic duct cell tumors[J].Cancer.2001;92:271-278.
[14]Liu JW,Li KZ,Dou KF,et al.Survivin antisense oligonucleotide induces apoptosis and sensitizes pancreatic cancer cells to Gemcitabine [J]. Chin J Gen Surg, 2004, 19(7): 401-3
[15] Kojima H, Iida M, Yaguchi Y, et al. Enhancement of Cisplatin sensitivity in squamous cell carcinoma of the head and neck transfected with a survivin antisense gene [J]. Arch Otolaryngol Head Neck Surg. 2006 Jun; 132(6):682-5.
[16] Carl D, Novina, Phillip A.Sharp the RNAi revolution. Nature. 2004; 430: 161-4. [17] Matzke MA, Birchler JA. RNAi-mediated pathways in the nucleus [J].Nature Reviews Genetics.2005; 6:24-35.
[18] Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy [J]. Cancer Gene Therapy. 2005; 12:217-227.
[19] Westphal S, Kalthoff H. Apoptosis: targets in pancreatic cancer [J]. Mol Cancer, 2003, 2(1): 6.
[20] Takahashi R, Deveraux Q, Trmm I, et al. A single BIR domain of XIAP sufficient for inhibiting caspases [J].J Biol Chem, 1998; 273, 7787-7790.
[21] Ambrosini G Adida C, Sirugo G, et al. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting[J].J Biol Chem, 1998,273(18): 11177-11182.
[22] LaCasse EC, Baird S, Korneluk RG, et al. The inhibitors of apoptosis and their emerging role in cancer [J].Oncogene, 1998, 17(25): 3247-3259.
[23] Hirohashi Y, Torgoe T, Maeda A, et al.HLA-A24-restricted cytotoxic T lymphocyte epitope of a tumor-associated protein, survivin [J]. Clin Cancer Res, 2002,8(6): 1731-1739.
[24] Grossman D,Meniff JM,U FZ,et al. Expression and targeting of the apoptosis inhibitor, survivin in human melanoma[J].J Invest Dermatol. 1999, 113(6): 1076-1082.
[25] Lu CD, Altieri DC, Tanigawa N, et al. Expression of a novel anti-apoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas[J].Cancer Res, 1998,58(22): 1802-1812.
[26] Kawasaki, Altieri DC, Lu CD, et al. Inhibition of apoptosis by survivin predicts short survival rates in colorectal cancer[J].Cancer Res, 1998, 58 (22): 5071- 5074.
[27] Kennedy SM, Driscoll O, Purcell R, et al. Prognostic importance of survivin in breast cancer[J].Br J Cancer, 2003, 88: 1077-1083.
[28] Monzo M, Roseu R, Felip E, et al. A novel anti-apoptosis gene: Re expression of survivin messenger RNA as a prognosis marker in non small cell lung cancer [J].J Clin Oncol,1999,17(7):2100-2106.
[29]Kami K,Doi R,Koizumi M,et al.Survivin expression is a prognostic marker in pancreatic cancer patients[J].Surgery 2004;136:443-448.
[30]Pennati M,Folini M,Zaffaroni N.Targeting survivin in cancer therapy[J].Expert Opin Ther Targets,2008,12(4):463-476.
[31]Leber R,Enomoto T,McGregor JA,et al.Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcmoma[J].Acta Obstet Gynecol Scand,2002,81(2):162-167.
[32]Jinfeng M,Kimura W,Sakurai F,et al.Histopathological study of intraductal papillary mucinous tumor of the pancreas:special reference to the roles of survivin and p53 in tumorigenesis of IPMT[J].Int J Gastrointest Cancer,2002,32(2-3):73-81.V[33]Qiao JG,Zhang YQ,Yin YC,et al.Expression of survivin in pancreatic cancer and its correlation to expression of Bcl-2[J].World J Gastroenterol,2004,10(18):2759-2761.
[34]梁智勇,刘彤华,罗玉凤,等.存活素在胰腺癌组织中的表达[J].中华病理学杂志,2005;34(2):67-70.
[35]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001,40(4),1117-1123.
[36]Suzuki A,Ito T,Kawano H,et al.survivin initiates procaspase-3/p21 complex formation as a result of interaction with CDK4 to resist Fas mediated cell death [J].Oncoge.2000,19(10):1346-1353.
[37]Andrade F,Roy S,Nicholson D,et al.Granzyme B directly and efficiently cleaves several downstream caspase substrate:implications for CTL-induced apoptosis[J].Immunity,1998,8(4):451-460.
[38]O'Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by endothelial cells[J].Am J Pathol,2000,156(2):393-398.
[39]Suzuki A,Hayashida M,Ito T,et al.Survivin initiates cell cycle entry by the competitive interaction with CDK4(P16(INK4a)and CDK2/cyclin E complex activation[J].Oncogene,2000,19(29):3225-3234.
[40]Mesri M,Wall NR,Li J,et al.Cancer gene therapy using a survivin mutant adenovirus[J].J Clin Invest,2001,108(7):981-990.
[41]Uchida H,Tanaka T,Sasaki K,et al.Adenovirus mediated transfer of siRNA against survivin induced apoptosis and at tenuated tumor cell growth in vitro and in vivo[J].Mol Ther,2004,10(1):162-171.
[42]Asanuma K,Moriai R,Yajima T,et al.Survivin as a radio resistance factor in pancreatic cancer[J].Jpn J Cancer Res,2000,91(11):1204-1209.
[43]Liu JW,Li KZ,Dou KF,et al.Survivin antisense oligonucleotide induces apoptosis and sensitizes pancreatic cancer cells to Gemcitabine[J].Chin J Gen Surg,2004,19(7):401-3.
[44]IkeguchiM,Liu J,Kaibara N.Expression of survivin mRNA and protein in gastric cancer cell line(MKN-45) during cisplatin treatment[J].Apoptosis,2002,7(1):23-29.
[45]Kappler M,BaeheM,Baterl F,et al.Knock down of survivin expression by small interfering RNA reduce the clonogenic survival of human sarcoma cell lines independently of p53[J].Cancer Gene Ther,2004,11(3):186-93.
[46]Napoli C,Lemieux C,and Jorgensen R.Introduction of a chalcone synthase gene into Petunia results in reversible co-suppression of homologous genes in trans[J].Plant Cell 2,1990:279-289.
[47]Guo S,Kemphues KJ.par-l,a gene required for establishing polarity in C.legans embryos,encodes a putative Ser/ Thr kinase that is asymmetrically distributed[J].Cell,1995,81(4):611-620.
[48]Fire A,Xu S,Montgomery MK,et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J].Nature,1998,391(6669):806-811.
[49]Paddison PJ,Caudy AA,Hanoon GJ,et al.Short hairpin RNAs(shRNAs)indue sequence specific silencing in mammalian cell[J].Genes Dev,2002,16(8):948-958.
[50]Zamore PD.RNA interference:listening to the sound of silence[J].Nat Struct Boil,2001,8(9):746-750
[51]卢听,郑启昌,熊俊,等.siRNA抑制肝癌细胞株HepG2 survivin基因表达的研究[J].华中科技大学学报(医学版),2004,33(6):696-9.
[52]Elbashir SM,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J].Nature,2001, 411(6836): 494-498.
[53] Shin S, Sung BJ, ChoYS, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and- 7 [J]. Biochemistry, 2001, 40 (4):1117-1123.
[54] O'Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin [J]. Proc Natl Acad Sci USA, 2000, 97(24): 13103-13107.
[55] Suzuki A, Ito T, Kawano H, et al. Survivin initiates procaspase-3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death [J].Oncogene,2000,19(10): 1346-1353
[56] Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/pl6(INK4a) and Cdk2/cyclinE complex activation [J].Oncogene,2000,19(29):3225-3234.
[57] Miller VM, Xia H, Marrs GL,et al. Allele-specific silencing of dominant disease genes[J]. Proc Natl Acad Sci USA, 2003, 100(12): 7195-7200.
[58] Bertrand JR, PottierM,VekrisA, et al. Comarison ofantisense oligonucleotides and siRNAs in cell culture andin vivo [J]. Biochem Biophys Res Commun, 2002, 296(4): 1000-1004.
[59] IornsE, Lord CJ, TurnerN, et al.Utilizing RNA interference to enhance cancerdrug discovery [J]. Nat Rev Drug Discov, 2007, 6(7): 556-568.
[60] Gan HZ, Zhang GZ, Zhao JS, et al.Reversal ofMDRl gene dependent multidrug resistance using shorthairpin RNA expression vector [J]. Chin Med J (Engl), 2005, 118(11): 893-902.
[61] Shin S, Sung BJ, ChoY S, et al. An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and-7 [J]. Biochemistry, 2001, 40(4): 1117-1123.
[62] HoffmanWH, Biade S, Zilfou JT,et al.Transcriptional repression of the anti-apoptotic survivin gene by wild type p53 [J]. Biol Chem, 2002, 277(5): 3247-3257.
[63] CaldasH, JiangY, HollowayMP, et al. Survivin splice variants regulate the balance between proliferation and cell death [J]. Oncogene, 2005, 24(12): 1994-2007.
[64] Trojan J, Kim SZ, Engels K, et al. In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer [J]. Anticancer Drugs. 2005, Jan; 16(1):87-91
[65] Grivicich I, Regner A, da Rocha AB, et al. The irinotecan/5-fluorouracil combination induces apoptosis and enhances manganese superoxide dismutase activity in HT-29 human colon carcinoma cells [J]. Chemotherapy. 2005, May; 51(2-3):93-102.
[66] Yokoi K, Kim SJ, Thaker P, et al. Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice [J]. Neoplasia. 2005, Jul; 7(7):696-704.
[67] Kanda T, Tada M, Imazeki F, et al. 5-aza-2'-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines [J]. Oncol Rep. 2005, Oct; 14(4):975-979.
[68] Cecconi D, Donadelli M, Scarpa A, et al. Proteomic Analysis of Pancreatic Ductal Carcinoma Cells after Combined Treatment with Gemcitabine and Trichostatin A. J Proteome Res [J]. 2005, Dec 12; 4(6): 1909-1916.
[69] Nomura T, Yamasaki M, Nomura Y, et al. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells [J]. Oncol Rep, 2005, 14(4): 993-997.
[70] Wang L, Zhang GM, Feng ZH. Down-regulation of survivin expression reversed multidrug resistance in adriamycin-resistant HL-60/ADR cell line [J]. Aeta Pharmacol Sin, 2003, 24(12): 1235-1240.
[71] Tarnawski A, Pai R, Chiou SK, et al. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B [J]. Biochem Biophys Res Commun, 2005, 334(1): 207-212.
[72] Zhang M, Mukherjee N, Bermudez RS, et al. Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo [J]. Prostate, 2005, 64(3): 293-302.
[73] IkeguchiM, Liu J, Kaibara N. Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment [J].Apoptosis, 2002, 7(1): 23-29.
[74] Jiang X,Wilford,Duensing S,et al. Participation of survivin in mitotic and apoptotic activities of normal and tumor-derived cells [J].Cell Biochem, 2001, 83(2): 342-354.
[75] Guan HT, Xue XH, Dai ZJ, et al. Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity [J]. World J Gastroenterol. 2006 May 14; 12(18):2901-7.
[76] Chandler NM, Canete JJ, Callery MP. Caspase-3 drives apoptosis in pancreatic cancer cells after treatment with gemcitabine [J]. J Gastrointest Surg. 2004, Dec; 8(8): 1072-1078.
[77] Nabhan C, Gajria D, Krett NL, et al. Caspase activation is required for gemcitabine activity in multiple myeloma cell lines [J]. Mol Cancer Ther. 2002, Nov; 1(13):1221-1227.
[78] Zhang S, Ding F, Luo A, et al. XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics [J]. Cancer Biol Ther. 2007 Jun; 6(6):973-80. Epub 2007 Mar 26.
[79] Lopes RB, Gangeswaran R, Mc Neish IA, et al. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy [J]. Int J Cancer. 2007 Jun 1; 120(11):2344-52.
[1]Ahmedin J,Rebecca S,Elizabeth W,et al.Cancer Statistics,2007[J].CA Cancer J Clin 2007;57:43-66.
[2]李新建.上海市胰腺癌的流行现状和趋势研究.外科理论与实践[J].2002;7(5):342-345.
[3]Aristu J,Canon R,Pardo F,et al.Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer[J].Am J Clin Oncol,2003;26(1):30-36.
[4]Breslin TM,Hess KR,Harbison DB,et al.Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas:treatment variables and survival duration[J].Ann Surg Oncol.2001;8:123-132.
[5]Perona R,Sanchez-Perez I.Control ofoncogenesis and cancer therapy resistance [J].Br J Cancer.2004;90(3):573-7.
[6]Nicholson DW.From bench to clinic with apoptosis-based therapeutic agents[J].Nature.2000;407:810-816.
[7]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol.1993;67:2168-74.
[8]Shin S,Sung BI,Cho YS,et al.An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7[J].Biochemist,2001;40(4),1117-1123.
[9]Burris HA,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial[J].J Clin Oncol.1997;15:2403-2413.
[10]Regine WF,Winter KW,Abrams R,et al.RTOG 9704 a phase Ⅲ study of adjuvant pre and post chemoradiation(CRT) 5-FU vs.gemcitabine(G) for resected pancreatic adenocarcinoma[J].J Clin Oncol.2006;24:4007.
[11]Neoptolemos JP,Dunn JA,Stocken DD,et al.Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer:a randomised controlled trial[J].Lancet.2001;358:1576-1585.
[12]Oettle H,Post S,Neuhaus P,et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer:a randomized controlled trial[J].JAMA.2007;297:267-277.
[13] ESPAC-3(v2) Phase Ⅲ Adjuvant Trial in Pancreatic Cancer Comparing 5FU and D-L-Folinic Acid vs. Gemcitabine [J]. National Cancer Research Network Trials Portfolio, 2004. (ISRCTN 37494643)
[14] Neoptolemos JP, StockenDD, FriessH, eta.l A randomized trial of chemoradio- therapy and chemotherapy after resection of pancreatic cancer [J]. N Engl JMed, 2004, 350(12): 1200-1210.
[15] Mornex F, Andre T, Louvet C, et al. Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: a multicenter phase Ⅱ study [J]. Proc Am Soc Clin Oncol. 2007; 25: 18s. Abstract 4520.
[16] Kim R, Saif MW. Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer? [J]. J Pancreas (Online), 2007; 8:279-288.
[17] Chauffert B, Mornex F, Bonnetain F, et al. Phase Ⅲ trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study [J]. J Clin Oncol. 2006; 24:4008.
[18] Posner M, Chang KJ, Rosemurgy A, et al. Multi-center phase Ⅱ/Ⅲ randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC) [J]. Proc Am Soc Clin Oncol. 2007; 25: 18s. Abstract 4518.
[19] Farrow B, Evers BM. Inflammation and the development of pancreatic cancer[J]. Surg Oncol. 2002; 10.153-169.
[20] Rasmussen H, Rasmussen C, Lempicki M, et al. TNFerade biologic: preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene [J]. Cancer Gene Ther. 2002; 9:951-957.
[21] BurrisHA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial [J]. J Clin Oncol, 1997; 15(6): 2403-2413.
[22] Prost P, Ychou M, Azria D. Gemcitabine and pancreatic cancer [J]. Bull Cancer, 2002; 89(1): 91-95.
[23] StathopouiosGP, SyrigosK, AravantinosG, eta.l Amulticenter phaseⅢtrial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patientswith locally advanced ormetastatic pancreatic cancer [J]. Br J Cancer, 2006; 95(5): 587-592.
[24] Saif MW. Pancreatic cancer: is this bleak landscape finally changing? Highlights from the '43rd ASCO Annual Meeting'. Chicago, IL, USA. June 1-5, 2008 [J]. J Pancreas (Online), 2007; 8:365-373.
[25] Cunningham D, Chau I, Stocken C, et al. Phase Ⅲ randomized comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer [J]. Eur J Cancer Suppl. 2005;3: 12. Abstract PS11.
[26] Song HS, Do YR, Chang HM, et al. A phase Ⅱ study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer [J]. Cancer Chemother Pharmacol. 2008 Jan 3; Epub ahead of print.
[27] Ore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group [J]. J Clin Oncol. 2007; Epub ahead of print.
[28] Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase Ⅲ study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study [J]. Proc Am Soc Clin Oncol 2007; 25:18s. Abstract LBA4509.
[29] Suwa H, Ohshio G, Arao S, et al. Immunohistochemical localization of P-glycoprotein and expression of the multidrug resistance-1 gene in human pancreatic cancer: relevance to indicator of better prognosis [J]. Jpn J Cancer Res 1996; 87(6): 641- 649.
[30] Miller DW, Fontain M, Kolar C, et al. The expression of multidrug resistance- associated protein (MRP) in pancreatic adenocarcinoma cell lines [J]. Cancer Lett 1996; 107(2): 301-306.
[31] Izquierdo MA, Scheffer GL, Flens MJ,et al. Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors [J]. Am J Pathol 1996; 148(3):871-877.
[32] Pallares-Trujillo J, Lopez-Soriano FJ, Argiles JM. Lipids: A key role in multidrug resistance? (Review) [J]. Int J Oncol 2000; 16(4): 783-798.
[33] Collier JD, Bennett MK, Hall A, et al. Expression of glutathione S-transferases in normal and malignant pancreas, an immunohistochemical study [J].Gut 1994; 35(2): 266-269.
[34] Nio Y, Dong M, Uegaki K, et al. p53 expression affects the efficacy of adjuvant chemotherapy after resection of invasive ductal carcinoma of the pancreas [J]. Anticancer Res 1998; 18(5B): 3773-3779.
[35] Shoemaker RH.Genetic and epigenetic factors in anticancer drug resistance [J]. J Natl Cancer Inst. 2000; 92(l):4-5.
[36] De Cesare M, Perego P, Rigbetti SC, et al. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts [J]. Eur J Cancer, 2005,41(8): 1213-1222.
[37] Kim R, Emi M, Tanabe K, et al. Therapeutic potential of antisense Bcl-2 as a chemosensitizer for cancer therapy [J]. Cancer, 2004, 101(11):2491-2502.
[38] Kim R, Tanabe K, Emi M, et al. Modulation of tamoxifen sensitivity antisense Bcl-2 and trastuzumab in breast carcinoma cells [J]. Cancer, 2005, 103(10): 2199-2207.
[39] Itob M, Noutomi T, Chiba H, et al. Bcl-xL antisense treatment sensitizes Bcl-xL-overexpressing squamous cell carcinoma cells to carboplatin [J]. Oral Oncol, 2002, 38 (8):752-756.
[40] Hopkins Donaldson S, Cathomas R, et al. Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bel-xL antisense treatment [J]. Int J Cancer, 2003,106 (2): 160-166.
[41] Simoes Wust AP, Schurpf T, Hall J, et al. Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. Breast Cancer Res Treat, 2002, 76 (2):157-166.
[42] Okouoyo S, Herzer K, Ucur E, et al. Rescue of death receptor and mitochondrial apoptosis signaling in resistant human NSCLC in vivo [J]. Int J Cancer, 2004, 108(4)580-587.
[43] Notarbartolo M, Cervello M, Poma P, et al. Expression of the IAPs in multidrug resistant tumor cells [J]. Oncol Rep,2004, 11( I): 133-136.
[44] Miller DW, Batrakova EV, Kabanov AV.et al. Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers [J]. Pharm Res 1999; 16(3): 396-401.
[45] Grunicke H, Hofmann J, Utz I, et al. Role of protein kinases in antitumor drug resistance [J]. Ann Hematol 1994; 69(Suppl l):Sl-6.
[46]Stein U,Walther W,Shoemaker RH,et al.Modulation of mdrl expression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance[J].Br J Cancer 1996;74(9):1384-1391.
[47]Wstanabe N,Tsuji N,Tsuji Y,et al.Endogenous Tumor Necrosis Factor Inhibits the Cytotoxicity of Exogenous Tumor Necrosis Factor and Adriamycin in Pancreatic Carcinoma Cells[J].Pancreas 1996;13(4):395-400.
[48]Holm PS,Scanlon KJ,Dietel M.Reversion of multidrug resistance in the P-glycoprotein-positive human pancreatic cell line(EPP85-181RDB) by introduction of a hammerhead ribozyme[J].Br J Cancer 1994;70(2):239-243.
[49]Kommann M,Danenberg KD,Arber N,et al.Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes[J].Cancer Res 1999;59(14):3505-3511.
[50]Stromskaya TP,Rybalkina EY,Shtil AA,et al.Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines[J].Br J Cancer 1998;71(11):1718-1725.
[51]MichaelisM,Kotchetkov R,Voge JU,et al.Cytomegalovirus infection blocks apoptosis in cancer cells[J].CMLS,Cell Mol Life Sci,2004,61(11):1307-1316.
[52]Asselin E,Mills GB,Tsang BK.XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells[J].Cancer Res,2001,61(5):1862-1868.
[53]夏曙,于世英.抑制PI3K/Akt信号转导通路提高化疗效果的实验研究[J].肿瘤,2006,26(4):311-313.
[54]Amy S.Clark,KipWest,Samantha Streicher,et al.Constitutive and Inducible Akt Activity PromotesResistance to Chemotherapy,Trastu-zumab,or Tamoxifen in Breast Cancer Cells[J].Molecular Cancer Therapeutics,2002,1(9):707-717.
[55]Mee Joo,JeG Chi,Hyucksang Lee.Expressions of HSP70 and HSP27 in Hepato- cellular Carcinoma[J].Korean Med Sci,2005,20(5):829-834.
[56]Kaur J,Kaur J,Ralhan R.Induction of apoptosis by abrogation of HSP70expression in human oral cancer cells[J].Int J Cancer,2000,85(1):1-5.
[57]Nylandsted J,RohdeM,Brand K,et al.Selective depletion of heat shock protein 70(Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2[J].Proc Natl Acad SciUSA,2000,97(14):7871-7876.
[58]Roussel E,Belanger M M,Couet J.G2 /M blockade by paclitaxel induces caveolin-1 expression inA549 lung cancer cells:caveolin-1 as amarker of cytotoxicity[J].Anticancer Drugs,2004,15(10):961-967.
[59]王立忠,贺兼斌,李杰平,等槲皮素联合顺铂对肺腺癌小鼠移植瘤及NF-κB和HIF-1a表达的影响[J].中国现代医学杂志,2006,16(9):1349-1357.
[60]Nadia Zaffaroni,Marzia Pennat,i Maria Grazia Daidone.Survivin as a target for new anticancer interventions[J].J.Cel.1 Mo.1 Med.,2005,9(2):360-372.
[61]Shin S,Sung BJ,ChoYS,et al.An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and-7[J].Biochemistry,2001,40(4):1117-1123.
[62]HoffmanWH,Biade S,Zilfou JT,et al.Transcriptional repression of the anti-apoptotic survivin gene by wild type p53[J].Biol Chem,2002,277(5):3247-3257.
[63]CaldasH,JiangY,HollowayMP,et al.Survivin splice variants regulate the balance between proliferation and cell death[J].Oncogene,2005,24(12):1994-2007.
[64]IkeguchiM,Liu J,Kaibara N.Expression of survivin mRNA and protein in gastric cancer cell line(MKN-45) during cisplatin treatment[J].Apoptosis,2002,7(1):23-29.
[65]JiangX,W ilford,Duensing S,et al.Participation of survivin in mitotic and apoptotic activities ofnormal and tumor-derived cells[J].Cell Biochem,2001,83(2):342-354.
[66]吴耀辉,邹萍,刘芳,等.多种化疗药对凋亡抑制蛋白Survivin在HL-60细胞中表达的影响[J].中国实验血液学杂志,2006,14(2):347-350.
[67]Lopes EC,Garcia MG,Vellon L,et al.Correlation between decreased apoptosis and multidrug resistance(MDR) in murine leukemic T cell lines[J].Leuk Lymphoma,2001,42(4):775-787.
[68]Palissot V,Belhoussine R,Carpentier Y,et al.Resistance to apoptosis induced by topoisomerase I inhibitors in multi-drug-resistant HL60 leukemic cells[J].Biochem Biophys Res Commun,1998,245(3):918-922.
[69]Robinson LJ,Roberts WK,Ling TT,et al.Human MDR 1 protein overexpression delays the aooototic cascade in Chinese hamster ovary fibroblasts [J]. Biochemistry, 1997, 36(37): 11169-11178.
[70] StrobelT, TaiYT, Korsmeyer S,et al. BAD partly reverses paclitaxel resistance in human ovarian cancer cells [J].Oncogene, 1998, 17(19): 2419-2427.
[71] Naijie Jing, Yidong Li,Weijun Xiong, et al.G-Quartet Oligonucleotides: A New Class of Signal Transducer andActivator of Transcription 3 Inhibitors That Suppresses Growth of Prostate and Breast Tumors through Induction of Apoptosis [J]. Cancer Research, 2004, 64(18): 6603-6609.
[72] Malay Mandal, Christine Borowsk,i Teresa Palomero,et al. The BCL2A1 gene as a pre-T cell receptor-induced regulatorof thymocyte survival [J]. JEM, 2005, 201(4): 603-614.
[73] Simone Fulda, Klaus-Michael Debatin. Sensitization forAnticancer Drug-Induced Apoptosis by Betulinic Acid [J]. Neoplasia, 2005, 7(2): 162-170.
[74] CarlosA Lopez, Eric TKimchi, Helena JMauceri, et al. Chemoinducible gene therapy: A strategy to enhance doxorubicin antitumor activity [J].Molecular Cancer Therapeutics, 2004, 3 (9): 1167-1175.
[75] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans [J]. Nature, 1998, 391 (6669): 806-811.
[76] Paddison PJ, Caudy AA, Hanoon GJ, et al. Short hairpin RNAs (shRNAs) indue sequence-specific silencing in mammalian cell [J].Genes Dev, 2002, 16(8): 948- 958.
[77] Bartel, DP. MicroRNAs: genomics, biogenesis, mechanism, and function [J]. Cell, 2004, 116(2): 281-297.
[78] Ramaswamy G, Slack FJ.SiRNA:A guide for RNA silencing [J]. Chem Biol, 2002,9(10): 1053-1055
[79] Zhang H, Kolb FA, Jaskiewicz L, et al. Single processing center models for human Dicer and bacterial RNase Ⅲ [J]. Cell, 2004, 118(1): 57-68.
[80] Zeng Y, Yi R, Cullen BR. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha [J]. EMBO J, 2005, 24(1): 138-148.
[81] Rivas FV, Tolia NH, Song JJ, et al. Purified Argonaute2 and an siRNA form recombinant human RISC [J]. Nat Struct MolBiol, 2005, 12(4): 340-349.
[82] Lingel A, Izaurralde E. RNAi: Finding the elusive endonuclease [J]. RNA, 2004, 10(11):1675-1679
[83] Schwarz DS, Hutvagner G, Du T, et al. Asymmetry in the assembly of the RNAi enzyme complex [J]. Cell, 2003, 115(2): 199-208.
[84] Song JJ, Smith SK, Hannon GJ, et al. Crystal structure of Argonaute and its implications for RISC slicer activity. Science, 2004, 305(5689): 1434-1437.
[85] Zeng Y, Cullen BR. Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences [J]. Biol Chem, 2005, 280(30): 27595-27603
[86] Pham JW, Pellino JL, Lee YS, et al. A Dicer-2-dependent 80s complex cleaves targeted mRNAs during RNAi in Drosophila [J]. Cell, 2004, 117(1): 83-94.
[87] Preall JB, Sontheimer EJ. RNAi: RISC Gets Loaded [J]. Cell, 2005, 123(4):543- 545.
[88] Hammond M. Dicing and slicing: the core machinery of the RNA interference pathway [J]. FEBS Lett, 2005, 579(26): 5822-5829.
[89] Winston WM, Molodowitch C, Hunter CP. Systemic RNAi in Celegans requires the putative transmembrane protein SED-1 [J]. Science, 2002, 295(5564): 2456- 2459.
[90] Kawasaki H, Taira K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells [J]. Nature, 2004, 431(7005): 211-217.
[91] Morris KV, Chan SW L, Jacobsen SE, et al. Small interfering RNA-induced transcriptional gene silencing in human cells [J]. Science, 2004, 305(5688): 1289-1292
[92] Grishok A, Pasqulnelli AE, Conte JM, et al. Genes and mechanisms related to RNA interference regulate expression of small temporal RNAs that control C. elegants developmental timing [J]. Cell, 2001, 106(1): 23-24.
[93] Pillai RS, Bhattacharyya SN, Artus CG, et al. Inhibition of translational Initiation by let-7 microRNA in human cells [J]. Science,2005, 309(5740): 1573-1576
[94] 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. [95] Lieberman J, Song E, Lee SK, et al. Interfering with disease: opportunities and roadb locks to harnessing RNA interference [J]. Trends Mol Med, 2003, 9(9): 397-403. [96] Jacque JM, Triques K, Srevenson M.Modulation of HIV- 1replication by RNA interference [J]. Nature, 2002, 418(13):435-438.
[97] Lee NS, Dohhjima T, Baner G, at al. Ex-pression of small inteference RNAs targeted against HIV-1rev transcriptions in human cells [J]. Nat Biotechool, 2002, 20 (19):500-505.
[98] Novina CD, Murray MF, Dykxhoorn DM, et al. siRNA-directed inhibition of HIV-linfection [J]. Nat Med, 2002, 8(15):681-686.
[99] Kapadia SB, Brideau-Andersen A, Chisari FV. Interference of hepatitis C virus RNA replication by short interfering RNAs [J]. Proc Natl Acad Sci USA,2003, 100 (4):2014-2018.
[100] McCaffrey AP, Nakai H, Pandey K, et al. Huang ZInhibition of hepatitis B virus in mice by RNA interference [J]. Nat Bioechnol, 2003, 21(6):639-644.
[101]Dector MA, Romero P, Lopez S, et al. Rotavirus gene silencing by small interfering RNAs [J]. EMBO Rep, 2002, 3(12):1175-1180.
[102] Gitlin L, Karekskg S, Andino R. short interfering RMA confers intracellular antiviral immunity in human cells [J]. Nature, 2002, 418:430-434.
[103]Lichner Z, Silhavy D, Burgyan J. Double-stranded RNA-binding proteins could suppress RNA interference-mediated anti-viral defences [J]. Gen Virol, 2003 84(pt4):975-980.
[104]Brumme lkamp TR, Bernards R, Afami R. Stable suppression of tummor orige-icity by virus-mediated RNA interference[J]. Cancer Cell,2002,2(3): 243- 247.
[105]Scherr M, Battmer K, Winkler T, et al. specific inhibition of bcr-abl gene expression by small interfering RNA[J]. Blood, 2003, 101(4):1556-1559.
[106]Heidenreich O, Krauter J. Riehle HAML/MTG8oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells [J]. Blood, 2003, 101(8):3157-3163.
[107]Bergamaschi D, Samuels V.0 'Neil NJiASPP oncoprotein is a key inhibitor of p53 conserved from worm to human [J]. Nat Genet, 2003, 33(2): 162-167.
[108] Ambrosini G, Adida C, Altieri DC.A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma [J]. Nature Med, 1997, 3(8): 917-921.
[109]Takahashi R, Deveraux Q, Tamm I, et al. A single BIR domain of XIAP sufficient for inhibiting caspase [J].J Biol Chem, 1998, 273(14):7787.
[110]Badran A,yoshida A,Ishikawa K,et al,Identification of anovel splice variant of the human anti-apoptopsis gene surviving[J].Biochem Biophys Res Commum, 2004; 314(3): 902.
[111] Ambrosini G, Adida C, Sirugo G,et al, Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting [J]. J Biol Chem, 1998,273(18): 11177-11182.
[112] Uren A G, Wang 1, Pakusch M, et al.Survivin and the inner cen-tromere protein INCENP show similar cell-cycle localization andgene knockout phenotype[J]. Curr Biol, 2002; 10(21):1319.
[113]Chakravarti A, Noll E, Black PM, et al. Quantitatively delennined survivin expression levels are of prognostic value in human gliomas [J]. J Clin Oncol, 2002, 20(4): 1063-1068.
[114] Deveraux QL, Reed JC.IAP family proteins-suppressors of apoptosis [J]. Genes, 1999; 13(3):239-252.
[115] Li F, Ambrosini G,,Chu EY,et al. Control of apoptosis and mitotic spindle checkpoint by surviving [J]. Nature, 1998, 396(6711):580.
[116] Skoufias DA, Mollinari C, Lacroix FB, et al.Human survivin is a kinetochore- associated passenger protein[J].J Cell Biol,2000,15( 7): 1575.
[117] Zhao J, Tenev T, Martins, et al. The ubiquitin-protrasone pathway regulates survivin degradation in a cell cycle-dependent manner [J].J Cell Sci, 2000,113 (23): 4363.
[118] Suzuki A, Hayashida M, Ito T, et al, survivin initiates cell cycle entry by the complex activation with CDK4/pl6(INK4a) and CDK2,cyclinE complex activation[J]. Oncogene, 2000; 19(29):3225-3234.
[119] Suzuki A,Ito T,Kawano H,et al. Survivin initiates procaspase/P21 complex formation as a result of interaction with CDK4 to resist FAS-mediated cell death [J].Oncogene, 2000; 19(10): 1346-1353.
[120]Wheatley SP, Kandels L, Adams RR, et al. INCENP binds directly to tubulin, and requires dynamic microtubules to target to the cleavage furrow [J].Exp, Cell Res, 2001b.262.122-127.
[121] O'Connor D S, Schechner J S, Adida C, et al.Control of apoptosis during angiogenesis by Survivin expression in endothelial cells[J].Am J Pathol,2000; 156(2):393-398.
[122]Papapetropoulos A, Fulton D, Mubboubi K, et al. Angiopioetin-1 inhibits endothelial cell [J].J Biol Chem, 2000; 275(13):9102.
[123]Harfouche R, Hassessian HM, Guo Y, et al. Mechanisms which mediate the antapoptotic effects of angiopoietin-1 on endothelial cells [J].Microvase Res, 2002, 64(1): 135-147.
[124] Alticri DC.Validating surviving as a cancer therapeutic target [J]. Nat. Rev. Cancer, 2003; 3:46-54.
[125] Tamm I, Wang Y, Sausville E, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs [J]. CancerRes, 1998, 58 (23): 5315-5320.
[126] Lu CD, Altieri DC.Tanigawa N.Expression of a novel anti-apoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas [J].Cancer Res,1998;58(9):1808.
[127]Endoh A,Asanuma K,Moriai R,et al.Expression of surviving mRNA in CD34-positive cells[J].Clin Chim AcTa,2001;306:149-151.
[128] Kawasaki H, Altieri DC, Lu CD,et al.Unhibition of apoptosis by survivin predicts Shorter survivin rates in colorectal cancer[J]. Cancer Res, 1998; 56(22):5071.
[129] Swana HS, Grossman D, Anthony JN, et al.Tumor content of the anti-apoptosis molecule survivin and recurrence of bladder cancer [J]. N Engl J Med, 1999; 341:452-453.
[130]ZHang Xiang-yang,Zeng Qiang,QI Fan,et al.Expression of survivin protein in prostate cancer and its clinical sign ificance[J].China Journl Of Modern Medicine,2006; 16:1060-1062.
[131] Mono M,Rosell R,Felip E,et al.A novel anti-apoptosis gene Rexpression of survivin messenger RNA as a prognosis marker in nonsmall-cell lung cancers[J].J Clin Oncol,1999;17:2100-2104.
[132] Satoh K, Kaneko K, Hirota M, et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct carcinoma[J].Cancer,2001,92(2):271-278.
[133] Smith SD,Wheeler MA,Plescia J,et al.Urine detection of survivin and diagnosis of bladder cancer[J].JAMA,2001;17;285(3):324-328.
[134]Kishi H, Igawa M, Kikuno N, et al. Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis [J]. J Urol, 2004, 171(5): 1855.
[135] Kren L, Brazdil J, Hermanova M, et al. Prognostic significance of anti-apoptosis proteins surviving and bcl-2 in non-small cell lung carcinomas: a clinicopathologic study of 102 cases [J]. App Immunohistochem Mol Morphol, 2004, 12(1):44.
[136]Nakamura M,Tsuji N,Asanuma K,et al. Survivin as a predictor of cis- diamminedichloroplatinum sensitivity in gastric cancer patients[J].Cancer Sci, 2004, 95(1):44-51.
[137]Kato l.Kuwababa Y, Mitani M,et al.Expression of surviving in esophageal cancer: correlation with the prognosis and response to chemotherapy[J]. lnt J Cancer, 2001,95 (2):92-95.
[138]Olie RA, Simoes-Wust AP, Banmann B,et al.Anovel antisense oligonucleotide targeting surviving expression induces apoptosis and sensitizes lung cancer cells to chemotherapy [J]. Cancer Res, 2000, 60(11):2805-2809.
[139]Newcomb EW. Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity [J]. Anticancer Drugs, 2004.15(5):411-419.
[140] Tu SP,Cui JT,Liston P, et al. Gene therapy for colon cancer by adeno-associated viral vector-mediated transfer of survivin Cys84Ala mutant[J] Gastroenterology, 2005, 128(2): 361-375.
[141]Fonaro M,Plescia J,Chheng S,et al.Fibronectin protects prostate cancer cells from tumor mecrosisi factor-alpha induced apoptosisi via the AKT/surviving pathway[J].J boil chem,2003;278(50):50402-50411.
[142] Ansell SM, Arendt BK, Grote DM.Inhibition of surviving expression suppresses the growth of aggressive non-hodgkin's lymphoma [J]. Leukemia, 2004;18(3). 616-623.
[143]Marzia P,Mara B,Micheiandrea DC.Ribozyme-mediated down-regulation of surviving expression sensitizes human melanoma cells to potecan in vitro and in invo[J].Carcinogenesis,2004;10(5):1093.
[144] Choi KS, Lee TH, Jung MH. Ribozyme-mediated cleavage of the human survivin mRNA and inhibition of antiapoptotic function of survivin in MCF-7 cells [J]. Cancer Gene Then 2003; 10(2):87-95.
[145] Fire A, Xu S, Montgomery MK, et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J]. Nature, 1998; 391(6669): 806-811.
[146]Kappler M,Bache M,Bartel F,et al.Knockdown of survivin expression by small interfering RNA reduces the clonogenic surviving of human sarcoma cell lines independently of p53[J].Cancer Gene Ther, 2004;11(3): 186-193.
[147] Schmitz M, Diestelkoetter P, Weigle B , et al . Generalion of survivin-specific CD8+T effector cells by dendritic cells pulsed with protein or selected peptides [J]. Cancer Res, 2000, 60:4845-4849.
[148]Wobser M, Keikavoussi P, Kunzmann V, et al. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin [J]. Cancer Immunol Immunother. 2006; 55(10): 1294-8.
[149] Nomura T, Yamasaki M, Nomura Y, et al. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells [J]. Oncol Rep, 2005, 14(4):993-997.
[150] Wang L, Zhang GM, Feng ZH. Down-regulation of survivin expression reversed multidrug resistance in adriamycin-resistant HL-60/ADR cell line [J]. Aeta Pharmacol Sin, 2003, 24(12): 1235-1240.
[151] Tarnawski A, Pai R, Chiou SK, et al. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B [J]. Biochem Biophys Res Commun, 2005, 334(1): 207-212.
[152] Zhang M, Mukherjee N, Bermudez RS, et al. Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo [J]. Prostate, 2005, 64(3):293-302.