Aptamer-protamine-siRNA复合物在肿瘤靶向治疗中的作用研究
|
摘要
肿瘤的治疗一直是临床医生和肿瘤研究专家所面临的难点,虽然现在以手术治疗、化疗以及放疗所结合的治疗手段可以延长肿瘤病人的生存率,但是其长期生存率仍然不理想,生物靶向治疗可能是一种很好的手段,自从RNA干扰技术在蠕虫身上被发现开启了RNAi的研究之后,一系列的研究在哺乳动物身上证明这种RNA干扰是通过siRNA实现的,这推动了基因调控理论的发展,也为基因研究提供了有力工具。逐渐的,RNAi技术开始应用于动物疾病模型的体内实验并且将其用于药物开发的步伐也明显加快。RNAi技术是通过激活选择性的mRNA的剪切以达到有效的基因沉默,虽然现在已经有一些基于RNAi技术的临床实验药物的出现,但不可否认,这几种尚未上市的药物都是局部使用的,而且具有各种各样的缺陷存在。目前存在于RNAi,应用面前主要的难题是采用什么样的载体来靶向的将siRNA运送到细胞里面以及这种载体的安全性问题。
面对上面的三个问题,在本研究中我们设计了一种新的siRNA的载体系统,即aptamer-protamine-siRNA纳米复合物,我们首先通过合成带有FAM的无靶向基因的siRNA制成aptamer-protamine-FAMsiRNA来验证了该复合物是可以靶向的进入到细胞中去的；然后合成了针对EGFP基因的siRNA,制成aptamer-protamine-siEGFP复合物,将其加入到转染了pEGFP质粒的细胞中,发现细胞表达绿色荧光明显减少,EGFP蛋白的表达量也明显减少；然后我们合成了aptamer-protamine-sisurvivin复合物来针对凋亡抑制蛋白家族成员survivin进行干扰,发现经该复合物干扰之后的细胞survivin在mRNA和蛋白质水平都有明显的降低,并且survivin降低后细胞呈现明显的生长变慢、凋亡出现等现象；接着,我们合成了针对细胞周期M期重要激酶的CDK1的aptamer-protamine-siCDKl,发现其对于细胞有明显的细胞阻滞效应,细胞主要阻滞在G2M期,生长速度变慢；在上述的体外实验中我们证实了合成的aptamer-protamine-siRNA是一种有效的siRNA载体之后,我们通过裸鼠成瘤模型来进一步验证了该复合物是一种有效的靶向干扰制剂,对于成瘤的裸鼠进行aptamer-protamine-sisurvivin注射,可以减缓肿瘤的生长,抑制肿瘤的增殖,同时我们对于生长激素是否可以对于生物靶向治疗具有影响在肿瘤模型实验中做了部分证实,我们发现同时注射生长激素组,肿瘤的成瘤更小,这可能和生长激素可以促进肿瘤细胞的增殖进而细胞容易被靶向治疗所干预有关。
通过我们的研究,我们合成了一种新的siRNA的载体,并且在体内外的实验中验证了其靶向性和有效性,这种载体有可能成为肿瘤靶向治疗的新手段。
Cancer therapy is still a difficult subject for doctors and pharmacists, although some radical operations could prolong some cancer patients'5 years or 10 years survival rates, the recurrence of most cancers still need us to deal with, maybe chemotherapy and radiotherapy could make benefits for some patients, but the side effects of them, for example, the normal tissues toxicities of chemotherapy and regional tissues adhesions of radiotherapy still can not be avoided. RNAi might be a good choice for cancer therapy. RNAi therapy is a new and hot way to treat disease by targeting specified genes strongly associated with disease. From the day of discovering RNAi in Caenorhabditis elegans and subsequently the exploration of siRNA in mammalian cells, these years'researches on RNAi have acquired large achievements. It has been not only a tool of gene research in laboratory, but also a way in clinical trials for some diseases therapy. But there are still many problems in RNAi applications, the main of which is the delivery. In recent times, formulations of RNAi in vivo research are mainly as conjugated with cholesterol or aptamer, embedded by liposome or lipoplexes, complexed with peptides or polymers and fused with antibodies. Although these methods of using siRNA could meet the results of silencing specified genes, but there are still some problems to be resolved, such as lack of targeted cell characteristics or high cell membrane toxicities. So, this gives us the enthusiasm to find a safe and effective way to deliver siRNA into targeted cells.
Here we designed a way to use siRNA, which is complexed with protamine and aptamer, so we called aptamer-protamine-siRNA nanoparticle. Then we performed four parts of experiments to verify the potency of the nanoparticle:(1) aptamer-parotamine-FAMsiRNA could be uptaken by cells, (2) aptamer-protamin-siEGFP could downrelgulate the expression of EGFP, (3) aptamer-protamine-sisurvivin could inhibit the expression of survivin, and the cell growth was obviously slower than the control group, some cells went to apoptosis. (4) in vivo test of the interfering effect of aptamer-protamine-siRNA in nude mice, we found that the tumors in aptamer-protamine-sisurvivin nanoparticle group were significantly smaller than vehicle group, and the expression of survivin could also be inhibited in vivo, the cell proliferation in nanoparticle group was significantly inhibited by the detection of PCNA and Ki67, also in this research we explored that growth hormone might have the ability to promote cancer cell's proliferation which could increase the sensitivity of cancer cells to targeted therapy.
Our research showed that aptamer-protamine-siRNA nanoparticle was an effective delivery to carry siRNA into cells and the siRNA could take part in the gene-silence activities. It could not only be a good delivery of siRNA in vitro tests but also be proved to be effective in vivo experiments. This nanoparticle could recognize targeted cells which express aptamer conjunctive antigens by aptamer, the siRNA it carried could inhibit the expression of specified gene, so aptamer-protamine-siRNA nanoparticle could act as a targeted RNAi delivery. This nanoparticle could be used not only on breast cancer but also on other cancers and other diseases just by changing the aptamer to another specified antigen conjunctive aptamer and replacing the siRNA to another gene siRNAs, so aptamer-protamine-siRNA nanoparticle might become a good method for gene silencing research and even for clinical diseases therapy.
面对上面的三个问题,在本研究中我们设计了一种新的siRNA的载体系统,即aptamer-protamine-siRNA纳米复合物,我们首先通过合成带有FAM的无靶向基因的siRNA制成aptamer-protamine-FAMsiRNA来验证了该复合物是可以靶向的进入到细胞中去的；然后合成了针对EGFP基因的siRNA,制成aptamer-protamine-siEGFP复合物,将其加入到转染了pEGFP质粒的细胞中,发现细胞表达绿色荧光明显减少,EGFP蛋白的表达量也明显减少；然后我们合成了aptamer-protamine-sisurvivin复合物来针对凋亡抑制蛋白家族成员survivin进行干扰,发现经该复合物干扰之后的细胞survivin在mRNA和蛋白质水平都有明显的降低,并且survivin降低后细胞呈现明显的生长变慢、凋亡出现等现象；接着,我们合成了针对细胞周期M期重要激酶的CDK1的aptamer-protamine-siCDKl,发现其对于细胞有明显的细胞阻滞效应,细胞主要阻滞在G2M期,生长速度变慢；在上述的体外实验中我们证实了合成的aptamer-protamine-siRNA是一种有效的siRNA载体之后,我们通过裸鼠成瘤模型来进一步验证了该复合物是一种有效的靶向干扰制剂,对于成瘤的裸鼠进行aptamer-protamine-sisurvivin注射,可以减缓肿瘤的生长,抑制肿瘤的增殖,同时我们对于生长激素是否可以对于生物靶向治疗具有影响在肿瘤模型实验中做了部分证实,我们发现同时注射生长激素组,肿瘤的成瘤更小,这可能和生长激素可以促进肿瘤细胞的增殖进而细胞容易被靶向治疗所干预有关。
通过我们的研究,我们合成了一种新的siRNA的载体,并且在体内外的实验中验证了其靶向性和有效性,这种载体有可能成为肿瘤靶向治疗的新手段。
Cancer therapy is still a difficult subject for doctors and pharmacists, although some radical operations could prolong some cancer patients'5 years or 10 years survival rates, the recurrence of most cancers still need us to deal with, maybe chemotherapy and radiotherapy could make benefits for some patients, but the side effects of them, for example, the normal tissues toxicities of chemotherapy and regional tissues adhesions of radiotherapy still can not be avoided. RNAi might be a good choice for cancer therapy. RNAi therapy is a new and hot way to treat disease by targeting specified genes strongly associated with disease. From the day of discovering RNAi in Caenorhabditis elegans and subsequently the exploration of siRNA in mammalian cells, these years'researches on RNAi have acquired large achievements. It has been not only a tool of gene research in laboratory, but also a way in clinical trials for some diseases therapy. But there are still many problems in RNAi applications, the main of which is the delivery. In recent times, formulations of RNAi in vivo research are mainly as conjugated with cholesterol or aptamer, embedded by liposome or lipoplexes, complexed with peptides or polymers and fused with antibodies. Although these methods of using siRNA could meet the results of silencing specified genes, but there are still some problems to be resolved, such as lack of targeted cell characteristics or high cell membrane toxicities. So, this gives us the enthusiasm to find a safe and effective way to deliver siRNA into targeted cells.
Here we designed a way to use siRNA, which is complexed with protamine and aptamer, so we called aptamer-protamine-siRNA nanoparticle. Then we performed four parts of experiments to verify the potency of the nanoparticle:(1) aptamer-parotamine-FAMsiRNA could be uptaken by cells, (2) aptamer-protamin-siEGFP could downrelgulate the expression of EGFP, (3) aptamer-protamine-sisurvivin could inhibit the expression of survivin, and the cell growth was obviously slower than the control group, some cells went to apoptosis. (4) in vivo test of the interfering effect of aptamer-protamine-siRNA in nude mice, we found that the tumors in aptamer-protamine-sisurvivin nanoparticle group were significantly smaller than vehicle group, and the expression of survivin could also be inhibited in vivo, the cell proliferation in nanoparticle group was significantly inhibited by the detection of PCNA and Ki67, also in this research we explored that growth hormone might have the ability to promote cancer cell's proliferation which could increase the sensitivity of cancer cells to targeted therapy.
Our research showed that aptamer-protamine-siRNA nanoparticle was an effective delivery to carry siRNA into cells and the siRNA could take part in the gene-silence activities. It could not only be a good delivery of siRNA in vitro tests but also be proved to be effective in vivo experiments. This nanoparticle could recognize targeted cells which express aptamer conjunctive antigens by aptamer, the siRNA it carried could inhibit the expression of specified gene, so aptamer-protamine-siRNA nanoparticle could act as a targeted RNAi delivery. This nanoparticle could be used not only on breast cancer but also on other cancers and other diseases just by changing the aptamer to another specified antigen conjunctive aptamer and replacing the siRNA to another gene siRNAs, so aptamer-protamine-siRNA nanoparticle might become a good method for gene silencing research and even for clinical diseases therapy.
引文
1. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998,391,806-811.
2. Elbashir, S. M. et al. Duplexes of 2.1-nucleotide RNAs mediate RNAinterference in cultured mammalian cells. Nature,2001,411,494-498.
3. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nature Med.2003,9,347-351.
4. Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vision 2003,9,210-216.
5. Bitko, V. et al. Inhibition of respiratory viruses by nasally administered siRNA. Nature Med.2005,11,50-55.
6. Li, B. J. et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nature Med.2005,11,944-951.
7. Tuerk C., Gold L. Systematic evolution of ligands by exponential enrichment:RNA ligands to bacteriophage T4 DNA polymerase. Science.1990,249,505-510.
8. Matranga, C. et al. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 2005,123,607-620.
9. Futaki, S. et al. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J. Biol. Chem. 2001,276,5836-40.
10. Chen CH, Chernis GA et al. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci U SA.2003,100:9226-31.
11. Salvesen GS, Ducket CS. IAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
12. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-584.
13. Garber K. Beyond the Nobel Prize:cell cycle research offers new view of cancer. J Natl Cancer Inst.2001,5;93(23):1766-8.
14. Hartwell LH, Kastan MB. Cell cycle control and cancer.Science.1994,16;266(5192): 1821-8.
15. Nasmyth K. Viewpoint:putting the cell cycle in order.Science.1996,6;274(5293):1643-5.
16. Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. Oncogene. 2008,7;27(34):4733-44.
17. Schmitt E, Beauchemin M, Bertrand R. Cdkl-dependent regulation of Cdc25B functions to coordinate mitotic events.Cell Cycle.20061;5(21):2543-7.
1. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391,806-811 (1998).
2. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature,411,494-498 (2001).
3. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nature Med.9,347-351 (2003).
4. Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vision 9,210-216 (2003).
5. Bitko, V. et al. Inhibition of respiratory viruses by nasally administered siRNA. Nature Med.11,50-55(2005).
6. Li, B. J. et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nature Med.11,944-951 (2005).
7. Chen CH, Chernis G,et al. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. PNAS,100:9226-31 (2003).
8. Bartlett, D. W. et al. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl Acad. Sci. USA 104,15549-15554 (2007).
1. Seisenberger G, Endress Y,et al. Real-time single-molecule imaging of the infection pathway of an adeno-associated virus, Science,2001;294(5548):1929-32
2. Van Roessel P, Brand AH. Imaging into the future:visualizing gene expression and protein interactions with fluorescent proteins. Nat Cell Biol.2002;4(1):E15-20.
3. Lippincott-Schwartz J. Development and use of fluorescent protein markers in living cells. Science,2003;300(5616):87-91.
4. Chalfie F, Tu Y,. et al. Green fluorescent protein as a marker for gene expression. Science.1994;263(5148):802-5.
5. Skosyrev VS, Rudenko NV, et al. EGFP as a fusion partner for the expression and organic extraction of small polypeptides. Protein Expr Purif.2003;27(1):55-62.
1. Sanna MG, et al. IAP suppression of apoptosis involves distinct mechanisms: theTAKl/JNKlsignaling cascade and caspase inhibition.Mol Cell Biol 2002;22:1754-66.
2. Deveraux QL, et al. Endogenous inhibitors of caspases. J Clin Immunol 1999;19:388-98.
3. Ambrosini G, et al. A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917-21.
4. Li F, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-4.
5. Altieri DC. The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 2006;18:609-15.
6. Adida C, et al. Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 1998;351:882-3.
7. Gianani R, et al.Expression of survivin innormal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol 2001;32:119-25.
8. Monzo M, et al. A novel antiapoptosis gene:re-expression of survivin messenger RNA as a prognosismarker in non-small-cell lung cancers. J Clin Oncol 1999; 17:2100-4.
10. Satoh K, et al. Tumor necrosis factor related apoptosis inducing ligand and its receptor expression and the pathway of apoptosis in human pancreatic cancer. Pancreas 2001;23:251-8.
11. Islam A, et al.High expression of survivin, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000;19:617-23.
12. Li F, Altieri DC. The cancer antiapoptosis mouse survivin gene:characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression. Cancer Res 1999;59:3143-51.
13. Marioni G, et al. Expressionof the apoptosis inhibitor protein survivin in primary laryngeal carcinoma and cervical lymph node metastasis. Anticancer Res 2006;26:3813-7.
1. Shapiro GI, Park J, Edwards CD, et al. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res 1995,55:6200-6209
2. Wang TC, Cardiff RD, Zukerberg L, et al. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994,369:669-671
3. Moreno G, Rodriguez S, Sanchez C, et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003,22:6115-6118
4. McClue SJ, Blake D, Clarke R, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 2002,102:463-468
5. Hamdouchi C, Keyser H, Collins E, et al. The discovery of a new structural class of cyclindependent kinase inhibitors, aminoimidazo pyridines. Mol Cancer Ther 2004,3:1-9
6. Hartwell LH, Kastan MB. Cell cycle control and cancer Science.1994,16;266(5192): 1821-8.
7. Nasmyth K. Viewpoint:putting the cell cycle in order. Science.1996,6;274(5293):1643-5.
8. Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription-factor. Oncogene.2008,7;27(34): 4733-44.
9. Schmitt E, Beauchemin M, Bertrand R. Cdkl-dependent regulation of Cdc25B functions to coordinate mitotic events.Cell Cycle.2006 1;5(21):2543-7.
10. Evan GI, Vouaden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001,411:342-348.
1. Schimer AD. Inhibitor of apoptosis proteins:translating basic knowledge into clinical practice. Cancer Res 2004;64:7183-7190.
2. Salvesen GS, Ducket CS. IAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
3. Kobayash K, Hatano M, Otaki M, et al. Expression of a murine homologue of inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci US A 1999;96: 1457-1462.
4.Mirza A,McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613-2622.
5. Jichao Qin, Deding Tao, et al. Down-regulation of cyclin E expression by caffeine promotes cancer cell entry into the S-phase of the cell cycle. Anticancer Research, 2004,24:2991-2996
6.龚建平.从Genomics, Proteomics到Cytomics,还是从Cytometry到Cytomics.癌症,2003,22(5)：449-451
7. Feng Y, Wu J, et al. Timing of apoptosis onset depends on cell cycle progression in peripheral blood lymphocytes and lymphocytic leukemia cells.Oncol Rep. 2007,17(6):1437-44.
8. Valerie YH, Randall JU, et al. Recombinant human growth hormone and recombinant human insulin like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects. The Journal of Clinical Endocrinology & Metabolism, 2001,86(5):221122219
9. Pupim LB, Flakoll PJ, Yu C, et al. Recombinant human growth hormone improves muscle amino acid up take and whole body protein metabolism in chronic hemodialysis patients. Am J Clin Nutr,2005,82 (6):123521243.
10. Tacke J,BolderU, et al. Long-term risk of gastrointestinal tumor recurrence after postoperative treatmentwith recombinant human growth hormone. JPEN,2000,24 (3): 1402144.
11. Khan AS, Smith LC, et al. Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice. Cancer Gene Ther.2005,12 (1):54260.
12. Feibig H H, Dengler W, et al. No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone. AntiCancer Drugs,2000,11 (8):6592664.
13. Harrison LE, Blumberg D, et al. Effect of human growth hormone on human pancreatic carcinoma growth, protein, and cell cycle kinetics. J Surg Res.1996;61(2):317-22.
14. Molinaro E, Viola D, et al. Recombinant human TSH (rhTSH) in 2009:new perspectives in diagnosis and therapy. Q J Nucl Med Mol Imaging.2009;53(5):490-502.
15. Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol.2006 Feb;64(2):115-21.
1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC.. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature.1998 Feb 19;391(6669):806-11
2. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature.2001 May 24;411(6836):494-8.
3. Kim, D. H., Rossi, J. J. Strategies for silencing human disease using RNA interference. Nat Rev Genet.2007 Mar;8(3):173-84.
4. Padmanabhan C, Zhang X, Jin H. Host small RNAs are big contributors to plant innate immunity.Curr Opin Plant Biol.2009 Aug;12(4):465-72.
5. Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol.2005 Jul;7(7):719-23.
6. Zhang H, Kolb FA, Brondani V, Billy E, Filipowicz W. Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J. 2002;21(21):5875-85.
7. Aza-Blanc, P. et al. Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. Mol. Cell 12,627-637 (2003).
8. Jacson AL, Bartz SR, et al. Expression profiling reveals off target gene regulation by RNAi. Nature Biotechnology,2003 Jun;21(6):635-7.
9. Xiaoyu Lin, Xiaoan Ruan, et al. siRNA-mediated off-target gene silencing triggered by a 7 nt complementation. Nucleic acids research 2005 Aug 9;33(14):4527-35.
10. Durrant JD, Amaro RE, et al. A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. PLoS Comput Biol.2010 Jan 22;6(1):e1000648.
11. Scleel M, Horning V, et al. SiRNA and isRNA:two edges of one sword. Molecular therapy,2006 Oct;14(4):463-70.
12. Layzer JM, McCaffrey AP, Tanner AK, Huang Z, Kay MA, Sullenger BA. In vivo activity of nuclease-resistant siRNAs. RNA.2004 May;10(5):766-7135. Bartlett,D. W., Davis, M. E. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic acids research,2006 Jan 12;34(1):322-33.
13. Gao S, Dagnaes-Hansen F, et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. DNA Repair. 2009,2;8(10):1215-24.
14. Fedorov Y, King A, et al. Different delivery methods-different expression profiles. Nat Methods,2005;2(4):241.
15. Reich SJ. Fosnot J, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Molecular vision,2003 May 30;9:210-6.
16. Bitko V, Musinyenko A, et al. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med,2005;11(1):50-5.
17. Li BJ, Tang Q, et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med.2005;11(9):944-51.
18. Ke B, Shen XD, et al. Small interfering RNA targeting heme oxygenase-1 (HO-1) reinforces liver apoptosis induced by ischemia-reperfusion injury in mice:HO-1 is necessary for cytoprotection. Hum Gene Ther.2009;20(10):1133-42.
19. Matsuyama W, Watanabe M, et al. Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation. J Immunol.2006; 176(3):1928-36.
20. Breit A, Wolff K, et al. The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and-4 receptors.J Biol Chem. 2006;281(49):37447-56.
21. Gabriele Dorn, Sadhana Patel, et al. SiRNA relieves chronic neuropathic pain. Nucleic Acids Res.2004;32(5):e49.
22. Soutschek J, Akinc A, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature.2004;432(7014):173-8.
23. Surace C, Arpicco S, et al. Lipoplexes targeting the CD44 hyaluronic acid receptor for efficient transfection of breast cancer cells. Mol Pharm.2009;6(4):1062-73.
24. McNamara JO, Andrechek ER, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol.2006;24(8):1005-15.
25. Chu TC, Twu KY, et al. Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006;34(10):e73.
26. Li, W., Szoka F. C. Lipid-based nanoparticles for nucleic acid delivery. Pharm Res, 2007;24(3):438-49.
27. Judge AD, Sood V, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol.2005;23(4):457-62.
28. Jere D, Arote R, et al. The suppression of lung tumorigenesis by aerosol-delivered folate-chitosan-graft-polyethylenimine/Aktl shRNA complexes through the Akt signaling pathway. Biomed Mater.2009;4(2):025020.
29. Kayo Miyawaki-Shimizu, Dan Predescu, et al. SiRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway. American journal of physiology,2006;290(2):L405-13.
30. Samorski R, Gissmann L, Osen W. Codon optimized expression of HPV 16 E6 renders target cells susceptible to E6-specific CTL recognition. Immunol Lett.2006; 107(1):41-9.
31. Juliano, R. L. Peptide-oligonucleotide conjugates for the delivery of antisense and siRNA. Curr Opin Mol Ther.2005;7(2):132-6.
32. Schakowski F, Gorschluter M, et al. A novel minimal-size vector (MIDGE) improves transgene expression in colon carcinoma cells and avoids transfection of undesired DNA. Mol Ther.2001;3:793-800.
33. Boussif B, Lezoualc'h B, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo:polyethylenimine. Proc Natl Acad Sci U S A.,1995;92(16): 7297-301.
34. Geisbert TW, Kagan E,et al. Postexposure protection of guinea pigs against lethal ebola virus challenge is conferred by RNA interference. J Infect Dis.2006; 193(12):1650-7.
35. Roomi MW, Jariwalla RJ, et al. Inhibition of cellular invasive parameters in influenza A virus-infected MDCK and Vero cells by a nutrient mixture. Biofactors.2008;33(1):61-75.
36. Grzelinski M, Urban-Klein B,et al. RNA interference-mediated gene silencing of pleiotrophin through polyethyleniminecomplexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts. Hum Gene Ther.2006;17(7):751-66.
37. Torchilin, V. P. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng.2006;8:343-75.
38. Zatsepin TS, Turner JJ, et al. Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. Curr Pharm Des.2005;11(28):3639-54.
39. Kim WJ, Chang CW,et al. Efficient siRNA delivery using water soluble lipopolymer for anti-angiogenic gene therapy J Control Release.2007; 118(3):357-63.
40. Schiffelers RM, Ansari A, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res.2004 Nov 1;32(19):e149.
41. Song E, Zhu P, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol.2005;23(6):709-17..
42. Schartner JM, Simonson WT, et al. Gene related to anergy in lymphocytes (GRAIL) expression in CD4+T cells impairs actin cytoskeletal organization during T cell/antigen-presenting cell interactions. J Biol Chem.2009;284(50):34674-81.
43. Jabs DA, Griffiths PD,et al. Fomivirsen for the treatment of cytomegalovirus retinitis. Am J Ophthalmol.2002;133(4):552-6.
44. Gragoudas ES, Adamis AP, et al. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med.2004;351(27):2805-16.
1. Meyerson M, Enders GH, et al. A family of human cdc2-related protein kinases. EMBO J 1992,11:2909-2917
2. Sausville EA. Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med 2002,8:S32-S37
3. Pines J. Cyclins, Wheels within wheels. Cell Growth Differ 1991,2:305-3.10,
4. Sherr CJ. Gl phase progression:Cycling on cue. Cell 1994,79:551-555,
5. Sherr CJ, Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev 1995,9:1149-1163
6. Harbour JW, Dean DC. The Rb/E2F pathway:Expanding roles and emerging paradigms. Genes Dev 2000,14:2393-2409
7. Harbour JW, Luo RX, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999,98:859-869
8. Geng Y, Eaton EN, et al. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 1996,12:1173-1180
9. Okuda M, Horn HF, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000,103:127-140
10. Sherr CJ, Roberts JM. CDK inhibitors:Positive and negative regulators of Gl-phase progression. Genes Dev 1999,13:1501-1512
11. Shapiro GI, Park J, et al. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res 1995,55:6200-6209
12. Wolfel T, Hauer M, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995,269:1281-1284
13. Wang TC, Cardiff RD, et al. Mammary hyperplasia and carcinoma in MMTV-cyclin Dl transgenic mice. Nature 1994,369:669-671
14. Motokura T, Bloom T, et al. A novel cyclin encoded by a bell-linked candidate oncogene. Nature 1991,350:512-515
15. Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005,23:6333-6338
16. Carrere N, Belaud-Rotureau MA, et al. The relative levels of cyclin D1a and D1b alternative transcripts in mantle cell lymphoma may depend more on sample origin than on CCND1 polymorphism. Haematologica 2005,90:854-856
17. Moreno G, Rodriguez S, et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003,22:6115-6118
18. Bernards R. CDK-independent activities of D type cyclins. Biochim Biochim Biophys Acta 1999,1424:M17-M22
19. Yang C, Ionescu-Tiba V, et al. The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 2004,164:1031-1038
20. Porter PL, Malone KE, et al. Expression of cell-cycle regulators p27Kipl and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 1997,3:222-225
21. Krek W, Ewen ME, et al. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 1994,78:161-172
22. Xu M, Sheppard KA, et al. Cyclin A/Cdk2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Mol Cell Biol 1994,14:8420-8431
23. Phillips A, Ernst M, et al. E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways. Mol Cell 1999,4:771-781
24. Vandel L, Kouzarides T. Residues phosphorylated by TFIIH are required for E2F-1 degradation during S-phase. EMBO J 1999,18:4280-4291
25. Ortega S, Prieto I, Odajima J, et al. Cyclin dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet,2003,35:25-31
26. Hu B, Mitra J, et al. S and G2 roles for cdk2 revealed by inducible expression of a dominant-negative mutant in human cells. Mol Cell Biol 2001,21:2755-2766,
27. Wang X, Gorospe M, et al. p27Kipl overexpression causes apoptotic death of mammalian cells. Oncogene 1997,15:2991-2997
28. Katayose Y, Kim M, et al. Promoting apoptosis:A novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res 1997,57:5441-5445
29. Sedlacek HH, Czech J, et al. flavopiridol, a new kinase inhibitor for tumor therapy. Int J Oncol 1996,9:1143-1168
30. Goffin J, Appleman L, et al. A phase I trial of gemcitabine followed by flavopiridol in patients with solid tumors. Lung Cancer 2003,41:S179
31. Li WW, Fan J, Bertino JR. Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 activity. Cancer Res 2001,61:2579-2582
32. Anderson M, Beattie JF, et al. Imidazopyridines:A potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hybridisation. Bioorg Med Chem Lett 2003,13:3021-3026
33. McClue SJ, Blake D, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 2002,102:463-468
34. Cai D, Byth KF, Shapiro GI. AZ703, an imidazopyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cancer Res 2006,66:435-444
35. Hamdouchi C, Keyser H, et al. The discovery of a new structural class of cyclindependent kinase inhibitors, aminoimidazo pyridines. Mol Cancer Ther 2004,3:1-9,
36. Connor DS, Wall NR, et al. A p34cdc2 survival checkpoint in cancer. Cancer Cell 2002, 2:43-54
37. Weaver BA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy:The mitotic checkpoint, adaptation, and cell death. Cancer Cell 2005,8:7-12
38. Bayart E, Grigorieva 0, et al. A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint. Cancer Res 2004,64:8954-8959
39. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and cdk inhibitors in human cancer. Adv Cancer Res1996,68:67-108
40. Motwani M, Delohery TM, Schwartz GK. Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxeltreated human gastric and breast cancer cells. Clin Cancer Res 1999,5:1876-1883
41. Motwani M, Rizzo C, et al. flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells. Mol Cancer Ther 2003,2:549-555
1. Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26:239-257.
2. Cryns V, Yuan J. Proteases to die for. Genes Dev 1998;12:1551-1570.
3. Schimer AD. Inhibitor of apoptosis proteins:translating basic knowledge into clinical practice. Cancer Res 2004;64:7183-7190.
4. Adams JM, Cory S. Life-or-death decisions by Bcl-2 protein family. Trends Biochem Sci 2001;26:61-66.
5. Dohi, T., Okada, K., Xia, F., et al. An IAP-IAP complex inhibits apoptosis. J. Biol. Chem. 2004,279,34087-34090.
6. Salvesen GS, Ducket CS. LAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
7. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-584.
8. Kobayash K, Hatano M, Otaki M, et al. Expression of a murine homologue of inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci US A 1999;96:1457-1462.
9. Van Antwerp, Martin SJ, Verma IM, et al. Inhibition of TNF-induced apoptosis by NF-kB. Trends Cell Biol 1998;8:107-111.
10.Mirza A,McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613-2622.
11. Salz, W., Eisenberg, D., Plescia, J., et al. A survivin gene signature predicts aggressive tumor behavior. Cancer Res.2005,65,3531-3534.
12. Zhao J,TenevT, Martins LM, et al. The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. J Cell Sci 2000;113 23:4363-4371.
13. Altieri DC. The case for survivin as regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 2006;18:609-615.
14. Casse EC, Baird S, Korneluk RG, et al. The inhibitors of apoptosis and their emerging role in cancer. Oncogene 1998; 17:3247-3259.
15. Marusawa H, Matsuzawa S,Welsh K, et al. HBXIP functions as cofactor of survivin in apoptosis suppression. EMBO J 2003;22:2729-2740.
16. Dohi T, Okada K, Xia F, et al. An IAP-IAP complex inhibits apoptosis. J Biol Chem 2004;279:34087-34090.
17. ZhangT, Otevrel T, Gao Z, et al. Evidence that APC regulates survivin expression:a possible mechanism contributing to stem cell origin of colon cancer. Cancer Res 2001,61:8664-8667.
18. Thomas, J., Liu, T., Cotter, M.A., et al. Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice.Cancer Res. 2007,67,5172-5178.
19. Islam A, Kageyam H, Takada N, et al. High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000; 19:617-623.
20. Hattori M, Sakamoto H, Satoh K,Yamamoto T. DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of Her 2 and survivin genes. Cancer Lett 2001; 169:155-164.
21. Engels K, Knuer SK, Metler D, et al. Dynamic intracellular survivin in oral squamous cell carcinoma:underlying molecular mechanism and potential as an early prognostic marker. J Pathol 2007;211:532-540.
22. Osaka E, Suzuki T, Osaka S, et al. Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem Cytochem 2006;39:95-100.
23. Kenney DM, Geschwindt RD, Kary MR, et al. Detection of newly diagnosed bladder cancer, bladder cancer recurrence and bladder cancer in patients with hematuria using quantitative RT-PCR of urinary survivin. Tumour Biol 2007; 28:57-62.
24. Gianani R, Jarboe E, Orlicky D, et al. Expression of survivin innormal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol 2001;32:119-125.
25. Srinivasula, S.M., and Ashwell, J.D. IAPs:what's in a name? Mol. Cell 2008,30,123-135.
26. Ambrosini G, Adida C, Sirugo G, et al. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 1998;273:11177-11182.
27. Harfouche R, Hassessian HM, GuoY, et al. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res 2002;64: 135-147.
28. Reed JC. The survivin goes in vivo. J Clin Invest 2001;108:965-969.
29. Zaffaroni N, Daidone MG. Survivin expression and resistance to anticancer treatments: perspectives for therapeutic interventions. Drug Resist Updat 2002;5:65-72.
30. Andersen MH, Thor SP. Deveraux, Q., et al. X-linked IAP is a direct inhibitor of cell death proteases. Nature,388:300-303,1997.
31. Bouchard, V., Harnois, C., Demers, M.J., et al.. B1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival:integration of complex regulatory mechanisms. Apoptosis 2008,13,531-542.
32. Li B, Fan J, Liu X, et al. Suppression of colorectal tumor growth by regulated survivin targeting. J Mol Med 2006;84:1077-1086.
2. Elbashir, S. M. et al. Duplexes of 2.1-nucleotide RNAs mediate RNAinterference in cultured mammalian cells. Nature,2001,411,494-498.
3. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nature Med.2003,9,347-351.
4. Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vision 2003,9,210-216.
5. Bitko, V. et al. Inhibition of respiratory viruses by nasally administered siRNA. Nature Med.2005,11,50-55.
6. Li, B. J. et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nature Med.2005,11,944-951.
7. Tuerk C., Gold L. Systematic evolution of ligands by exponential enrichment:RNA ligands to bacteriophage T4 DNA polymerase. Science.1990,249,505-510.
8. Matranga, C. et al. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 2005,123,607-620.
9. Futaki, S. et al. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J. Biol. Chem. 2001,276,5836-40.
10. Chen CH, Chernis GA et al. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci U SA.2003,100:9226-31.
11. Salvesen GS, Ducket CS. IAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
12. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-584.
13. Garber K. Beyond the Nobel Prize:cell cycle research offers new view of cancer. J Natl Cancer Inst.2001,5;93(23):1766-8.
14. Hartwell LH, Kastan MB. Cell cycle control and cancer.Science.1994,16;266(5192): 1821-8.
15. Nasmyth K. Viewpoint:putting the cell cycle in order.Science.1996,6;274(5293):1643-5.
16. Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. Oncogene. 2008,7;27(34):4733-44.
17. Schmitt E, Beauchemin M, Bertrand R. Cdkl-dependent regulation of Cdc25B functions to coordinate mitotic events.Cell Cycle.20061;5(21):2543-7.
1. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391,806-811 (1998).
2. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature,411,494-498 (2001).
3. Song, E. et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nature Med.9,347-351 (2003).
4. Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vision 9,210-216 (2003).
5. Bitko, V. et al. Inhibition of respiratory viruses by nasally administered siRNA. Nature Med.11,50-55(2005).
6. Li, B. J. et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nature Med.11,944-951 (2005).
7. Chen CH, Chernis G,et al. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. PNAS,100:9226-31 (2003).
8. Bartlett, D. W. et al. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl Acad. Sci. USA 104,15549-15554 (2007).
1. Seisenberger G, Endress Y,et al. Real-time single-molecule imaging of the infection pathway of an adeno-associated virus, Science,2001;294(5548):1929-32
2. Van Roessel P, Brand AH. Imaging into the future:visualizing gene expression and protein interactions with fluorescent proteins. Nat Cell Biol.2002;4(1):E15-20.
3. Lippincott-Schwartz J. Development and use of fluorescent protein markers in living cells. Science,2003;300(5616):87-91.
4. Chalfie F, Tu Y,. et al. Green fluorescent protein as a marker for gene expression. Science.1994;263(5148):802-5.
5. Skosyrev VS, Rudenko NV, et al. EGFP as a fusion partner for the expression and organic extraction of small polypeptides. Protein Expr Purif.2003;27(1):55-62.
1. Sanna MG, et al. IAP suppression of apoptosis involves distinct mechanisms: theTAKl/JNKlsignaling cascade and caspase inhibition.Mol Cell Biol 2002;22:1754-66.
2. Deveraux QL, et al. Endogenous inhibitors of caspases. J Clin Immunol 1999;19:388-98.
3. Ambrosini G, et al. A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917-21.
4. Li F, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-4.
5. Altieri DC. The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 2006;18:609-15.
6. Adida C, et al. Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 1998;351:882-3.
7. Gianani R, et al.Expression of survivin innormal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol 2001;32:119-25.
8. Monzo M, et al. A novel antiapoptosis gene:re-expression of survivin messenger RNA as a prognosismarker in non-small-cell lung cancers. J Clin Oncol 1999; 17:2100-4.
10. Satoh K, et al. Tumor necrosis factor related apoptosis inducing ligand and its receptor expression and the pathway of apoptosis in human pancreatic cancer. Pancreas 2001;23:251-8.
11. Islam A, et al.High expression of survivin, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000;19:617-23.
12. Li F, Altieri DC. The cancer antiapoptosis mouse survivin gene:characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression. Cancer Res 1999;59:3143-51.
13. Marioni G, et al. Expressionof the apoptosis inhibitor protein survivin in primary laryngeal carcinoma and cervical lymph node metastasis. Anticancer Res 2006;26:3813-7.
1. Shapiro GI, Park J, Edwards CD, et al. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res 1995,55:6200-6209
2. Wang TC, Cardiff RD, Zukerberg L, et al. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994,369:669-671
3. Moreno G, Rodriguez S, Sanchez C, et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003,22:6115-6118
4. McClue SJ, Blake D, Clarke R, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 2002,102:463-468
5. Hamdouchi C, Keyser H, Collins E, et al. The discovery of a new structural class of cyclindependent kinase inhibitors, aminoimidazo pyridines. Mol Cancer Ther 2004,3:1-9
6. Hartwell LH, Kastan MB. Cell cycle control and cancer Science.1994,16;266(5192): 1821-8.
7. Nasmyth K. Viewpoint:putting the cell cycle in order. Science.1996,6;274(5293):1643-5.
8. Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription-factor. Oncogene.2008,7;27(34): 4733-44.
9. Schmitt E, Beauchemin M, Bertrand R. Cdkl-dependent regulation of Cdc25B functions to coordinate mitotic events.Cell Cycle.2006 1;5(21):2543-7.
10. Evan GI, Vouaden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001,411:342-348.
1. Schimer AD. Inhibitor of apoptosis proteins:translating basic knowledge into clinical practice. Cancer Res 2004;64:7183-7190.
2. Salvesen GS, Ducket CS. IAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
3. Kobayash K, Hatano M, Otaki M, et al. Expression of a murine homologue of inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci US A 1999;96: 1457-1462.
4.Mirza A,McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613-2622.
5. Jichao Qin, Deding Tao, et al. Down-regulation of cyclin E expression by caffeine promotes cancer cell entry into the S-phase of the cell cycle. Anticancer Research, 2004,24:2991-2996
6.龚建平.从Genomics, Proteomics到Cytomics,还是从Cytometry到Cytomics.癌症,2003,22(5)：449-451
7. Feng Y, Wu J, et al. Timing of apoptosis onset depends on cell cycle progression in peripheral blood lymphocytes and lymphocytic leukemia cells.Oncol Rep. 2007,17(6):1437-44.
8. Valerie YH, Randall JU, et al. Recombinant human growth hormone and recombinant human insulin like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects. The Journal of Clinical Endocrinology & Metabolism, 2001,86(5):221122219
9. Pupim LB, Flakoll PJ, Yu C, et al. Recombinant human growth hormone improves muscle amino acid up take and whole body protein metabolism in chronic hemodialysis patients. Am J Clin Nutr,2005,82 (6):123521243.
10. Tacke J,BolderU, et al. Long-term risk of gastrointestinal tumor recurrence after postoperative treatmentwith recombinant human growth hormone. JPEN,2000,24 (3): 1402144.
11. Khan AS, Smith LC, et al. Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice. Cancer Gene Ther.2005,12 (1):54260.
12. Feibig H H, Dengler W, et al. No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone. AntiCancer Drugs,2000,11 (8):6592664.
13. Harrison LE, Blumberg D, et al. Effect of human growth hormone on human pancreatic carcinoma growth, protein, and cell cycle kinetics. J Surg Res.1996;61(2):317-22.
14. Molinaro E, Viola D, et al. Recombinant human TSH (rhTSH) in 2009:new perspectives in diagnosis and therapy. Q J Nucl Med Mol Imaging.2009;53(5):490-502.
15. Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol.2006 Feb;64(2):115-21.
1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC.. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature.1998 Feb 19;391(6669):806-11
2. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature.2001 May 24;411(6836):494-8.
3. Kim, D. H., Rossi, J. J. Strategies for silencing human disease using RNA interference. Nat Rev Genet.2007 Mar;8(3):173-84.
4. Padmanabhan C, Zhang X, Jin H. Host small RNAs are big contributors to plant innate immunity.Curr Opin Plant Biol.2009 Aug;12(4):465-72.
5. Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol.2005 Jul;7(7):719-23.
6. Zhang H, Kolb FA, Brondani V, Billy E, Filipowicz W. Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J. 2002;21(21):5875-85.
7. Aza-Blanc, P. et al. Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. Mol. Cell 12,627-637 (2003).
8. Jacson AL, Bartz SR, et al. Expression profiling reveals off target gene regulation by RNAi. Nature Biotechnology,2003 Jun;21(6):635-7.
9. Xiaoyu Lin, Xiaoan Ruan, et al. siRNA-mediated off-target gene silencing triggered by a 7 nt complementation. Nucleic acids research 2005 Aug 9;33(14):4527-35.
10. Durrant JD, Amaro RE, et al. A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. PLoS Comput Biol.2010 Jan 22;6(1):e1000648.
11. Scleel M, Horning V, et al. SiRNA and isRNA:two edges of one sword. Molecular therapy,2006 Oct;14(4):463-70.
12. Layzer JM, McCaffrey AP, Tanner AK, Huang Z, Kay MA, Sullenger BA. In vivo activity of nuclease-resistant siRNAs. RNA.2004 May;10(5):766-7135. Bartlett,D. W., Davis, M. E. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic acids research,2006 Jan 12;34(1):322-33.
13. Gao S, Dagnaes-Hansen F, et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. DNA Repair. 2009,2;8(10):1215-24.
14. Fedorov Y, King A, et al. Different delivery methods-different expression profiles. Nat Methods,2005;2(4):241.
15. Reich SJ. Fosnot J, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Molecular vision,2003 May 30;9:210-6.
16. Bitko V, Musinyenko A, et al. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med,2005;11(1):50-5.
17. Li BJ, Tang Q, et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med.2005;11(9):944-51.
18. Ke B, Shen XD, et al. Small interfering RNA targeting heme oxygenase-1 (HO-1) reinforces liver apoptosis induced by ischemia-reperfusion injury in mice:HO-1 is necessary for cytoprotection. Hum Gene Ther.2009;20(10):1133-42.
19. Matsuyama W, Watanabe M, et al. Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation. J Immunol.2006; 176(3):1928-36.
20. Breit A, Wolff K, et al. The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and-4 receptors.J Biol Chem. 2006;281(49):37447-56.
21. Gabriele Dorn, Sadhana Patel, et al. SiRNA relieves chronic neuropathic pain. Nucleic Acids Res.2004;32(5):e49.
22. Soutschek J, Akinc A, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature.2004;432(7014):173-8.
23. Surace C, Arpicco S, et al. Lipoplexes targeting the CD44 hyaluronic acid receptor for efficient transfection of breast cancer cells. Mol Pharm.2009;6(4):1062-73.
24. McNamara JO, Andrechek ER, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol.2006;24(8):1005-15.
25. Chu TC, Twu KY, et al. Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006;34(10):e73.
26. Li, W., Szoka F. C. Lipid-based nanoparticles for nucleic acid delivery. Pharm Res, 2007;24(3):438-49.
27. Judge AD, Sood V, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol.2005;23(4):457-62.
28. Jere D, Arote R, et al. The suppression of lung tumorigenesis by aerosol-delivered folate-chitosan-graft-polyethylenimine/Aktl shRNA complexes through the Akt signaling pathway. Biomed Mater.2009;4(2):025020.
29. Kayo Miyawaki-Shimizu, Dan Predescu, et al. SiRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway. American journal of physiology,2006;290(2):L405-13.
30. Samorski R, Gissmann L, Osen W. Codon optimized expression of HPV 16 E6 renders target cells susceptible to E6-specific CTL recognition. Immunol Lett.2006; 107(1):41-9.
31. Juliano, R. L. Peptide-oligonucleotide conjugates for the delivery of antisense and siRNA. Curr Opin Mol Ther.2005;7(2):132-6.
32. Schakowski F, Gorschluter M, et al. A novel minimal-size vector (MIDGE) improves transgene expression in colon carcinoma cells and avoids transfection of undesired DNA. Mol Ther.2001;3:793-800.
33. Boussif B, Lezoualc'h B, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo:polyethylenimine. Proc Natl Acad Sci U S A.,1995;92(16): 7297-301.
34. Geisbert TW, Kagan E,et al. Postexposure protection of guinea pigs against lethal ebola virus challenge is conferred by RNA interference. J Infect Dis.2006; 193(12):1650-7.
35. Roomi MW, Jariwalla RJ, et al. Inhibition of cellular invasive parameters in influenza A virus-infected MDCK and Vero cells by a nutrient mixture. Biofactors.2008;33(1):61-75.
36. Grzelinski M, Urban-Klein B,et al. RNA interference-mediated gene silencing of pleiotrophin through polyethyleniminecomplexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts. Hum Gene Ther.2006;17(7):751-66.
37. Torchilin, V. P. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng.2006;8:343-75.
38. Zatsepin TS, Turner JJ, et al. Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. Curr Pharm Des.2005;11(28):3639-54.
39. Kim WJ, Chang CW,et al. Efficient siRNA delivery using water soluble lipopolymer for anti-angiogenic gene therapy J Control Release.2007; 118(3):357-63.
40. Schiffelers RM, Ansari A, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res.2004 Nov 1;32(19):e149.
41. Song E, Zhu P, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol.2005;23(6):709-17..
42. Schartner JM, Simonson WT, et al. Gene related to anergy in lymphocytes (GRAIL) expression in CD4+T cells impairs actin cytoskeletal organization during T cell/antigen-presenting cell interactions. J Biol Chem.2009;284(50):34674-81.
43. Jabs DA, Griffiths PD,et al. Fomivirsen for the treatment of cytomegalovirus retinitis. Am J Ophthalmol.2002;133(4):552-6.
44. Gragoudas ES, Adamis AP, et al. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med.2004;351(27):2805-16.
1. Meyerson M, Enders GH, et al. A family of human cdc2-related protein kinases. EMBO J 1992,11:2909-2917
2. Sausville EA. Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med 2002,8:S32-S37
3. Pines J. Cyclins, Wheels within wheels. Cell Growth Differ 1991,2:305-3.10,
4. Sherr CJ. Gl phase progression:Cycling on cue. Cell 1994,79:551-555,
5. Sherr CJ, Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev 1995,9:1149-1163
6. Harbour JW, Dean DC. The Rb/E2F pathway:Expanding roles and emerging paradigms. Genes Dev 2000,14:2393-2409
7. Harbour JW, Luo RX, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999,98:859-869
8. Geng Y, Eaton EN, et al. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 1996,12:1173-1180
9. Okuda M, Horn HF, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000,103:127-140
10. Sherr CJ, Roberts JM. CDK inhibitors:Positive and negative regulators of Gl-phase progression. Genes Dev 1999,13:1501-1512
11. Shapiro GI, Park J, et al. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res 1995,55:6200-6209
12. Wolfel T, Hauer M, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995,269:1281-1284
13. Wang TC, Cardiff RD, et al. Mammary hyperplasia and carcinoma in MMTV-cyclin Dl transgenic mice. Nature 1994,369:669-671
14. Motokura T, Bloom T, et al. A novel cyclin encoded by a bell-linked candidate oncogene. Nature 1991,350:512-515
15. Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005,23:6333-6338
16. Carrere N, Belaud-Rotureau MA, et al. The relative levels of cyclin D1a and D1b alternative transcripts in mantle cell lymphoma may depend more on sample origin than on CCND1 polymorphism. Haematologica 2005,90:854-856
17. Moreno G, Rodriguez S, et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003,22:6115-6118
18. Bernards R. CDK-independent activities of D type cyclins. Biochim Biochim Biophys Acta 1999,1424:M17-M22
19. Yang C, Ionescu-Tiba V, et al. The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 2004,164:1031-1038
20. Porter PL, Malone KE, et al. Expression of cell-cycle regulators p27Kipl and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 1997,3:222-225
21. Krek W, Ewen ME, et al. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 1994,78:161-172
22. Xu M, Sheppard KA, et al. Cyclin A/Cdk2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Mol Cell Biol 1994,14:8420-8431
23. Phillips A, Ernst M, et al. E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways. Mol Cell 1999,4:771-781
24. Vandel L, Kouzarides T. Residues phosphorylated by TFIIH are required for E2F-1 degradation during S-phase. EMBO J 1999,18:4280-4291
25. Ortega S, Prieto I, Odajima J, et al. Cyclin dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet,2003,35:25-31
26. Hu B, Mitra J, et al. S and G2 roles for cdk2 revealed by inducible expression of a dominant-negative mutant in human cells. Mol Cell Biol 2001,21:2755-2766,
27. Wang X, Gorospe M, et al. p27Kipl overexpression causes apoptotic death of mammalian cells. Oncogene 1997,15:2991-2997
28. Katayose Y, Kim M, et al. Promoting apoptosis:A novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res 1997,57:5441-5445
29. Sedlacek HH, Czech J, et al. flavopiridol, a new kinase inhibitor for tumor therapy. Int J Oncol 1996,9:1143-1168
30. Goffin J, Appleman L, et al. A phase I trial of gemcitabine followed by flavopiridol in patients with solid tumors. Lung Cancer 2003,41:S179
31. Li WW, Fan J, Bertino JR. Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 activity. Cancer Res 2001,61:2579-2582
32. Anderson M, Beattie JF, et al. Imidazopyridines:A potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hybridisation. Bioorg Med Chem Lett 2003,13:3021-3026
33. McClue SJ, Blake D, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 2002,102:463-468
34. Cai D, Byth KF, Shapiro GI. AZ703, an imidazopyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cancer Res 2006,66:435-444
35. Hamdouchi C, Keyser H, et al. The discovery of a new structural class of cyclindependent kinase inhibitors, aminoimidazo pyridines. Mol Cancer Ther 2004,3:1-9,
36. Connor DS, Wall NR, et al. A p34cdc2 survival checkpoint in cancer. Cancer Cell 2002, 2:43-54
37. Weaver BA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy:The mitotic checkpoint, adaptation, and cell death. Cancer Cell 2005,8:7-12
38. Bayart E, Grigorieva 0, et al. A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint. Cancer Res 2004,64:8954-8959
39. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and cdk inhibitors in human cancer. Adv Cancer Res1996,68:67-108
40. Motwani M, Delohery TM, Schwartz GK. Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxeltreated human gastric and breast cancer cells. Clin Cancer Res 1999,5:1876-1883
41. Motwani M, Rizzo C, et al. flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells. Mol Cancer Ther 2003,2:549-555
1. Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26:239-257.
2. Cryns V, Yuan J. Proteases to die for. Genes Dev 1998;12:1551-1570.
3. Schimer AD. Inhibitor of apoptosis proteins:translating basic knowledge into clinical practice. Cancer Res 2004;64:7183-7190.
4. Adams JM, Cory S. Life-or-death decisions by Bcl-2 protein family. Trends Biochem Sci 2001;26:61-66.
5. Dohi, T., Okada, K., Xia, F., et al. An IAP-IAP complex inhibits apoptosis. J. Biol. Chem. 2004,279,34087-34090.
6. Salvesen GS, Ducket CS. LAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
7. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580-584.
8. Kobayash K, Hatano M, Otaki M, et al. Expression of a murine homologue of inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci US A 1999;96:1457-1462.
9. Van Antwerp, Martin SJ, Verma IM, et al. Inhibition of TNF-induced apoptosis by NF-kB. Trends Cell Biol 1998;8:107-111.
10.Mirza A,McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002;21:2613-2622.
11. Salz, W., Eisenberg, D., Plescia, J., et al. A survivin gene signature predicts aggressive tumor behavior. Cancer Res.2005,65,3531-3534.
12. Zhao J,TenevT, Martins LM, et al. The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. J Cell Sci 2000;113 23:4363-4371.
13. Altieri DC. The case for survivin as regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 2006;18:609-615.
14. Casse EC, Baird S, Korneluk RG, et al. The inhibitors of apoptosis and their emerging role in cancer. Oncogene 1998; 17:3247-3259.
15. Marusawa H, Matsuzawa S,Welsh K, et al. HBXIP functions as cofactor of survivin in apoptosis suppression. EMBO J 2003;22:2729-2740.
16. Dohi T, Okada K, Xia F, et al. An IAP-IAP complex inhibits apoptosis. J Biol Chem 2004;279:34087-34090.
17. ZhangT, Otevrel T, Gao Z, et al. Evidence that APC regulates survivin expression:a possible mechanism contributing to stem cell origin of colon cancer. Cancer Res 2001,61:8664-8667.
18. Thomas, J., Liu, T., Cotter, M.A., et al. Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice.Cancer Res. 2007,67,5172-5178.
19. Islam A, Kageyam H, Takada N, et al. High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000; 19:617-623.
20. Hattori M, Sakamoto H, Satoh K,Yamamoto T. DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of Her 2 and survivin genes. Cancer Lett 2001; 169:155-164.
21. Engels K, Knuer SK, Metler D, et al. Dynamic intracellular survivin in oral squamous cell carcinoma:underlying molecular mechanism and potential as an early prognostic marker. J Pathol 2007;211:532-540.
22. Osaka E, Suzuki T, Osaka S, et al. Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem Cytochem 2006;39:95-100.
23. Kenney DM, Geschwindt RD, Kary MR, et al. Detection of newly diagnosed bladder cancer, bladder cancer recurrence and bladder cancer in patients with hematuria using quantitative RT-PCR of urinary survivin. Tumour Biol 2007; 28:57-62.
24. Gianani R, Jarboe E, Orlicky D, et al. Expression of survivin innormal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol 2001;32:119-125.
25. Srinivasula, S.M., and Ashwell, J.D. IAPs:what's in a name? Mol. Cell 2008,30,123-135.
26. Ambrosini G, Adida C, Sirugo G, et al. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 1998;273:11177-11182.
27. Harfouche R, Hassessian HM, GuoY, et al. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res 2002;64: 135-147.
28. Reed JC. The survivin goes in vivo. J Clin Invest 2001;108:965-969.
29. Zaffaroni N, Daidone MG. Survivin expression and resistance to anticancer treatments: perspectives for therapeutic interventions. Drug Resist Updat 2002;5:65-72.
30. Andersen MH, Thor SP. Deveraux, Q., et al. X-linked IAP is a direct inhibitor of cell death proteases. Nature,388:300-303,1997.
31. Bouchard, V., Harnois, C., Demers, M.J., et al.. B1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival:integration of complex regulatory mechanisms. Apoptosis 2008,13,531-542.
32. Li B, Fan J, Liu X, et al. Suppression of colorectal tumor growth by regulated survivin targeting. J Mol Med 2006;84:1077-1086.