摘要
研究背景：膀胱癌在全球恶性肿瘤中位居第九位,其中在男性恶性肿瘤中居第七位,而女性中居第十七位,其中移行细胞癌(BTCC)占90%以上,给患者家庭和社会带来沉重的心理压力和经济负担。虽然在我国膀胱癌发病率远低于西方发达国家,但是近年来,我国部分城市膀胱癌发病率有增高趋势,且城市居民膀胱癌死亡率明显高于农村。非肌层浸润性膀胱癌行经尿道膀胱肿瘤电切术(TUR-BT)后并行膀胱内灌注化疗或免疫治疗后仍容易复发,易发展为肌层浸润性膀胱癌。而肌层浸润性膀胱癌,根治性手术难度高、并发症多以及辅助性化疗和放疗效果不佳。所以探索膀胱癌有效治疗的新方法一直是肿瘤治疗研究的热点。
细胞增殖是高度有组织的时序调控过程。细胞进行有丝分裂必须依靠纺锤体检查点(spindle checkpoint),又称有丝分裂检查点(mitotic checkpoint)监控纺锤体形态、染色体着丝点与微管连接及其产生的张力、染色体排列,确保姐妹染色单体精确分离完成有丝分裂。纺锤体检查点功能缺陷将导致染色单体错误分配,产生非整倍体子代细胞,致使最终肿瘤发生。有丝分裂缺陷产生非整倍体导致的肿瘤在众多肿瘤发生中已得到证实。Aurora蛋白家族是一种丝／苏氨酸蛋白激酶,在细胞有丝分裂的进程中起重要作用,它包括Aurora A, Aurora B, Aurora C 3种,业已证明许多实体肿瘤都存在Aurora A的过度表达。
目前正在开发的3个小分子Aurora激酶抑制剂(ZM447439,Hesperadin, VX-680)均非针对某一种Aurora激酶的特异性抑制剂。研究提示,VX-680对激酶的抑制作用更有临床应用作用。肿瘤细胞水平的实验证实VX-680可诱导多种肿瘤细胞凋亡,能抑制包括乳腺癌、淋巴瘤、前列腺癌、胰腺癌、黑色素瘤、颈部肿瘤等众多肿瘤细胞增殖。所以Aurora激酶抑制剂将有可能成为肿瘤治疗的有力武器。
Aurora激酶抑制剂在治疗肿瘤中具有广阔前景,我们通过体外实验研究VX-680对人膀胱癌T24细胞的抑瘤作用,并从诱导细胞凋亡、调控细胞分裂和增殖等方面对其作用机理进行较深入的研究,为BTCC的治疗提供新的思路。
第一章人膀胱移行细胞癌中Aurora A, CyclinD1, CyclinB1和Bcl-2的表达及其相关性的研究
目的：探讨Aurora A, CyclinD1, CyclinB1和Bcl-2在BTCC中的表达及其意义
方法：用免疫组化的方法检测Aurora A, CyclinD1, CyclinB1和Bcl-2在56例BTCC和15例正常膀胱组织中的表达情况,并分析其与BTCC临床病理因素的关系。
结果：膀胱癌组织Aurora A阳性率为51.8%(29／56),高于正常膀胱组织的13.3%(2/15), (P<0.01); CyclinD1阳性率为46.4%(26／56),高于正常膀胱组织的6.7%(1/15), (P<0.01); CyclinB1阳性率为75.0%(42／56),高于正常膀胱组织的33.3%(5／15),(P<0.01)；Bcl-2的表达为62.5%(35／56),高于正常膀胱组织的6.7%(1/15), (P<0.01)。Aurora A, CyclinB1和Bcl-2阳性率与BTCC的病理分级呈正相关,但是CyclinD1随病理分级增加而阳性率下降。Aurora A阳性率与临床分期呈正相关,CyclinD1则呈负相关；CyclinB1和Bcl-2阳性率与临床分期无关。Aurora A阳性率与CyclinD1 (R=0.508, P<0.01)、CyclinB1 (R=0.594, P<0.01)和Bcl-2 (R=-0.535, P＜0.01)阳性率明显相关。
结论：
1.BTCC组织中Aurora A、CyclinD1、CyclinB1和Bcl-2的阳性率高于正常膀胱组织。
2. BTCC组织中Aurora A、CyclinD1、CyclinB1和Bcl-2的阳性率高低与BTCC的肿瘤病理分级明显相关,病理分级与Aurora A、CyclinB1和Bcl-2阳性率呈正相关,与CyclinD1阳性率呈负相关。
3. BTCC的肿瘤临床分期与Aurora A阳性率呈正相关,与CyclinD1阳性率呈负相关,与CyclinB1和Bcl-2阳性率与临床分期无关。
第二章Aurora激酶抑制物VX-680对人膀胱癌T24细胞增殖和凋亡影响
目的：探讨Aurora激酶抑制物VX-680对人膀胱癌T24细胞生物学行为的影响,即细胞增殖和细胞凋亡的影响。
方法：设定不同浓度的Aurora激酶抑制物VX-680作用不同时间于T24细胞,利用MTT法检测细胞增殖,流式细胞术检测T24细胞的凋亡指数,Hochest染色观察细胞形态学变化。
结果：Aurora激酶抑制物VX-680不同浓度(0nM,100nM,300nM,500nM)作用T24细胞于四个不同时间(12h,24h,48h,72h),MTT法检测细胞的生长抑制率,流式细胞术检测其凋亡率,Hochest染色观察细胞形态学变化,均发现呈明显的剂量效应关系和时间效应关系(P<0.05),分别在72h和500nM时其效应最明显,在72h时VX-680的IC50=761.222nM。MTT法检测72h时细胞存活率,VX-680浓度100nM：0.790±0.038,300nM：0.737±0.033,500nM：0.532±0.013,各浓度间均有差异(P<0.05)。流式细胞术检测其凋亡率,72h时VX-680浓度为0nM：(0.493±0.033)%,100nM：(6.608±0.550)%,300nM：(12.225±1.232)%,500nM：(18.275±4.986)%,各浓度组间两两相比差异性显著(P<0.01)。Hochest染色可见到不同程度的凋亡细胞,低剂量VX-680(100nM)处理细胞后,细胞凋亡较少,增加VX-680剂量(500nM),细胞凋亡明显增多,并且可见凋亡小体形成。
结论：
1.VX-680作用于人膀胱癌T24细胞后,对T24细胞的增殖有明显抑制作用,并且呈显著的剂量效应关系和时间效应关系。
2.VX-680作用于人膀胱癌T24细胞后,明显诱导细胞凋亡,凋亡的诱导作用呈显著剂量效应关系和时间效应关系。
第三章Aurora激酶抑制物VX-680抑制人膀胱癌T24细胞分子生物学机制的研究
目的：探讨VX-680抑制人膀胱癌T24细胞的分子生物学机制。
方法：设定不同浓度的VX-680作用不同时间于T24细胞,半定量RT-PCR检测T24细胞的Aurora A, CyclinD1, CyclinB1和Bcl-2mRNA的变化,Western blot检测Aurora A, CyclinD1, CyclinB1和Bcl-2蛋白的表达。
结果：半定量RT-PCR检测,不同浓度(0nM,100nM,300nM,500nM) VX-680作用不同时间(12h,24h,48h,72h)于T24细胞后,降低Aurora A、CyclinD1、CyclinB1和Bcl-2 mRNA表达比值和其蛋白表达比值,并呈明显的时间效应关系和剂量效应关系。不同VX-680浓度作用72h时Aurora A mRNA表达比值(Aurora A/ GAPDH)分别为,0nM组：0.749±0.012,100nM组：0.638±0.014,300nM组：0.272±0.011,500nM组：0.253±0.003,各组间差异均有统计学意义(P<0.05); CyclinD1、CyclinB1和Bcl-2 mRNA表达比值在72h时也有类似趋势。Western blot检测,Aurora A、CyclinD1、CyclinB1和Bcl-2基因在蛋白表达水平。72h时各浓度组细胞Aurora A蛋白表达比值(Aurora A/GAPDH)分别为,0nM组：0.766±0.016,1O0nM：0.637±0.013,300nM：0.478±0.009,500nM：0.335±0.004,各组间均差异明显(P<0.01); CyclinD1、CyclinB1和Bcl-2 mRNA基因在蛋白表达比值在72h时也有类似趋势。但是短时间(12h)作用于T24细胞时,不同浓度VX-680(0 nM,100 nM,300 nM,500 nM)对Aurora A、CyclinD1、CyclinB1和Bcl-2mRNA表达比值下降不明显,各浓度组间均无统计学意义(P>0.05)。
结论：
1.VX-680引起的Aurora A、CyclinD1、CyclinB1和Bcl-2的表达下调可以从多个通路抑制细胞增殖和诱导凋亡,并呈剂量效应关系和时间效应关系。
2. Aurora A与CyclinD1、CyclinB1和Bcl-2基因及蛋白的表达下调呈现明显相关性,他们之间可能存在相互调控。
Studies on the Influence of Aurora kinase inhibitor VX-680 on the proliferation and apoptosis in Human Bladder Carcinoma Cell Line T24
Background:Urinary bladder cancer ranks ninth in worldwide cancer incidence, while it ranks seventh in male cancer incidence and ranks seventeenth in female. More than 90% of UBC is bladder transitional cell carcinoma(BTCC), from which the patients families and society suffer heavy burden. In china, the incidence of the UBC has been increasing in some cities, that is no less than it in rural areas of china and is no more than western countries in the world. Superficial bladder cancer have a tendency to recurrence after posteroperative chemotherapy and immunotherapy and progression to muscle-invasive bladder cancer. Sugery therapy, radical cystoectomy, is associated severe complications, while neoadjuvant chemotherapy and radiotherapy have a poor outcome. To explore the new treatment to UBC is always a focus in cancer research.
Proliferation is organic modulation of cell. Mitotic is dependent on spindle checkpoint, which inspection of spindle shape、centromere connection to microtubule and tension、alignment of chromosome, to ensure that sister chromosome can separate into daughter cell accurately. It is proved that faults of mitotic checkpoint result to aneuploid in daughter cell, which can lead to carcinogenesis in various cancers. Aurora A is one of three serine/threonine kinases(A, B and C) that are evolutionally conserved and regulate mitotic progression in various organisms, Aurora kinases is overexpressed in various cancers.
To date, a growing number of inhibitors of Aurora kinases have been described including Hesperadin, ZM447439, and VX-680, whereas VX-680 inhibits all three family members. VX-680 can block cell-cycle progression and induces apoptosis in diverse range of human tumor types, such as breast cancer, lymphoma, prostate cancer, pancreatic cancer. So VX-680 may be a potent therapy of carcinoma. We evaluated the in vitro effects and mechanism on T24 cells of VX-680 involved in proliferation and apoptosis, and provided a new idea to therapy of tumor.
Part I
Expression of Aurora A, CyclinDl,CyclinBl and Bcl-2 and its correlation in BTCC
Objective To investigate the expression of Aurora A, CyclinDl, CyclinB 1 and Bcl-2 in BTCC with regard to the clinical significance.
Methods Expressions of Aurora A, CyclinD1, CyclinB 1 and Bcl-2 were detected by immmunohistochemical staining in 56 cases of BTCC and 15 cases of normal bladder tissues as controls. The relevance between the expressions of Aurora A, CyclinD1, CyclinB 1 and Bcl-2 and the clinical pathology of the patients of BTCC were studied.
Results Immmunohistochemical staining demonstrated that the positive rate of Aurora A, CyclinD1,CyclinB 1 and Bcl-2 respectively was 51.8%(29/56),46.4%(26/56),75.0%(42/56) and 62.5%(35/56)in BTCC, which is significantly higher than normal bladder tissues as 13.3%(2/15), 6.7%(1/15),33.3%(5/15) and 6.7%(1/15) (P<0.01) respectively. The positive rate of Aurora A, CyclinB 1 and Bcl-2 were significantly positive correlated with the grade of the tumor (P<0.05), but CyclinD1 with negative correlation. And no correlation was found between The positive rate of CyclinB 1、Bcl-2 and clinical staging, but Aurora A with positive correlation and Bcl-2 with negative one. There is a significantly verse relationship between the positive rate of Aurora A and CyclinD1(P< 0.01), but a positive correlation between Aurora A and CyclinB1、Bcl-2(P＜0.01).
Conclusion
1. The expression of Aurora A, CyclinD1, CyclinB 1 and Bcl-2 was significantly increasing in BTCC tissues compared to normal bladder tissues.
2. The expression of Aurora A, CyclinD1, CyclinB1 and Bcl-2 significantly correlated with the grade of the tumor, Aurora A, CyclinB1 and Bcl-2 with positive correlation and CyclinDl with negative one.
3. The expression of CyclinB1 and Bcl-2 was not relevant with the clinical staging, but Aurora A with positive relation and CyclinD1 with negative one.
PartⅡ
Effects of VX-680 on proliferation and apoptosis of human bladder cancer cell line T24
Objective To explore the effects of VX-680 on biological behavior of T24 cells, including proliferation inhibition and cell apoptosis.
Methods The effect of VX-680 on human bladder cancer T24 cells was evaluated with various concentration of VX-680 treatment for various phase by MTT assay. The cell apoptosis of human bladder cancer T24 cells was determined with flow cytometry and the apoptosis index was detected. The shape change of T24 cell was inspected by hoechst staining.
Results The dose-dependent manner and time-dependent manner was found, significantly, between the detection of proliferation inhibition、apoptosis、Hochest staining of T24 cell and Aurora kinases inhibitor VX=680 (P< 0.05).Both effects of VX-680 can reach to the climax in a concentration of 500nM or in a time of 72h. The IC50 of VX-680 may be 761.222nM in 72h. The survival rate, significantly decreasing with increasing concentration in 72h (P< 0.05), of T24 cell, 100nM:0.790±0.038; 300nM:0.737±0.033; 500nM:0.532±0.013. The apoptosis index, significantly increasing with elevating concentration in 72h(P<0.01), of T24 cell, OnM:(0.493±0.033)%, 100nM: (6.608±0.550)%,300nM:(12.225±1.232)%,500nM:(18.275+4.986)%. Observed by hoechst staining, the apoptotic cells is gradually increasing with elevating concentration of VX-680, the apoptotic body found in high concentration.
Conclusion Our data suggested VX-680 treatment lead to proliferation inhibition and induces apoptosis of the human bladder T24 cell line, in a significant dose-dependent and time-dependent manner.
PartⅢ
Study on the molecular biological mechanism of VX-680 in human bladder cancer cell line T24
Objective To investigate the molecular biological mechanism of VX-680, by which cell apoptosis and proliferation inhibition found in human bladder cancer cell line T24.
Methods The effect of VX-680 on human bladder cancer T24 cells was assessed with varying concentration of VX-680 treatment for different phase. Semi-quantitive RT-PCR and Western blot were used to detect the expression of Aurora A, CyclinD1, CyclinB1 and Bcl-2 respectively.
Results The dose-dependent manner and time-dependent manner was found, significantly, in down-regulated expression of Aurora A、CyclinD1、CyclinB1 and Bcl-2 related to the various concentration(OnM, 100nM,300nM,500nM) of VX-680 or treatment time (12h,24h,48h, 72h) by Semi-quantitive RT-PCR and Western blot. The expression ratio of Aurora A mRNA(Aurora A/GAPDH) in 72h was 0.749±0.012(0nM), 0.638±0.014(100nM),0.272±0.011(300nM),0.253±0.003(500nM), VX-680 down-regulated expression of Aurora A mRNA in Semi-quantitive RT-PCR tests (P<0.05). The expression ratio of Aurora A protein(Aurora A/GAPDH) in 72h was 0.766±0.016(0nM), 0.637±0.013(100nM),0.478±0.009(300nM),0.335±0.004(500nM), VX-680 significantly down-regulated expression of Aurora A protein in Western blot tests (P<0.01). It is also found that VX-680 down-regulated the expression of CyclinD1、CyclinB1 and Bcl-2 in similar to it of Aurora A in both tests, Semi-quantitive RT-PCR and Western blot(P<0.05). However, no significant decreasing expression of Aurora A、CyclinD1、CyclinB1 and Bcl-2mRNA, respectively, in treatment time of 12h in Semi-quantitive RT-PCR tests.
Conclusion
1. VX-680 can inhibit proliferation and induce apoptosis of T24 cell, by means of down-regulating Aurora A、CyclinD1、CyclinB1 and Bcl-2 through multiple pathway.
2. The significant correlation found between down-regulated expression of Aurora A and it of CyclinD1、CyclinB1、Bcl-2 respectively, which may be regulated each other.
引文
[1]Garcia M, Jemal A, Ward EM, et al. Global cancer facts and Wgs 2007. AmericanCancer Society, Atlanta.
[2]Ferlay J, Bray F, Pisani P, Parkin DM (2004). GLOBOCAN 2002:cancer incidence, mortality and prevalence worldwide. IARCCancerBase No.5.version 2.0. IARC Press, Lyon.
[3]Parkin DM. The global burden of urinary bladder cancer. Scand J Urol Nephrol, 2008,Suppl(218):12-20.
[4]American Cancer Society Cancer facts & Wgures. Available at:http://www. cancer.org/downloads/STT/CAFF2007PWSecured.pdf.
[5]Parkin MD, Bray F, Ferlay J, et al. Global Cancer Statistics,2002. CA Cancer J Clin,2005,55(2):74-108.
[6]魏矿荣,陈振雄,梁智恒,等.中山市1970-1999年膀胱癌发病趋势分析.中国肿瘤,2005,14(4)：235-237.
[7]张薇,项永兵,刘振伟,等,1973-1999年上海市区老年人恶性肿瘤发病趋势分析.中华老年医学杂志,2005,24(9)：701-704.
[8]许放,张莉梅,林红,等.大连市区1991-2005年恶性肿瘤发病趋势分析.中国肿瘤,2008,17(4)：274-277.
[9]项永兵,张薇,高立峰,等.恶性肿瘤发病率的时间趋势分析方法.中华流行病学杂志,2004,25(2)：173-177.
[10]中华人民共和国卫生部.2008中国卫生统计年鉴.中国协和医科大学出版社：227-228.
[11]Fleshner NE, Herr HW, Stewart AK, et al. The National Cancer Data Base report on bladder carcinoma. Cancer,1996,78(7):1505-1513.
[12]Ro JY, Staerkel GA, Ayala AG. Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am,1992,19(3):435-553.
[13]Tolley DA, Parmar MK, Grigor KM, et al. The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer:a further report with 7 years of follow up. J Urol,1996,155(4):1233-1238.
[14]Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta/T1 bladder cancer using EORTC risk tables:a combined analysis of 2596 patients from seven EORTC trials. Eur Urol,2006,49(3):466-477.
[15]Millan RF, Chechile TQ Salvador BJ, et al, Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol,2000, 163(1):73-78.
[16]A Stenzl, N.C.Cowan, M. De Santis, et al. EAU Guidelines on bladder cancer muscle-invasive and metastatic. Eur Urol,2009,55(4):815-825.
[17]Crane R, Gadea B, Littlepage L, et al. Aurora A, meiosis mitosis. Biol Cell, 2003,96(3):215-229.
[18]Glover DM, Leibowitz MH, Mclean DA, et al. Mutation in aurora prevent centrosome separation leading to the formation of monopolar spindl. Cell,1995, 81(1):95-105.
[19]Pihan GA, Purohit A, Wallace J, et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res,1998,58(17):3974-3985.
[20]Marumoto T, Hirota T, Morisaki T, et al. Roles of Aurora A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells,2002,7(11): 1173-1182.
[21]Sen S, Zhou H, Zhang RD, et al. Amplification/overexpression of a Mitotic kinase gene in human bladder cancer. Journal of the National Cancer Institute, 2002,94(17):1320-1329.
[22]Mhawech-Fauceglia P, Fischer G, Beck A, et al. Rafl, Aurora-A/STK15 and E-cadherin biomarkers expression in patients with pTa/pTl urothelial bladder carcinoma; a retrospective TMA study of 246 patients with long-term follow-up. Eur J Surg Oncol,2006,32(4):439-444.
[23]E.Comperat, P.Camparo, R. Haus., et al. Aurora-A/STK-15 is a predictive factor for recurrent behavior in non-invasive bladder carcinoma:a study of 128 cases of non-invasive neoplasms.Virchows Arch,2007,455(4):419-424.
[24]Park HS, Park WS, Bondaruk J, et al. Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. Natl Cancer Inst,2008, 100(19):1401-1411.
[25]伍钢,孟睿,答邦明,等.Aurora A反义寡核苷酸对人肺癌细胞系A549细胞生长与细胞周期的影响.临床肿瘤学杂志,2007,12(6)：406-412.
[26]武文,屈艺,刘小康,等.Aurora A表达与人前列腺癌细胞对紫杉醇敏感性的相关性研究.四川大学学报(医学版),2007,38(2)：306-308.
[27]Harrington E A, Bebbington D, Moore J, et al. VX-680, a potent and selective small molecule inhibitor of the Aurora kinases, suppresses tumor growt h in vivo. Nature Med,2004,10(3):262-267.
[28]Cho HJ, Kim JK, Kim KD, et al. Up-regulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells. Cancer Lett,2006,237(1):56-66.
[29]Bai Y, Mao QQ, Qin J, et al. Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci,2010,101(2):488-493.
[30]Lin JG, Chen GW, Li TM, et al. Aloe-emodin induces apoptosis in T24 human bladder cancer cells through the p53 dependent apoptotic pathway. J Urol,2006, 175(1):343-347.
[31]Marumoto T, Honda S, Hara T, et al. Aurora-A Kinase Maintains the Fidelity of Early and Late Mitotic events in HeLa Cells. J Biol. Chem,2003, 278(51):51786-51795.
[32]Takeno S, Noguchi T, Kikuchi R, et al.Pmguostic value of cyclinBl in patients with esophageal squamous cell carcinoma. Cancer,2002,94(11):2874-2881.
[33]Hassan KA, El-Naggar AK, Soria JC, et al. Clinical significance of cyclinB1 protein expression in squamous cell carcinoma of the tongue. Clin Cancer Res, 2001,7(8):2458-2462.
[34]Soria JC, Jang SJ, Khuri FR, et al. Overexpression of cyc1in B1 in early-stage non-small cell lung cancer and its clinical implication. CancerRes,2000,60(15): 4000-4004.
[35]Sallinen SL, Sallinen PK, Kononen JT, et al. CyclinD1 expression in asrocytomas is associated with cell proliferation activitand patient prognosis. Pathology,1999,188 (3):289-293.
[36]Schwandner O, Bruch HP, Broll R. p21, p27, cyclinD1, and p53 in rectal cancer: immunohistology with prognostic significance. Int J ColorectalDis,2005,17 (1): 11-19.
[37]Cai FG, Xiao JS, Ye QF, et al. Effects of ischemic preconditioning on cyclinD1 expression during early ischemic reperfusion in rats. World J Gastroenterol,2006, 12 (18):2936-2940.
[38]Yu J, Miehlke S, EbertMP, et al. Expression of cyclin genes in human gastric cancer and in first degree relatives. Chin Med J (Engl),2002,115 (5):710-715.
[39]Mukund Dole, Neuez G, Mercham A K, et al. bcl-2 inhibited chemotherapy-induced apoptosis in neuroblastoma. Cancer Res,1994,54(12):3253-3259.
[40]Miyashite T, Reed J C. Bcl-2 gene transfer increase relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res,1992,52 5407-5411.
[41]Meraldi P, Honda R, Nigg EA, et al. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Current Opinion Genetics & Development,2004,14(1):29-36.
[42]Mhawech-Fauceglia P, Fischer G, Alvarez V Jr, et al. Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder carcinoma using a panel of biomarkers:A high throughput tissue microarray analysis. BJU Int,2007, 100(5):1182-1187.
[43]屈艺,张林,母得志,等.Aurora-A在人前列腺癌中的表达.四川大学学报(医学版),2008,39(1)：1-5.
[44]Moghaddam SJ, Haghighi EN, Samiee S, et al. Immunohistochemical analysis of p53, cyclinD1, RBI, c-fos and N-ras gene expression in hepatocellular carcinoma in Iran. World J Gastroenterol,2007,13 (4):588-593.
[45]Rose SL, Buller RE. The role of p53 mutation in BRCA1-associated ovarian cancer. Minerva Ginecol,2002,54 (3):201-209.
[46]Zhou JX, Niehans GA, SharA, et al. Mechanisms of G1 checkpoint loss in resected early stage non-small cell lung cancer. Lung Cancer,2001, (1):27-38.
[47]Lee GG, Yamamoto S, Morimura K, et al. Significance of cyclinD1 overexpression in transitional cell carcinomas of the urinary bladder and its correlation with histopathologist features.Cancer,1997,79(4):780-789.
[48]Suwa Y, Takano Y, Iki M, et al. CyclinD1 protein in overexpression is related to tumor differentiation, but not to tumor progression or proliferative activity, in transitional cell carcinoma of the bladder. J Urol,1998,160(3 pt 1):897-900.
[49]Wager U, Suess K, Luginbuhl T, et al. CyclinDl overexpression lacks prognostic significance in superficial urinary bladder cancer. J Pathol,1999,18(1):44-50.
[50]方艺,吴志平.CyclinD1和p27蛋白在膀胱移行细胞癌中的表达.遵义医学院学报,2005,28(5)：421-422.
[51]李彬,徐涛,赵晖,等.P27Kip1、 CyclinD1在膀胱癌中的表达及其意义.实用医学杂志,2006,22(22)：2607.
[52]邱晓峰,韩恩善,陈福宝.cyclinD1蛋白在膀胱移行上皮细胞癌中的表达及其意义.宁夏医学院学报,2006,28(6)：482-483.
[53]钟凯华,柳建军,曹军,等.膀胱移行细胞癌RASSF1A和Cyclin-D1与Bcl-2蛋白的表达及意义.中华肿瘤防治杂志,2007,14(21)：1632-1635.
[54]郭柏鸿,张志华,陈一成,等.膀胱癌中Smad4、 Ki-67、 CyclinD1基因表达及临床意义.兰州大学学报(医学版),2008,34(3)：43-47.
[55]Liu F, Li X, Wang C, et al. Downregulation of p21-activated kinase-1 inhibits the growth of gastric cancer cells involving Cyclin B1. Int J Cancer,2009,125(11): 2511-2519.
[56]Laura A. Vella, Min Yu, Steven R, et al. Healthy individuals have T-cell and antibody responses to the tumor antigen Cyclin B1 that when elicited in mice protect from cancer. Proc Natl Acad Sci,2009,106(33):14010-14015.
[57]Aaltonen K, Amini RM, Heikkila P, et al. High Cyclin B1 expression is associated with poor survival in breast cancer. Br J Cancer,2009, 100(7):1055-1060
[58]张学锋,曾甫清,汪良.Survivin和CyclinB1在膀胱癌中的表达及其意义.临床泌尿外科杂志,2005,20(7)：432-434.
[59]叶木石,柳建军,曹军,等.p34 cyclinB1在膀胱移行细胞癌的表达及意义.现代肿瘤医学,2007,15(7)：988-990.
[60]Belushkina NN, Khomiakova TI, Khomiakov IuN. Cell death and specifics of its regulation in tumour cells. Ross Fiziol Zh Im I M Sechenova,2009, 95(10):1093-1107.
[61]Da Cruz Perez DE, Pires FR, Alves FA, et al. Salivary gland tumors in children and adolescents:a clinicopathologic and immunohistochemical study of fifty three cases. Int J Pediatr Otorhinolaryngol.2004,68(7):895-902.
[62]王养民,王荣霞,哈英娣,等.Bcl-2在膀胱肿瘤中的表达及临床意义.西北国防医学杂志,2000,21(2)：107-108.
[63]沈宏伟,易路,汪小明,等.Caspase-3与Bcl-2蛋白在膀胱移行细胞癌中的表达及意义.癌症,2004,23(2)：181-184.
[64]张磊,李钢,史立新,等.膀胱癌中Fas、 FasL、 Bcl-2及Bax的表达及意义.解放军医学杂志,2006,31(2)：141-142.
[65]陈兵海,杨建军,姚茂银.P-gp、 MRP、 Bcl-2、 Bax在膀胱癌中的表达及其意义.东南大学学报(医学版),2007,26(4)：279-282.
[66]马毅,曾甫清.Bcl-2与VEGF在膀胱移行细胞癌的表达及其意义.临床泌尿外科杂志,2008,23(1)：55-57
[67]McKnight JJ, Gray SB, O'Kane HF, et al.Apoptosis and chemotherapy for bladder cancer. J Uro1.2005.173(3):683-690.
[68]Miyashita T, Reed J C. Bcl-2 gene transfer increase relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs.Cancer Res,1992, 52(19):5407-5411.
[69]刘贤奎,孔垂泽,时京.转染Bcl-2基因的膀胱癌细胞多药耐药性研究.中华肿瘤防治杂志,2006,13(15)：1151-1153.
[70]Shindo M, Nakono H, Kuroyanagi H, et al. cDNA cloning, expression, subcellular location, and chromosomal assignment of mammalian Aurora homologues, Aurora-related kinase(ARK)1 and 2. Biochem Biophys Res Commun,1998,244(1):285-292.
[71]Sasayama T, Marumoto T, Kunitoku N, et al. Overexpression of Aurora-A targets cytoplasmic polyadenylation element binding protein and prom otesmRNA polyadenylation of CDK1 and cyclinBl. Genes Cells,2005,10 (7): 627-638.
[72]Bischoff J R, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified inhuman colorectal cancers. EMBO J,1998, 17(11):3052-3065.
[73]Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP and survivin in mitosis. Mol Biol Cell,2003,14(8): 3325-3341.
[74]Gradilone A, Gazzaniga P, Ribuffo D, et al. Survivin, bcl-2, bax, and bcl-X Gene Expression in Sentinel Lymph Nodes From Melanoma Patients. Journal of Clinical Oncology,2003,21(2):306-312.
[75]Coco-martin JM, Balkenende A, Verschoor T, et al. CyclinD1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line. Cancer Res,1999,59 (5):1134-1140.
[76]Giles FJ, Cortes J, dones D, et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T3151-BCR/ABL mutation.Blood,2007,109(2):500-502.
[77]Farid Gizatullin, Yao Yao, Victor Kung, et al. The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint Function. Cancer Res, 2006,66(15):7668-7677.
[78]Warren Fiskus, Yongchao Wang, Rajeshree Joshi, et al. Co-treatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. Clin Cancer Res,2008,14(19):6106-6115.
[79]Edmund Chun Yu Lee, Anna Frolov, Rile Li, et al. Targeting Aurora Kinases for the Treatment of Prostate Cancer. Cancer Res,2006,66 (10):4996-5002.
[80]Yannick Arlot-Bonnemains, Enke Baldini, Benedicte Martin, et al. Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines. Endocrine-Related Cancer,2008,15(2):559-568.
[81]关中,薛红漫,冯公侃,等.Aurora激酶抑制剂VX-680对头颈肿瘤细胞增殖的影响.医药世界,2006,11：16-17.
[82]滑芳,张红真,房桂英,等.Aurora-A激酶抑制剂VX-680对人子宫内膜癌细胞化疗敏感性的影响.河北医药,2008,30(8)：1096-1097.
[83]Fulda S. Tumor resistance to apoptosis. Int J Cancer,2009,124 (3):511-515.
[84]Schwartzman RA, Cidlowski JA. Apoptosis:the biochemistry and molecular biology of programmed cell death. Endocr Rev,1993,14(2):133-151.
[85]Bain J, Plater L, Elliton M, et al. The selectivity of protein kinase inhibitors:a further update. Biochem J,2007,408(3):297-315.
[86]Marumoto T, Zhang D, Saya H. Aurora A-a guardian of poles. Nat Rev Cancer, 2005,5(1):42-50.
[87]Sasai K, Katayama H, Stenoien DL, et al. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil Cytoskeleton,2004,59(4):249-263.
[88]Yan X, Cao L, Li Q, et al. Aurora C is directly associated with Survivin and required for cytokinesis. Genes Cells 2005,10(6):617-626.
[89]Knowlton AL, Lan W, Stukenberg P. Aurora B is enriched at merotelic attachment sites, where it regulated MCAK. Curr. Biol.2006,16 (17): 1705-1710.
[90]Hauf S, Cole RW, LaTerra S, et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Biol Chem,2003,161 (2):281-294.
[91]Li X, Sakashita G, Matsuzaki H, et al. Direct association with inner centromere protein (INCENP) activates the novel chromosomal passenger protein, Aurora-C. J Biol Chem,2004,279(45):47201-47211.
[92]Meraldi P, Honda R, Nigg EA. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/-cells. EMBOJ,2002,21 (4):483-492.
[93]Yang H, Ou CC, Fddman RI, et al. Aurora A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res,2004, 64(2):463-467.
[94]Anand S, Penrhyn-Lowe S, Venkitaraman AR. Aurora-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to taxol. Cancer Cell,2003,3(1):51-62.
[95]Hata T, Furukawa T. Sunamura M, et al. RNA interference targeting Aurora kinase a suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res,2005,65(7):2899-2905.
[96]Lin YG, lmmaneni A, Memtt WM, et al.Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth. Clin Caneer Ras,2008,14(17):5437-5446.
[97]Tsuno T, Natsume A, Katsumata S, el al. Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances antitumor effect of temozolomide in human glioma cells. J Neurooncol, 2007,83(3):249-258.
[98]Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcll-linked candidate oncogene. Nature,1991,350(6318):462-463.
[99]Kim JK, Jung KH, Noh JH, et al, Targeted disruption of S100P suppresses tumor cell growth by down-regulation of cyclinD1 and CDK2 in human hepatocellular carcinoma. Int J Oncol,2009,35(6):1257-1264.
[100]Wu PP, Jin YL, Shang YF, et al. Restoration of DLC1 gene inhibits proliferation and migration of human colon cancer HT29 cells. Ann Clin Lab Sci,2009, 39(3):263-269.
[101]Liu H, Wang J, Xu X, et al. Suppressive effect of resveratrol on growth of U251 human glioma cells and its correlated mechanism. Zhongguo Zhong Yao Za Zhi, 2009,34(8):1027-1031.
[102]Jakman M, Lindon C, Nigg EA, et al. Active cyclinBl-CDK1 first appears on centrosomes in prophase. N at Cell Biol,2003,5 (2):143-148.
[103]Shen M, Feng Y, Gao C, et al. Detection of cyclinB1 expression in G1-phase cancer cell lines and cancer tissues by postsorting western blot analysis. Cancer Res,2004,64 (5):1607-1610.
[104]Li X K, Motwani M, Tong W, et al. Huanglian, a Chinese herbal extract, inhibits cell growth by'supp ressing the expression of cyclinB1 and inhibiting CDC2 kinase activity in human cancercells. Mol Pharmacol,2000,58 (6): 1287-1293
[105]Yuan J, Yan R, Kramer A, et al. CyclinB1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene,2004,23 (34):5843-5852.
[106]Yin XY, Grove L, Datta NS. Inverse regulation of cyclinB1 by c-myc and p53 and induction of tetraploidy by cyclinB1 overexpression. Cancer Res,2001,61 (17):6487-6493.
[107]Mahitosh Mandal, Rakesh Kumer. Bcl-2 modulates telomerase activity. J Biol Chem,1997,272 (22):14183-14187.
[108]郑连文,李付彪,吉日嘎拉,等.Bcl-2反义寡核苷酸诱导膀胱癌EJ细胞凋亡的研究.中国老年学杂志,2004,24：1148-1150.
[109]Habib GM. Arsenite causes down-regulation of Akt and c-Fos, cell cycle dysfunction and apoptosis in glutathione-deficient cell. J Cell Biochem,.2010 Mar 24, [Epub ahead of print].
[110]Bangaru ML, Chen S, Woodliff J, et al. Curcumin (diferuloylmethane) induces apoptosis and blocks migration of human medulloblastoma cells. Anticancer Res,2010,30(2):499-504.
[111]Lokeshwar VB, Lopez LE, Munoz D, et al. Antitumor Activity of Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone in Prostate Cancer Cells. Cancer Res,2010 Mar 23. [Epub ahead of print].
[112]Barimaga M. Death by dozens of cuts. Science,1998,280(5360):32-34
[113]Yamamoto Y, Eguchi S, Junpei A, et al. Intercellular centrosome number is correlated with the copy number of chromosomes in bladder cancer. Cancer Genet Cytogenet,2009,191(1):38-42.
[1]Stenoien DL, Sen S, Mancini MA, et al. Dynamic association of a tumor amplified kinase, Aurora A, with the centrosome andmitotic spindle. Cell Motil Cytoskeleton,2003,55(2):134-146.
[2]Bolanos-Garcia V M. Aurora kinases. Int J Biochem Cell Biol,2005,37(8):1572-1577.
[3]Bischoff J R, Anderson L, Zhu Y, et al. A homologue of Dorsophila Aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J,1998, 17(11):3052-3065.
[4]Carpinelli P, Moll J. Aurora kinases and their inhibitors:more than one target and one drug. Adv Exp Med Biol,2008,610:54-73.
[5]Kollareddy M, Dzubak P, Zheleva D, et al. Aurora kinases:structure, functions and their association with cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub.2008,152(l):27-33.
[6]Mar Carmena, Sandrine Ruchaud, William C Earnshaw. Making the Auroras glow: regulation of Aurora A and B kinase function by interacting proteins. Curr Opin Cell Biol.2009,21(6):796-805
[7]Carmena M, Earnshaw WC. The Cellular Geography of Aurora Kinases. Nat Rev Mol Cell Biol,2003,4(11):842-854.
[8]Lukasiewicz KB, Lingle WL. Aurora A, centrosome structure, and the centrosome cycle. Environ Mol Mutagen,2009,50(8):602-619.
[9]Kimura M, Matsuda Y, Yoshioka T, et al. Identification and characterization of STK12/Aik2:a human gene related to aurora of Drosophila and yeast IPL1. Cytogenet. Cell Genet,1998, 82(3-4):147-152.
[10]Bernard M, Sanseau P, Henry C, et al. Cloning of STK13, a third human protein kinase related to Drosophila Aurora and budding yeast Ipll that maps on chromosome 19ql3.3-ter. Genomics,1998,53(3):406-409.
[11]Marumoto T, Honda S, Hara T, Nitta M, et al. Aurora A Kinase Maintains the Fidelity of Early and Late Mitotic events in HeLa Cells. J Biol Chem,2003,278(51):51786-51795.
[12]Saeki, Ouchi M, Ouchi T. Physiological and oncogenic Aurora A pathway. Int J Biol Sci, 2001,5(7):758-762.
[13]Marumoto T, Zhang D, Saya H. Aurora A a guardian of poles. N at Rev Cancer,2005, 5(1):42-50.
[14]Adams RR, Maiato H, Earnshaw WC, et al. Essential Roles of Drosophila Inner Centromere Protein (INCENP) and Aurora B in Histone H3 Phosphorylation, Metaphase Chromosome Alignment, Kinetochore Disjunction, and Chromosome Segregation. J Biol Chem,2001, 15(4):865-880.
[15]Knowlton AL, Lan W, Stukenberg PT. Aurora B is enriched at merotelic attachment sites, where it regulated MCAK. Curr Biol,2006,16(17):1705-1710.
[16]Hauf S, Cole RW, LaTerra S, et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Biol Chem,2003,161(2):281-294.
[17]Li X, Sakashita G, Matsuzaki H, et al. Direct association with inner centromere protein (INCENP) activates the novel chromosomal passenger protein, Aurora-C. J Biol Chem, 2004,279(45):47201-47211.
[18]Tseng TC, Chen SH, Hsu YP, et al.Protein kinase profile of sperm and eggs: cloning and characterization of two novel testis specific protein kinases(AIE1 AIE2) related to yeast and fly chromosome segregation regulators. DNA Cell Biol,1998,17(10):823-833.
[19]Sasai K, Katayama H, Stenoien D L, et al. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora B kinase function in mitotic cells. Cell Motil Cytoskeleton,2004,59 (4):249-263.
[20]Fuller BG, Stukenberg PT. Cell division:righting the check. Curr Biol,2009, 19(14):1182-1187
[21]钟亚莉,童彤,杨观瑞,等.Aurora A在细胞中的功能以及与肿瘤的关系.国外医学遗传学分册,2005,28(5)：313-316.
[22]Kufer TA, Sillje HH, Komer R, et al. Human TPX2 is required for targeting Aurora A kinase to the spindle. J Cell Bid,2002,158(4):617-623.
[23]Katayama H, Zhou H, Li Q, et al. Interaction and feedback regulation Between STK15/BTA/Aurora-A kinase and protein phosphatase Through mitotic cell division cycle. J Biol Chem,2001,276 (49):46219-46224.
[24]Sasayama T, Marumoto T, Kunitoku N, et al. Overexpression of Aurora-A targets cytoplasmic polyadenylation element binding protein and prom otesmRNA polyadenylation of CDK1 and cyclinB1. Genes Cells,2005,10 (7):627-638.
[25]Hirom T, Kunitoku N, Sasayama T, et al. Aurora-A and an interacting activator, the LIM protein Ajuba, fire require for mitotic commitment in human cells. Cell, 2003,114(5):585-598.
[26]Salinover DL, Leach CA, Stukenberg PT, et al.Activation of Aurora A kinase by protein phosphatase inhibitor-2, a bifunctional signaling protein. Proc Natl Acad Sci USA,2004.101 (23):8625-8630.
[27]王晓霞,樊飞跃,詹启敏.有丝分裂激酶Aurora-A活性调节分子机制.医学分子生物学杂志,2005,2(6)：436-439.
[28]Vaguawlli P, Earnshaw WC. Chromosomal passengers:the four-dimensional regulation of mitotic events.Chromosoma,2004,113(5):211-222.
[29]Gassmann R, Carvalho A, Henzing AJ, et al. Borealin:a novel chromosomal passenger required for stability of the bipolar mitotic spindle. Cell Biol,2004, 166(2):179-191.
[30]Chen J, Jin S, Tahir SK, et al. Survivin enhances Aurora B kinase activity and localizes Aurora B in human cells. J Biol Chem,2003,278 (1):486-490.
[31]Gerben Vader, RH Medema, Lens SM. The chromosomal passenger complex: guiding Aurora-B through mitosis. J Cell Biol,2006,173(6):833-837.
[32]Vas AC, Clarke DJ. Aurora B kinases restrict chromosome decondensation to telophase of mitosis. Cell Cycle,2008,7(3):293-296
[33]Adams RR, Carmena M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol,2001, 11(2):49-54.
[34]Boss DS, Beijnen JH, Schellens JH. Clinical experience with aurora kinase inhibitors:a review. Oncologist,2009,14(8):780-793.
[35]Dutertre S, Descamps S, Prigent C. On the role of Aurora-A in centrosome fun-ction. Oncogene,2002,21 (40):6175-6183.
[36]Roghi C, Giet R, Uzbekov R, et al. The Xenopus protein kinase pEg2 associates with the centrosome in a cell cycle-dependent manner, binds to the spindle microtubules and is involved in bipolar mitotic spindle assembly. J Cell Sci, 1998, 111(pt5):557-572.
[37]Hannak E, Kirkham M, Hyman AA, et al. Aurora A kinase is required for centro-some maturation in Caenorhabditis elegans. J Cell Biol,2001,155 (7):1109-1116.
[38]Giet R, McLean D, Descamps S, et al. Drosophila Aurora A kinaseis required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol,2002,156 (3):437-451.
[39]Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome mat-uration and actin-dependent asymmetric protein localization during mitosis. Curr Biol,2002,12 (8):640-647.
[40]Giet R, Prigent C. The Xenopus laevis aurora/Ipllp-related kinase pEg2 participates in the stability of the bipolar mitotic spindle. Exp Cell Res,2000, 258(1):145-151.
[41]Sugimoto K, Urano T, Zushi H, et al. Molecular dynamics of Aurora A kinase in living mitotic cells simultaneously visualized with histone H3 and nuclear membrane protein importinalpha. Cell Struct Funct,2002,27 (6):457-467.
[42]Marumoto T, Hirota T, Morisaki T, et al. Roles of Aurora-A kinase in mitotic entry and G2 checkpoint in mamalian cells. Genes Cells,2002,7 (11):1173-1182.
[43]Hodgman R, Tay J, Mendez R, et al. CPEB phosphorylation and cytoplasmic polyadenylation are catalyzed by the kinase IAK1/PEg2 in maturing mouse oocytes. Development,2001,128(14):2815-2822.
[44]Gigoux V, L'Hoste S, Raynaud F, et al. Identification of Aurora kinases as RasGAP Src homology 3 domain-binding proteins. J Biol Chem,2002,277 (26):23742-23746.
[45]Ouchi M, Fujiuchi N, Sasai K, et al. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem,2004,279(19):19643-19648.
[46]Hirota T, Lipp JJ, Toh BH, et al. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature,2005, 438(7071):1176-1180.
[47]May KM, Hardwick KG The spindle checkpoint. Journal of Cell Science,2006, 119(pt20)4139-4142.
[48]Andrews PD, Ovechkina Y, Morrice N, et al. Aurora B regulates MCAK at the mitotic centromere. Dev Cell.2004,6(2):253-268.
[49]Goto H, Yasui Y, Kawajiri A. Aurora B regulates the cleavage furrow-specific vimentin phosphorylation in the cytokinetic process. J Biol Chem,2003, 278(10):8526-8530.
[50]Minoshima Y, Kawashima T, Hirose K, et al. Phosphorylation by Aurora B converts MgcRacGAP to a RhoGAP during cytokinesis. Dev Cell,2003, 4(4):549-560.
[51]Slattery SD, Mancini MA, Brinkley BR, et al. Aurora C kinase supports mitotic progression in the absence of Aurora-B. Cell Cycle,2009,8(18):2984-94.
[52]Meraldi P, Honda R, Nigge A, et al. Aurora kinases link chromosome
segregation and cell division to cancer susceptibility. Curr Opin Genet Dev, 2004,14(1):29-36.
[53]Wang X X, Liu R, Jin S Q, et al. Overexpression of Aurora A kinase promotes tumor cell proliferation and inhibit sapoptosis in esophageal squamous cell carcinoma cell line. Cell Res,2006,16(4):356-366.
[54]Pihan GA, Purohit A, Wallace J, et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res,1998,58(17):3974-3985.
[55]Lingle WL, Lutz WH, Ingle JN, et al. Centrosome hypertrophy in human breast tumors:implications for genomic stability and cell polarity. Proc Natl Acad Sci USA,1998,95(6):2950-2955.
[56]Meraldi P, Honda R, Nigg EA. Aurora A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/-cells. EMBOJ,2002,21 (4):483-492.
[57]Katayama H, Sasai K, Kawai H, et al. Phosphorylation by Aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nature Genet, 2004,36 (1):55-62.
[58]Liu Q, Kaneko S, Yang L, et al. Aurora A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine-215. J Biol Chem,2004, 279 (50):52175-52182.
[59]Eyers PA, Maller JL. Regulation of Xenopus Aurora A activation by TPX2. J Biol Chem,2004,279 (10):9008-9015.
[60]Yang H, Ou CC, Fddman RI, et al. Aurora A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res,2004, 64(2):463-467.
[61]Li D, Zhu J, Firozi PF, et al. Overexpression of oncogenic STK15/BTAK/ Aurora A kinase in human pancreatic cancer. Clin Cancer Res,2003,9 (3):991-997.
[62]Gritsko TM, Coppola D, Paciga JE. Activation and overexpression of centrosome kinase BTAKP Aurora-A in human ovarian cancer. Clinical Cancer Research, 2003,9 (4):1420-1429.
[63]Jeng YM, Peng SY, Lin CY, et al. Overexpression and amplification of Aurora A in hepatocellular carcinoma. Clin Cancer Res,2004,10 (6):2065-2071.
[64]Mhawech-Fauceglia P, Fischer G, Beck A, et al. Rafl, Aurora-A/STK15 and E-cadherin biomarkers expression in patients with pTa/pT1 urothelial bladder carcinoma; a retrospective TMA study of 246 patients with long-term follow-up. Eur J Surg Oncol,2006,32(4):439-444.
[65]Park HS, Park WS, Bondaruk J, et al. Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. Natl Cancer Inst,2008, 100(19):1401-1411.
[66]Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplifiedkinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer,2001,84 (6):824-831.
[67]Sen S, Zhou H, Zhang RD, et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst,2002,94 (17):1320-1329.
[68]Miyoshi Y, Iwao K, Egawa C, et al. Association of centrosomal kinase STK15/ BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer,2001,92 (3):370-373.
[69]Warner SL, Bearss DJ, Han H, et al.Targeting Aurora-2 kinase in cancer. Mol CancerTher,2003,2(6):589-595.
[70]Mountzios G, Terpos E, Dimopoulos MA. Aurora kinases as targets for cancer therapy. Cancer Treat Rev,2008,34(2):175-182.
[71]Ducat D, Zheng Y. Aurora kinases in spindle assembly and chromosome segregation. Exp Cell Res,2004,301(1):60-67.
[72]Farmer JP, Lamba M, Lamba WR, et al. Lymphoproliferative lesions of the lacrimal gland:clinicopathological, immunohistochemical andmolecular genetic analysis. Can J Ophthalmol,2005,40(2):151-160.
[73]Mortlock A, Keen NJ, Jung FH, et al. Progress in the development of selective inhibitors of Aurora kinases. Curr Top Med Chem,2005,5(8):199-213.
[74]Zeng WF, Navarane k, Prayson RA, et al. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol,2007, 60(2):218-221.
[75]Lkezoe T, Jing Y, Nishioka C, et al. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther,2007,6(6): 1851-1857.
[76]Lopez-rios F, Chuai S, Flores R, et al. Global gene expression profiling of pleural mesotheliomas:overexpression of Aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res,2006,66(6):2970-2979.
[77]单人锋,周福庆,吴波,等.Aurora-B在肝癌组织中的表达及其意义.世界华人消化杂志,2009,17(3)：270-272.
[78]Paolo Chieffi, Laura Cozzolino, Annamaria Kisslinger, et al. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation.The prostate,2005,66(3):326-333.
[79]Chen YJ, Chen CM, Twu NF, et al. Overexpression of Aurora B is associated with poor prognosis in epithelial ovarian cancer patients. Virchows Arch,2009, 455(5):431-40.
[80]Ditchfield C, Johnson V L, Tighe A, et al. Aurora B couples chromosome align-mentwith anaphase by targeting BubRl,Mad2, and Cenp-E to kinetochores. J Cell Biol,2003,161 (2):267-280.
[81]Murata-HoriM, Wang YL. The kinase activity of Aurora B is required for kinetochore-microtubule interactions duringmitosis. Curr B iol,2002,12 (11): 894-899.
[82]Kimura M, Matsuda Y, Yoshioka T, et al. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipll-related protein kinase, AIK3. J Biol Chem,1999,274(11):7334-7340.
[83]Takahashi T, Futamura M, Yoshimi N, et al. Centrosomal kinases, HsAIRK1 and HsAIRK3, are overexpressed in primary colorectal cancers. Jpn J Cancer Res.2000, 91(10):1007-1014.
[84]Harrington E A, Bebbington D, Moore J, et al. VX-680, a potent and selective small molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med,2004,10 (3):262-267.
[85]Farid Gizatullin, Yao Yao, Victor Kung, et al. The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint Func tion. Cancer Res, 2006,66(15):7668-7677.
[86]Yannick Arlot-Bonnemains, Enke Baldini, Benedicte Martin, et al. Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines. Endocrine-Related Cancer,2008,15(2):559-568.
[87]Edmund Chun Yu Lee, Anna Frolov, Rile Li, et al. Targeting Aurora Kinases for the Treatment of Prostate Cancer. Cancer Res,2006,66 (10):4996-5002.
[88]关中,薛红漫,冯公侃,等.Aurora激酶抑制剂VX-680对头颈肿瘤细胞增 殖的影响.医药世界,2006,11：16-17.
[89]滑芳,张红真,房桂英,等.Aurora-A激酶抑制剂VX2680对人子宫内膜癌细胞化疗敏感性的影响.河北医药,2008,30(8)：1096-1097.
[90]Jetton N, Rothberg KG, Hubbard JG, The cell cycle as a therapeutic target against Trypanosoma brucei:Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. Mol Microbiol,2009,72(2):442-458
[91]Ladygina NG, Latsis RV, Yen T. Effect of the pharmacological agent hesperadin on breast and prostate tumor cultured cells. Biomed Khim,2005,51(2):170-176.
[92]Modugno M, Casale E, Soncini C, et al.Crystal structure of the T315I/Abl mutant in complex with the aurora kinases inhibit or PHA-739358. Cancer Res, 2007,67(17):7987-7990.
[93]Anand S, Penrhyn·lowes, Venkitaraman AR. Aurora-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell,2003,3(1):51-62.
[94]Mortlock AA, Foote KM, Heron NM, et al. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora Bldnase. J Med Chem,2007,50(9):2213-2224.
[95]Wilkinson RW, Odedra R, Heaton SP, et al. AZD1152, a selective inhibitor of Aurora B kinase,inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res,2007,13(12):3682-3688.