卵巢黏液性肿瘤相关凋亡调控基因的表达及意义
|
摘要
目的:通过检测bcl-2、bax、survivin、smac和fas在卵巢黏液性肿瘤中的表达,分析卵巢黏液性肿瘤发生发展过程中凋亡调控相关基因的作用,进而揭示凋亡调控机制的紊乱是卵巢黏液性肿瘤恶变过程中的一个重要环节。
方法:应用免疫组化SABC法,检测bcl-2、bax、survivin、smac和fas在55例原发性卵巢黏液性肿瘤中的表达;应用免疫电镜胶体金标记法检测smac在原发性卵巢黏液性肿瘤中的亚细胞表达部位及表达趋势。
结果:(1)Bcl-2在良性、交界性和恶性组中的阳性表达率分别为10%、46.67%和85%;良性与交界性、交界性与恶性比较均具有统计学差异(P<0.05),良性与恶性比较有显著统计学差异(P<0.01)。三组中bax阳性表达率分别为80%、60%和10%;良性与交界性比较无统计学差异(P>0.05),交界性与恶性、良性与恶性比较有显著统计学差异(P<0.01)。Bcl-2/bax比率在良性、交界性和恶性组平均值分别为0.24±0.42、0.85±1.56、15.46±19.58;良性与交界性比较无统计学差异(P>0.05);而交界性与恶性、良性与恶性比较均有统计学差异(P<0.05)。
(2)Survivin在良性、交界性和恶性组中的胞浆阳性表达率分别为10%、80%和100%;良性与交界性、良性与恶性比较均有显著统计学差异(P<0.01),而交界性与恶性比较无统计学差异(P>0.05)。Survivin胞核阳性表达率分别为5%、40%、25%;良性与交界性组比较有统计学差异(P<0.05),良性与恶性以及交界与恶性比较均无统计学差异(P>0.05)。三组中smac阳性表达率分别为95%、60%和15%;良性与交界性、交界性与恶性比较均有统计学差异(P<0.05) ,良性与恶性比较有显著统计学差异(P<0.01)。
(3) Fas在良性、交界性和恶性组中的阳性表达率分别为65%、53.33%和45%;良性与交界性、交界性与恶性、良性与恶性比较均无统计学差异(P>0.05)。
(4) Bcl-2、bax、survivin、smac基因间存在不同程度的相关性。Bcl-2和survivin呈正相关(r=0.870, P<0.01);bax和smac呈正相关(r=0.944, P<0.01);bcl-2和bax呈负相关(r=-0.208, P<0.01);survivin和smac呈负相关(r= -0.153, P<0.01);bcl-2和smac呈负相关(r= -0.146,P<0.01);bax和survivin呈负相关(r= -0.185,P<0.01)。
(5) Smac金标颗粒在良性、交界性和恶性组中计数分别如下:其在胞浆内分别为28.79±6.68、13.91±1.98和6.98±0.96;良性与交界性以及良性与恶性比较有显著统计学差异(P<0.01),交界与恶性组间比较有统计学差异(P<0.05);线粒体内计数分别为24.11±7.18、11.06±1.87和5.24±1.72,良性与交界组以及良性与恶性组间比较有显著统计学差异(P<0.01),交界与恶性组间比较有统计学差异(P<0.05);线粒体外分别为4.67±2.98、2.86±0.95和1.74±1.25,组间比较均无统计学差异(P>0.05)。
结论:
1、在卵巢粘液性肿瘤的良恶性演变过程中存在凋亡调控的紊乱,其中线粒体途径可能为诱导凋亡紊乱的主要通路。Survivin的表达调节是一早期事件,但其表达部位的改变则是一连续性过程,survivin的胞核表达可能与肿瘤的良性生物学行为有关;而bax则是一晚期事件,交界性卵巢粘液性囊腺瘤患者检测到bax的缺如提示有潜在恶变的可能;bcl-2和smac的表达异常在卵巢粘液性肿瘤的良恶性演变过程中是一连续性事件。
2、Bcl-2/bax比率可能与卵巢粘液性肿瘤的良恶性程度密切相关。
3、在卵巢粘液性肿瘤的恶性演变过程中,下调的smac蛋白主要为储存在线粒体膜间的非活性形式蛋白,而非释放到胞浆中的活性形式蛋白。
Objective: To analysis the function of apoptosis regulation related genes during the development and progress of ovarian mucinous tumors, by detecting the expressions of bcl-2、bax、survivin、smac and fas in ovarian mucinous tumors,so as to reveal the dysfunction of apoptosis regulation mechanism is an important link during the canceration of ovarian mucinous tumors.
Methods: 55 paraffin specimen of primary ovarian mucinous tumors were collected. IHC were used to detect the proteins of bcl-2、bax、survivin、smac and fas;the immune electron microscope marked by colloidal gold were used to detect the deuto-cell expression position and the trend of smac protein .
Results: (1)The positive expression rates of bcl-2 in benign、borderline and malignant ovarian mucinous tumors were 10%、46.67% and 85%; and there were different significances of bcl-2 between benign and boderline(P<0.05),boderline and malignant(P<0.05),benign and malignant(P<0.01).Bax were 80%、60% and 10%;and there were different significances of bax between boderline and malignant(P<0.01), benign and malignant(P<0.01),while no significance between benign and borderline (P>0.05).The ratios of bcl-2/bax were 0.24±0.42、0.85±1.56、15.46±19.58 respectively in benign、borderline and malignant ovarian mucinous tumors;and there were different significances between boderline and malignant(P<0.05), benign and malignant (P<0.05),while no significance between benign and borderline(P>0.05).
(2)The cytoplasm positive expression rates of survivin in benign、borderline and malignant ovarian mucinous tumors were 10%、80% and 100%; and there were different significances of survivin between benign and boderline(P<0.01), benign and malignant(P<0.01),while no significance between boderline and malignant (P>0.05). The nucleus positive expression rates of survivin in benign、borderline and malignant ovarian mucinous tumors were5%、40%、25%;and there was different significance of survivin between benign and boderline(P<0.05),while no significance between boderline and malignant, benign and malignant(P>0.05).Smac were 95%、60% and 15%;and there were different significances of smac between benign and boderline (P<0.05),boderline and malignant(P<0.05), benign and malignant(P<0.01).
(3) The positive expression rates of fas in benign, borderline and malignant ovarian mucinous tumors were 65%、53.33% and 45%;and there were no different significance of fas among benign、borderline and malignant groups(P>0.05).
(4) There were correlations among bcl-2、bax、survivin and smac proteins. There was postive correlation between bax and smac(r=0.944,P<0.01);bcl-2 and survivin(r=0.870,P<0.01).There was negative correlation between bcl-2 and bax (r=-0.208,P<0.01);survivin and smac(r=-0.153,P<0.01);bcl-2 and smac(r=-0.146, P<0.01);bax and survivin(r= -0.185,P<0.01).
(5) The smac granules marked by colloidal counted in the three groups were as follows: the intracytoplasm smac granules were 28.79±6.68、13.91±1.98 and 6.98±0.96;and there were different significances between benign and boderline (P<0.01),boderline and malignant(P<0.05),benign and malignant(P<0.01).The smac granules storing between the two layer membrane of mitochondrion were 24.11±7.18、11.06±1.87、5.24±1.72 respectively;and there were different significances between benign and boderline(P<0.01),boderline and malignant(P<0.05),benign and malignant (P<0.01).The smac granules located out of mitochondrial membrane were 4.67±2.98、2.86±0.95 and 1.74±1.25;and there were no different significances among them(P>0.05).
Conclusions: (1) The dysfunction of apoptosis regulation exists in ovarian mucinous tumors during the progress from benign to malignant,and the mitochondrion path mignt be the major pathway inducing dysfunction of apoptosis.The regulation of the expression of survivin is a pristine event while the change of the expression position is a continuous event ,and the nucleus expression is positive correlation with the benign biological behaviors;however,bax is a late event ,detecting the absence of bax protein in borderline ovarian mucinous tumor patient maybe suggest a potential canceration;the abnormal expressions of bcl-2 and smac protein are a continuous event during the progress from benign、borderline to maligant groups (2)The ratio of bcl-2/bax may be more related with the benign or malignant extents in ovarian mucinous tumors (3)The down regulated smac proteins mainly are the inactive patterns storing between the two layer membrane of mitochondrion,nor the releasing active patterns out of mitochondrial membrane during the progress from benign to malignant ovarian mucinous tumors.
方法:应用免疫组化SABC法,检测bcl-2、bax、survivin、smac和fas在55例原发性卵巢黏液性肿瘤中的表达;应用免疫电镜胶体金标记法检测smac在原发性卵巢黏液性肿瘤中的亚细胞表达部位及表达趋势。
结果:(1)Bcl-2在良性、交界性和恶性组中的阳性表达率分别为10%、46.67%和85%;良性与交界性、交界性与恶性比较均具有统计学差异(P<0.05),良性与恶性比较有显著统计学差异(P<0.01)。三组中bax阳性表达率分别为80%、60%和10%;良性与交界性比较无统计学差异(P>0.05),交界性与恶性、良性与恶性比较有显著统计学差异(P<0.01)。Bcl-2/bax比率在良性、交界性和恶性组平均值分别为0.24±0.42、0.85±1.56、15.46±19.58;良性与交界性比较无统计学差异(P>0.05);而交界性与恶性、良性与恶性比较均有统计学差异(P<0.05)。
(2)Survivin在良性、交界性和恶性组中的胞浆阳性表达率分别为10%、80%和100%;良性与交界性、良性与恶性比较均有显著统计学差异(P<0.01),而交界性与恶性比较无统计学差异(P>0.05)。Survivin胞核阳性表达率分别为5%、40%、25%;良性与交界性组比较有统计学差异(P<0.05),良性与恶性以及交界与恶性比较均无统计学差异(P>0.05)。三组中smac阳性表达率分别为95%、60%和15%;良性与交界性、交界性与恶性比较均有统计学差异(P<0.05) ,良性与恶性比较有显著统计学差异(P<0.01)。
(3) Fas在良性、交界性和恶性组中的阳性表达率分别为65%、53.33%和45%;良性与交界性、交界性与恶性、良性与恶性比较均无统计学差异(P>0.05)。
(4) Bcl-2、bax、survivin、smac基因间存在不同程度的相关性。Bcl-2和survivin呈正相关(r=0.870, P<0.01);bax和smac呈正相关(r=0.944, P<0.01);bcl-2和bax呈负相关(r=-0.208, P<0.01);survivin和smac呈负相关(r= -0.153, P<0.01);bcl-2和smac呈负相关(r= -0.146,P<0.01);bax和survivin呈负相关(r= -0.185,P<0.01)。
(5) Smac金标颗粒在良性、交界性和恶性组中计数分别如下:其在胞浆内分别为28.79±6.68、13.91±1.98和6.98±0.96;良性与交界性以及良性与恶性比较有显著统计学差异(P<0.01),交界与恶性组间比较有统计学差异(P<0.05);线粒体内计数分别为24.11±7.18、11.06±1.87和5.24±1.72,良性与交界组以及良性与恶性组间比较有显著统计学差异(P<0.01),交界与恶性组间比较有统计学差异(P<0.05);线粒体外分别为4.67±2.98、2.86±0.95和1.74±1.25,组间比较均无统计学差异(P>0.05)。
结论:
1、在卵巢粘液性肿瘤的良恶性演变过程中存在凋亡调控的紊乱,其中线粒体途径可能为诱导凋亡紊乱的主要通路。Survivin的表达调节是一早期事件,但其表达部位的改变则是一连续性过程,survivin的胞核表达可能与肿瘤的良性生物学行为有关;而bax则是一晚期事件,交界性卵巢粘液性囊腺瘤患者检测到bax的缺如提示有潜在恶变的可能;bcl-2和smac的表达异常在卵巢粘液性肿瘤的良恶性演变过程中是一连续性事件。
2、Bcl-2/bax比率可能与卵巢粘液性肿瘤的良恶性程度密切相关。
3、在卵巢粘液性肿瘤的恶性演变过程中,下调的smac蛋白主要为储存在线粒体膜间的非活性形式蛋白,而非释放到胞浆中的活性形式蛋白。
Objective: To analysis the function of apoptosis regulation related genes during the development and progress of ovarian mucinous tumors, by detecting the expressions of bcl-2、bax、survivin、smac and fas in ovarian mucinous tumors,so as to reveal the dysfunction of apoptosis regulation mechanism is an important link during the canceration of ovarian mucinous tumors.
Methods: 55 paraffin specimen of primary ovarian mucinous tumors were collected. IHC were used to detect the proteins of bcl-2、bax、survivin、smac and fas;the immune electron microscope marked by colloidal gold were used to detect the deuto-cell expression position and the trend of smac protein .
Results: (1)The positive expression rates of bcl-2 in benign、borderline and malignant ovarian mucinous tumors were 10%、46.67% and 85%; and there were different significances of bcl-2 between benign and boderline(P<0.05),boderline and malignant(P<0.05),benign and malignant(P<0.01).Bax were 80%、60% and 10%;and there were different significances of bax between boderline and malignant(P<0.01), benign and malignant(P<0.01),while no significance between benign and borderline (P>0.05).The ratios of bcl-2/bax were 0.24±0.42、0.85±1.56、15.46±19.58 respectively in benign、borderline and malignant ovarian mucinous tumors;and there were different significances between boderline and malignant(P<0.05), benign and malignant (P<0.05),while no significance between benign and borderline(P>0.05).
(2)The cytoplasm positive expression rates of survivin in benign、borderline and malignant ovarian mucinous tumors were 10%、80% and 100%; and there were different significances of survivin between benign and boderline(P<0.01), benign and malignant(P<0.01),while no significance between boderline and malignant (P>0.05). The nucleus positive expression rates of survivin in benign、borderline and malignant ovarian mucinous tumors were5%、40%、25%;and there was different significance of survivin between benign and boderline(P<0.05),while no significance between boderline and malignant, benign and malignant(P>0.05).Smac were 95%、60% and 15%;and there were different significances of smac between benign and boderline (P<0.05),boderline and malignant(P<0.05), benign and malignant(P<0.01).
(3) The positive expression rates of fas in benign, borderline and malignant ovarian mucinous tumors were 65%、53.33% and 45%;and there were no different significance of fas among benign、borderline and malignant groups(P>0.05).
(4) There were correlations among bcl-2、bax、survivin and smac proteins. There was postive correlation between bax and smac(r=0.944,P<0.01);bcl-2 and survivin(r=0.870,P<0.01).There was negative correlation between bcl-2 and bax (r=-0.208,P<0.01);survivin and smac(r=-0.153,P<0.01);bcl-2 and smac(r=-0.146, P<0.01);bax and survivin(r= -0.185,P<0.01).
(5) The smac granules marked by colloidal counted in the three groups were as follows: the intracytoplasm smac granules were 28.79±6.68、13.91±1.98 and 6.98±0.96;and there were different significances between benign and boderline (P<0.01),boderline and malignant(P<0.05),benign and malignant(P<0.01).The smac granules storing between the two layer membrane of mitochondrion were 24.11±7.18、11.06±1.87、5.24±1.72 respectively;and there were different significances between benign and boderline(P<0.01),boderline and malignant(P<0.05),benign and malignant (P<0.01).The smac granules located out of mitochondrial membrane were 4.67±2.98、2.86±0.95 and 1.74±1.25;and there were no different significances among them(P>0.05).
Conclusions: (1) The dysfunction of apoptosis regulation exists in ovarian mucinous tumors during the progress from benign to malignant,and the mitochondrion path mignt be the major pathway inducing dysfunction of apoptosis.The regulation of the expression of survivin is a pristine event while the change of the expression position is a continuous event ,and the nucleus expression is positive correlation with the benign biological behaviors;however,bax is a late event ,detecting the absence of bax protein in borderline ovarian mucinous tumor patient maybe suggest a potential canceration;the abnormal expressions of bcl-2 and smac protein are a continuous event during the progress from benign、borderline to maligant groups (2)The ratio of bcl-2/bax may be more related with the benign or malignant extents in ovarian mucinous tumors (3)The down regulated smac proteins mainly are the inactive patterns storing between the two layer membrane of mitochondrion,nor the releasing active patterns out of mitochondrial membrane during the progress from benign to malignant ovarian mucinous tumors.
引文
[1]陈钢,王肇敏.卵巢黏液性肿瘤中胃肠型上皮化生与恶变的关系[J].中华病理学杂志.1992,21(3):174-176.
[2]Oltvai ZN,Milliman CL,Korsmeyer SJ.Bcl-2 heterolimerizes in vivo with a conser- ved homolog.Bax,that accelerates programmed cell dearth[J].Cell.1993,74(4): 609-619.
[3]Ambrosini G, Adida C, Sirugo G, Altieri DC. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting[J].J Biol Chem. 1998 ,273(18):11177-82.
[4]王晓红,符立梧.凋亡抑制蛋白家族与肿瘤治疗的研究进展[J].药学学报Acta Pharmaceutica Sinica.2006,41(2):103-107.
[5]段春燕.线粒体释放促凋亡因子与细胞凋亡[J].泸州医学院学报. 2003,26(6):553-554.
[6]李奎,刘英,康相涛.主要凋亡基因对细胞凋亡的调控[J].解剖科学进展. 2007,13(1):62-65,70.
[7]杨光华,文继舫,王美清,等.病理学[M].人民卫生出版社,P:294-294.
[8]Ozdemir E, Kakehi Y, Okuno H, et al. Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas[J].J Urol.1999,161 (4):1359-63.
[9]Nicholson DW,Thornberry NA.Apoptosis.Life and death decisions[J].Science. 2003,299(5604):214-215.
[10]Marx D, Binder C, Meden H, et al. Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer[J].Anticancer Res.1997,17(3C):2233-40.
[11]金琳芳,陈同钰.Bcl-2基因蛋白家族与细胞凋亡[J].医学综述.2005,11(5):446-447.
[12]刘红,房朝晖,李魁秀,等.卵巢癌中LPA受体、Bcl-2和Bax基因的表达和意义[J].河北医科大学学报.2008,29(5):677-680.
[13]Kar R, Sen S, Singh A, et al. Role of Apoptotic Regulators in Human Epithelial Ovarian Cancer[J]. Cancer Biol Ther.2007,6(7):1101-1105.
[14]Tai YT, Strobel T, Kufe D, et al. In vivo cytotoxicity of ovarian cancer cellsthrough tumor-selective expression of the Bax gene[J].Cancer Res,1999,59(9):2121 -2126.
[15]Korsmeyer SJ, Shutter JR, Veis DJ, et al.Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death[J].Semin Cancer Biol.1993,4 (6):327-32.
[16]徐旸,罗淑红,殷旭光.Bcl-2和Bax蛋白在上皮性卵巢癌中的表达及临床意义[J].检验医学与临床.2008,5(19):1193-1195.
[17]Chan WY, Cheung KK, Schorge JO, et al. Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers[J].Am J Pathol, 2000,156(2):409-417.
[18]谭毅,蔡德修,段晓琼.Bc1-2、bax、c-myc和p53蛋白在卵巢上皮性肿瘤中的表达[J].临床肿瘤学杂志.1998,3(3):6-8.
[19]董宇明,张辉,张丽敏,等.Survivin在上皮性卵巢癌中的表达及意义[J].中国妇幼保健.2008,23(8):1124-1126.
[20]Takai N, Miyazaki T, Nishida M, et al. Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma[J].Int J Mol Med,2002,10 (2):211-216.
[21]孙艳.李勇,范立侨,等. survivin胞浆与胞核表达在原发性和转移性上皮卵巢癌中的意义[J].肿瘤防治研究.2008,85(6):445-446.
[22]Kleinberg L, Fl?renes VA, Silins I, et al.Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma [J].Cancer. 2007,109(2):228-238.
[23]Sui L, Dong Y, Ohno M, et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors[J]. Int J Oncol,2002,21 (2):315-320.
[24]朱红玲,周家德.Survivin和Caspase-3在卵巢上皮性癌中的表达[J].中国妇幼保健.2008,23(13):1860-1863.
[25]Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition[J].Cell,2000,102 (1):33 -42.
[26]Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins[J].Cell, 2000,102(1):43-53.
[27]AdrainC, EmmaMC, SeamosJM. Apoptosis associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2[J].EmboJ, 2001,20(23):6627.
[28]王志成,龚守良.Smac/DIABLO与肿瘤[J].中国实验诊断学.2006,10(8):942-945.
[29]Petrucci E, Pasquini L, Petronelli A, et al. A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells[J].Gynecol Oncol, 2007,105(2):481-492.
[30]McNeish IA, Lopes R, Bell SJ, et al. Survivin interacts with Smac/DIABLO in ovarian carcinoma cells but is redundant in Smac-mediated apoptosis[J]. Exp Cell Res. 2005,302(1):69-82.
[31]胡琼,李维山,郑洪.卵巢黏液性肿瘤caspase-3、caspase-9和Smac的表达及其意义[J].临床与实验病理学杂志.2007,23(2):156-158.
[32]Lee RK, Spielman J, Zhao DY, et al. Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells[J]. J Immunol.1996,157(5):1919-25.
[33]龚菲力主编医学免疫学[M].科学出版社,P:254.
[34]Ghahremani M, Foghi A, Dorrington JH. Etiology of ovarian cancer: a proposed mechanism[J].Med Hypotheses,1999,52(1):23-26.
[35]Ghahremani M, Foghi A, Dorrington JH. Activation of Fas ligand/receptor system kills ovarian cancer cell lines by an apoptotic mechanism[J].Gynecol Oncol, 1998,70(2):275-281.
[36]张弘,张菊青,任雁.卵巢肿瘤细胞DNA倍体分析及Fas表达研究[J].中国妇幼保健.2007,22(29):4171-4173.
[37]张淑兰,赵长清,林蓓,等.凋亡抑制基因survivin在卵巢上皮性癌组织中的表达及其与bcl-2、bax蛋白表达的关系[J].中华妇产科杂志.2003,38(4):203-206.
[38]Godlewski MM, Gorka M, Lamparska-Przybysz M, et al. Minute kinetics of proapoptotic proteins: BAX and Smac/DIABLO in living tumor cells revealed by homeostatic confocal microscopy[J]. Cytotechnology. 2004,45(3):141-53.
[39]黄广龙,方陆雄,漆松涛.颅咽管瘤骨桥蛋白免疫组化及免疫电镜研究[J].Chin J Nerv Ment Dis.2007,33(1):54-56.
[40]王自能,刘咏仪,楼湘莹.人卵巢粘液性肿瘤来源的再确认[N].电子显微学报.2004,23(4):323-323.
[1] Oltvai ZN,Milliman CL,Korsmeyer SJ. Bcl-2 heterolimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell dearth[J].Cell,1993, 74(4): 609-619.
[2]谭毅,蔡德修,段晓琼.Bc1-2、bax、c-myc和p53蛋白在卵巢上皮性肿瘤中的表达[J].临床肿瘤学杂志,1998,3(3) :6-8.
[3] Cao LQ, Chen XM, Li X. Expressions and their clinical significance of bcl-2 and nm23 in epithelial ovarian carcinoma[N]. Hunan Yi Ke Da Xue Xue Bao,2000,25(2):188-190 .
[4] Kar R, Sen S, Singh A, et al. Role of Apoptotic Regulators in Human Epithelial Ovarian Cancer[J]. Cancer Biol Ther, 2007 ,6(7) : 1101-1105.
[5] Munakata S, Enomoto T, Tsujimoto M, et al. Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms [J].Br J Cancer,2000, 82(8):1446-1452.
[6] Chan WY, Cheung KK, Schorge JO, et al. Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers[J]. Am J Pathol, 2000, 156(2): 409-417.
[7] Xu G, Zhou H, Wang Q, et al. Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines[J].Mol Cancer Res,2006 ,4(4):235-246.
[8] Tai YT, Strobel T, Kufe D, et al. In vivo cytotoxicity of ovarian cancer cells through tumor-selective expression of the BAX gene[J].Cancer Res, 1999 ,59(9):2121-2126.
[9]严瑞兰,王剑波,惠宏襄,等.促凋亡基因bax在上皮性卵巢肿瘤中的表达及意义[N].第四军医大学学报,1998,19(3):322-324
[10] Takai N, Miyazaki T, Nishida M, et al. Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma[J]. Int J Mol Med, 2002,10(2):211-216.
[11] Sui L, Dong Y, Ohno M, et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors[J]. Int J Oncol, 2002 ,21(2):315-320.
[12] Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition[J].Cell, 2000 ,102(1):33-42.
[13] Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins[J].Cell, 2000 ,102(1):43-53.
[14]丛江琳,李敏,王泽华. Smac基因在卵巢上皮性肿瘤中的表达及其临床意义[J].中华妇产科杂志,2006,41(8):570-571.
[15] Petrucci E, Pasquini L, Petronelli A, et al. A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells[J]. Gynecol Oncol, 2007 ,105(2):481-92.
[16] Zheng LD, Wu CH, Tong QS, et al. Regulatory effects on apoptotic activities of gastric cancer cell line by over-expression of Smac gene[J]. Zhonghua Bing Li Xue Za Zhi,2005,34(2):92-96
[17] Bao ST, Gui SQ, Lin MS. Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int,2006 ,5(4):580-583.
[18] Ghahremani M, Foghi A, Dorrington JH. Etiology of ovarian cancer: a proposed mechanism[J].Med Hypotheses, 1999 ,52(1):23-26.
[19] Reed J, Hakam A, Nicosia SV, et al. Significance of Fas receptor protein expression in epithelial ovarian cancer[J].Hum Pathol, 2005 ,36(9):971-976.
[20] Ghahremani M, Foghi A, Dorrington JH. Activation of Fas ligand/receptor system kills ovarian cancer cell lines by an apoptotic mechanism[J].Gynecol Oncol, 1998 ,70(2):275-281.
[2]Oltvai ZN,Milliman CL,Korsmeyer SJ.Bcl-2 heterolimerizes in vivo with a conser- ved homolog.Bax,that accelerates programmed cell dearth[J].Cell.1993,74(4): 609-619.
[3]Ambrosini G, Adida C, Sirugo G, Altieri DC. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting[J].J Biol Chem. 1998 ,273(18):11177-82.
[4]王晓红,符立梧.凋亡抑制蛋白家族与肿瘤治疗的研究进展[J].药学学报Acta Pharmaceutica Sinica.2006,41(2):103-107.
[5]段春燕.线粒体释放促凋亡因子与细胞凋亡[J].泸州医学院学报. 2003,26(6):553-554.
[6]李奎,刘英,康相涛.主要凋亡基因对细胞凋亡的调控[J].解剖科学进展. 2007,13(1):62-65,70.
[7]杨光华,文继舫,王美清,等.病理学[M].人民卫生出版社,P:294-294.
[8]Ozdemir E, Kakehi Y, Okuno H, et al. Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas[J].J Urol.1999,161 (4):1359-63.
[9]Nicholson DW,Thornberry NA.Apoptosis.Life and death decisions[J].Science. 2003,299(5604):214-215.
[10]Marx D, Binder C, Meden H, et al. Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer[J].Anticancer Res.1997,17(3C):2233-40.
[11]金琳芳,陈同钰.Bcl-2基因蛋白家族与细胞凋亡[J].医学综述.2005,11(5):446-447.
[12]刘红,房朝晖,李魁秀,等.卵巢癌中LPA受体、Bcl-2和Bax基因的表达和意义[J].河北医科大学学报.2008,29(5):677-680.
[13]Kar R, Sen S, Singh A, et al. Role of Apoptotic Regulators in Human Epithelial Ovarian Cancer[J]. Cancer Biol Ther.2007,6(7):1101-1105.
[14]Tai YT, Strobel T, Kufe D, et al. In vivo cytotoxicity of ovarian cancer cellsthrough tumor-selective expression of the Bax gene[J].Cancer Res,1999,59(9):2121 -2126.
[15]Korsmeyer SJ, Shutter JR, Veis DJ, et al.Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death[J].Semin Cancer Biol.1993,4 (6):327-32.
[16]徐旸,罗淑红,殷旭光.Bcl-2和Bax蛋白在上皮性卵巢癌中的表达及临床意义[J].检验医学与临床.2008,5(19):1193-1195.
[17]Chan WY, Cheung KK, Schorge JO, et al. Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers[J].Am J Pathol, 2000,156(2):409-417.
[18]谭毅,蔡德修,段晓琼.Bc1-2、bax、c-myc和p53蛋白在卵巢上皮性肿瘤中的表达[J].临床肿瘤学杂志.1998,3(3):6-8.
[19]董宇明,张辉,张丽敏,等.Survivin在上皮性卵巢癌中的表达及意义[J].中国妇幼保健.2008,23(8):1124-1126.
[20]Takai N, Miyazaki T, Nishida M, et al. Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma[J].Int J Mol Med,2002,10 (2):211-216.
[21]孙艳.李勇,范立侨,等. survivin胞浆与胞核表达在原发性和转移性上皮卵巢癌中的意义[J].肿瘤防治研究.2008,85(6):445-446.
[22]Kleinberg L, Fl?renes VA, Silins I, et al.Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma [J].Cancer. 2007,109(2):228-238.
[23]Sui L, Dong Y, Ohno M, et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors[J]. Int J Oncol,2002,21 (2):315-320.
[24]朱红玲,周家德.Survivin和Caspase-3在卵巢上皮性癌中的表达[J].中国妇幼保健.2008,23(13):1860-1863.
[25]Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition[J].Cell,2000,102 (1):33 -42.
[26]Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins[J].Cell, 2000,102(1):43-53.
[27]AdrainC, EmmaMC, SeamosJM. Apoptosis associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2[J].EmboJ, 2001,20(23):6627.
[28]王志成,龚守良.Smac/DIABLO与肿瘤[J].中国实验诊断学.2006,10(8):942-945.
[29]Petrucci E, Pasquini L, Petronelli A, et al. A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells[J].Gynecol Oncol, 2007,105(2):481-492.
[30]McNeish IA, Lopes R, Bell SJ, et al. Survivin interacts with Smac/DIABLO in ovarian carcinoma cells but is redundant in Smac-mediated apoptosis[J]. Exp Cell Res. 2005,302(1):69-82.
[31]胡琼,李维山,郑洪.卵巢黏液性肿瘤caspase-3、caspase-9和Smac的表达及其意义[J].临床与实验病理学杂志.2007,23(2):156-158.
[32]Lee RK, Spielman J, Zhao DY, et al. Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells[J]. J Immunol.1996,157(5):1919-25.
[33]龚菲力主编医学免疫学[M].科学出版社,P:254.
[34]Ghahremani M, Foghi A, Dorrington JH. Etiology of ovarian cancer: a proposed mechanism[J].Med Hypotheses,1999,52(1):23-26.
[35]Ghahremani M, Foghi A, Dorrington JH. Activation of Fas ligand/receptor system kills ovarian cancer cell lines by an apoptotic mechanism[J].Gynecol Oncol, 1998,70(2):275-281.
[36]张弘,张菊青,任雁.卵巢肿瘤细胞DNA倍体分析及Fas表达研究[J].中国妇幼保健.2007,22(29):4171-4173.
[37]张淑兰,赵长清,林蓓,等.凋亡抑制基因survivin在卵巢上皮性癌组织中的表达及其与bcl-2、bax蛋白表达的关系[J].中华妇产科杂志.2003,38(4):203-206.
[38]Godlewski MM, Gorka M, Lamparska-Przybysz M, et al. Minute kinetics of proapoptotic proteins: BAX and Smac/DIABLO in living tumor cells revealed by homeostatic confocal microscopy[J]. Cytotechnology. 2004,45(3):141-53.
[39]黄广龙,方陆雄,漆松涛.颅咽管瘤骨桥蛋白免疫组化及免疫电镜研究[J].Chin J Nerv Ment Dis.2007,33(1):54-56.
[40]王自能,刘咏仪,楼湘莹.人卵巢粘液性肿瘤来源的再确认[N].电子显微学报.2004,23(4):323-323.
[1] Oltvai ZN,Milliman CL,Korsmeyer SJ. Bcl-2 heterolimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell dearth[J].Cell,1993, 74(4): 609-619.
[2]谭毅,蔡德修,段晓琼.Bc1-2、bax、c-myc和p53蛋白在卵巢上皮性肿瘤中的表达[J].临床肿瘤学杂志,1998,3(3) :6-8.
[3] Cao LQ, Chen XM, Li X. Expressions and their clinical significance of bcl-2 and nm23 in epithelial ovarian carcinoma[N]. Hunan Yi Ke Da Xue Xue Bao,2000,25(2):188-190 .
[4] Kar R, Sen S, Singh A, et al. Role of Apoptotic Regulators in Human Epithelial Ovarian Cancer[J]. Cancer Biol Ther, 2007 ,6(7) : 1101-1105.
[5] Munakata S, Enomoto T, Tsujimoto M, et al. Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms [J].Br J Cancer,2000, 82(8):1446-1452.
[6] Chan WY, Cheung KK, Schorge JO, et al. Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers[J]. Am J Pathol, 2000, 156(2): 409-417.
[7] Xu G, Zhou H, Wang Q, et al. Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines[J].Mol Cancer Res,2006 ,4(4):235-246.
[8] Tai YT, Strobel T, Kufe D, et al. In vivo cytotoxicity of ovarian cancer cells through tumor-selective expression of the BAX gene[J].Cancer Res, 1999 ,59(9):2121-2126.
[9]严瑞兰,王剑波,惠宏襄,等.促凋亡基因bax在上皮性卵巢肿瘤中的表达及意义[N].第四军医大学学报,1998,19(3):322-324
[10] Takai N, Miyazaki T, Nishida M, et al. Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma[J]. Int J Mol Med, 2002,10(2):211-216.
[11] Sui L, Dong Y, Ohno M, et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors[J]. Int J Oncol, 2002 ,21(2):315-320.
[12] Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition[J].Cell, 2000 ,102(1):33-42.
[13] Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins[J].Cell, 2000 ,102(1):43-53.
[14]丛江琳,李敏,王泽华. Smac基因在卵巢上皮性肿瘤中的表达及其临床意义[J].中华妇产科杂志,2006,41(8):570-571.
[15] Petrucci E, Pasquini L, Petronelli A, et al. A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells[J]. Gynecol Oncol, 2007 ,105(2):481-92.
[16] Zheng LD, Wu CH, Tong QS, et al. Regulatory effects on apoptotic activities of gastric cancer cell line by over-expression of Smac gene[J]. Zhonghua Bing Li Xue Za Zhi,2005,34(2):92-96
[17] Bao ST, Gui SQ, Lin MS. Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int,2006 ,5(4):580-583.
[18] Ghahremani M, Foghi A, Dorrington JH. Etiology of ovarian cancer: a proposed mechanism[J].Med Hypotheses, 1999 ,52(1):23-26.
[19] Reed J, Hakam A, Nicosia SV, et al. Significance of Fas receptor protein expression in epithelial ovarian cancer[J].Hum Pathol, 2005 ,36(9):971-976.
[20] Ghahremani M, Foghi A, Dorrington JH. Activation of Fas ligand/receptor system kills ovarian cancer cell lines by an apoptotic mechanism[J].Gynecol Oncol, 1998 ,70(2):275-281.