IL-8基因对人宫颈癌裸鼠皮下移植瘤生长的影响及其机制探讨
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摘要
目的:宫颈癌是全球发病率居第二位的妇女恶性肿瘤,在我国的发病率居首位[1],其高发区连接成片,且发病人群有年轻化的趋势[2],成为严重威胁妇女健康的疾病之一。宫颈癌的发生、发展是一个由量变到质变,由渐变到突变的过程。局部浸润和淋巴结转移不仅影响手术效果,而且直接关系患者预后。淋巴结转移是宫颈癌的主要转移途径,在早期即可发生。有文献报道,无淋巴结转移者五年生存率为82.2%。有淋巴结转移者五年生存率为50.8%[3]。尽管宫颈癌的治疗研究已近百年,成绩显著,但其疗效还未能达到普遍接近“早期宫颈癌5年生存率90%-100%”的水平。近些年来,随着细胞工程和基因工程技术的发展,肿瘤免疫治疗亦得以迅猛发展,细胞因子基因治疗成为目前研究的热点。
IL-8是1987年Yoshimur等[4]发现的第一个趋化因子。IL-8可以促进肿瘤细胞的增生,使肿瘤细胞向内皮细胞迁移[5]。随着对IL-8及其受体生物学活性和作用机制研究的深入,发现其受体在宫颈癌的发生发展中起着重要作用。IL-8受体(IL-8 receptor, IL-8R)存在于许多种类型的细胞中,甚至包括一些不表达IL-8的细胞,主要包括IL-8RA和IL-8RB两种类型。增殖细胞核抗原(proliferating cell nuclear antige PCNA)是目前研究最透彻的肿瘤细胞增殖标记物之一,其表达显示出与增殖细胞存在直接相互关系。PCNA的异常表达与宫颈癌的发生发展相关。目前,裸鼠移植瘤模型已成为研究恶性肿瘤的生物学特征和筛选抗癌药物的主要工具。本实验成功建立了Hela细胞裸鼠移植瘤模型。应用RT-PCR技术研究IL-8受体IL-8RA,IL-8RB在宫颈癌组织中的表达;应用免疫组织化学技术研究增殖细胞核抗原(PCNA)在Hela细胞裸鼠移植瘤内的表达,探讨转染白细胞介素8 (IL-8)基因对裸鼠宫颈癌Hela细胞体内成瘤的影响并对其可能的机制进行研究。以期为宫颈癌的诊治和预后判断提供新的指标。方法:
1材料:稳定表达IL-8的宫颈癌细胞株Hela/hIL-8细胞和转染空载体的Hela/pcDNA3.1(+)细胞株均有本室保存。实验动物:无特定病原体(specific pathogen free,SPF)级BALB/C裸小鼠,雌性,4-6周龄,体重16-18g,购自北京协和动物中心。
2皮下移植瘤动物模型的建立使用21只BALB/C遗传背景的雌性裸小鼠作为实验动物,随机分成三组,分别于右后背部皮下注Hela/hIL-8、Hela/pcDNA3.1(+)和Hela三种细胞悬液0.2ml(细胞总数约为5×106个)。
3观察各组裸鼠的肿瘤生长情况和出瘤时间,每周测量肿瘤大小并比较,9周后杀死小鼠取肿瘤标本及肺组织。
4半定量RT-PCR技术:用RT-PCR技术在相同条件下检测各组肿瘤组织IL-8RA及IL-8RB的表达情况,然后进行统计学分析。
5免疫组织化学法:采用SP法,按试剂盒说明书进行操作。分别检测空质粒组,阴性对照组及IL-8组PCNA的表达情况,然后进行统计学分析。
6 HE染色法:检测Hela/hIL-8组、Hela/pcDNA3.1(+)组和Hela组肺转移的发生率。
结果:
1成功建立Hela/hIL-8细胞、Hela/pcDNA3.1(+)细胞和Hela细胞裸鼠皮下移植瘤模型。
2转染IL-8cDNA对裸鼠皮下移植瘤生长的影响:IL-8组成瘤时间为16.00±1.53天,空质粒组成瘤时间为19.90±1.28天,阴性对照组成瘤时间为19.70±1.25天,各组成瘤率均为100%。各组成瘤时间比较有统计学意义(P<0.05)。接种肿瘤细胞后7、8、9周,IL-8组肿瘤生长明显活跃、肿瘤体积也大于空质粒组和阴性对照组,且两两比较有统计学意义(P<0.05)。实验前6周各组肿瘤体积比较无明显差别。
3 RT-PCR结果显示:IL-8组、pcDNA3.1(+)组和阴性对照组均有IL-8RA和IL-8RB的表达,各组之间IL-8RAmRNA、IL-8RBmRNA表达相对系数(Ar)无显著差异(P>0.05)。
4 PCNA免疫组化结果:IL-8组肿瘤组织内阳性表达明显增加,阳性目标平均光密度值明显高于空质粒组和阴性对照组的平均光密度值(P<0.05)。两两比较结果显示,IL-8组与空质粒组,IL-8组与阴性对照组均有明显差异(P<0.05),空质粒组与阴性对照组之间无明显差异(P>0.05)。
5各动物实验组肺组织均未见癌细胞转移。
结论:
1 Hela细胞裸鼠移植瘤可模拟宫颈癌在体内的状态。
2 Hela/hIL-8细胞可显著促进宫颈癌肿瘤组织的增殖。
3 IL-8基因可使PCNA表达上调,并通过此途径对宫颈癌细胞起促进增殖作用。
4 IL-8可能通过与受体IL-8RA及IL-8RB结合的途径促进宫颈癌组织的生长,但IL-8并不能促进其受体高表达。
5 PCNA可能作为一种新的肿瘤标志物应用在宫颈癌的早期筛查、诊断、治疗及预后判断中。
6 IL-8基因有望成为宫颈癌基因治疗的靶点。
Objective: Carcinoma of the uterine cervix is the second commonest female cancer worldwide, The Prevalence lies in first Place in our country (China) [1].The areas of its high occurance are all connected with each other and people who develop it are at a much younger age than before[2]. It become one of the main disease which severely threaten health of women in our country. The genesis and development of uterine cervix cancer is a procedure that become from quantitative change to qualitative alteration and from anamorphosis to mutation. Local infiltration and lymph node metastasis not only influence operation effect but also direct to the prognosis. Lymph node metastasis is the main route of metastasis of uterine cervix cancer,and takes place early. It has been reported that the five-year survival rate of the patients who had no lymph node metastases was 82.2% and the patients who had lymph node metastasis was 50.8%[3].Although the study in the treatment of UCC has continued hundred of years, the result is very striking, five-year survival rate of early UCC have not reach 90%-100%. In recent years, with cell engineering and generic engineering technology development, tumor immunotherapy has been rapidly developed. Cytokine gene therapy become a hot research.
IL-8 is the first chemotatic factor that discovered by Yoshimur[4] in 1987. IL-8 promote the hyperplasia and immigration of tumour cell[5].Along with the investigation in mechanism of IL-8 and acceptors deeply, hinted that IL-8 play an important role in the development of tumer. IL-8 receptors exist in many types of cells,even including some of the cells which did not express IL-8. They mainly include two types: IL-8RA and IL-8RB. PCNA(Proliferating cell Nuclear Antigen) is one of the best known endogenous proliferation markers. PCNA expression appeared to more directly correlate with the presence of proliferating cells. The abnormal expression of PCNA may be involved in the pathogenesis and development of cervical cancer. In recent years, nude mice model transplanted with human cancer has become the main tool of the study of the biological characteristics of cancer and screening of anti-cancer drugs. To get IL-8 transplanted cervical cancer, we establish animal model of transplantated tumor; Expression of IL-8RA and IL-8RB in the cervical tumor tissue of the three groups, was detected by using semiquantitative RT-PCR; The expression of PCNA was examined by S-P immunohistochemical method . In order to provide a new index of diagnosis and treatment and prognosis judgment of cervical cancer, we study the effects of exogenous IL-8 expression on the growth of human cervical cancer transplanted in nude mice and its possible mechanisms.
Methods:
1 Specimens : Stable expression of IL-8 in cervical cancer cell lines Hela/hIL-8 cell、Hela/pcDNA3.1(+) cell and Hela cell are given by Animal Experimental Center of Hebei Medical University. Laboratory animal: SPF (specific pathogen free) level feamale nude mouse, 4-6weeks, 16-18g weight, purchased from Animal Center of Beijing union.
2 Establish animal model of transplantated tumor. Female nude mouse are divided into Hela/hIL-8 group, Hela/pcDNA3.1(+)group and Hela group, and injected diffrent cell suspension 0.2ml(total cellular score is 5×106) into the back of mouse.
3 Observe the time of the tumour appears and the growth of tumour, measure tumor size weekly, kill the mice and get tumour after 9 weeks. The volume of tumour in each group was compared in different time.
4 Semi-quantitative RT-PCR: The present study was performed to detect the expression of IL-8RA and IL-8RB in the cervical tumor tissue of the three groups,then analyzed the results.
5 Immunohistochemistry was performed by using the S-P method. We sued anti-PCNA(1:100 dilution) to detect the expression of PCNA protein in samples, then analyzed the results.
6 HE staining : We used HE staining to detect the incidence of lung metastasis in Hela/hIL-8 group、Hela/pcDNA3.1(+)group and Hela group.
Result:
1 Establish animal model of transplantation tumor successfully by Hela/hIL-8 cells、Hela/pcDNA3.1(+) cells and Hela cells.
2 The effects of exogenous IL-8 expression on the growth of human cervical cancer transplanted in nude mice: Compared with other groups, tumour volume of IL-8 group is much larger than Hela/pcDNA3.1(+)group and Hela group. It have statistical significance(P<0.05). Days of tumour growth of Hela group, empty plasmid group and IL-8 group is 19.70±1.25, 19.90±1.28, 16.00±1.53. Rate of tumor growth is 100%. Tumor volume of Hela/hIL-8 group is much bigger than Hela/pcDNA3.1(+)group and Hela group in 7, 8, 9 week . It have statistical significance(P<0.05). There have no difference in other times.
3 Semi-quantitative RT-PCR: In the present study, we examined the expression of IL-8RAmRNA and IL-8RBmRNA in the Hela/hIL-8 group, Hela/pcDNA3.1(+)group and Hela group. No significant difference was found (P>0.05 ).
4 The immunohistochemical result of PCNA. The PCNA in Hela/hIL-8 group was much higher than other two groups. Light absorption value of PCNA of Hela group, empty plasmid group and IL-8 group are 0.0794±0.0098, 0.0812±0.0100, 0.1072±0.0049. There was statistical significance(P<0.05).
5 Cancer cells couldn’t found in lung in each group.
Conclusion:
1 Nude mice model transplanted with human cancer could simulate the state of cervical cancer in the body .
2 Hela/hIL-8 cells can explicitly promote the proliferation of cervical tumor.
3 IL-8 promote the proliferation of cervical cancer cells through the way of enhancing the express of PCNA.
4 IL-8 promote the growth of cervical cancer may through the way of binding with IL-8 receptor A and B, but it can not let IL-8 receptors express more.
5 PCNA may be used as tumor marker in the diagnosis, treatment and prognostic evaluation.
6 IL-8 gene is expected to become targets of gene therapy for cervical cancer.
IL-8是1987年Yoshimur等[4]发现的第一个趋化因子。IL-8可以促进肿瘤细胞的增生,使肿瘤细胞向内皮细胞迁移[5]。随着对IL-8及其受体生物学活性和作用机制研究的深入,发现其受体在宫颈癌的发生发展中起着重要作用。IL-8受体(IL-8 receptor, IL-8R)存在于许多种类型的细胞中,甚至包括一些不表达IL-8的细胞,主要包括IL-8RA和IL-8RB两种类型。增殖细胞核抗原(proliferating cell nuclear antige PCNA)是目前研究最透彻的肿瘤细胞增殖标记物之一,其表达显示出与增殖细胞存在直接相互关系。PCNA的异常表达与宫颈癌的发生发展相关。目前,裸鼠移植瘤模型已成为研究恶性肿瘤的生物学特征和筛选抗癌药物的主要工具。本实验成功建立了Hela细胞裸鼠移植瘤模型。应用RT-PCR技术研究IL-8受体IL-8RA,IL-8RB在宫颈癌组织中的表达;应用免疫组织化学技术研究增殖细胞核抗原(PCNA)在Hela细胞裸鼠移植瘤内的表达,探讨转染白细胞介素8 (IL-8)基因对裸鼠宫颈癌Hela细胞体内成瘤的影响并对其可能的机制进行研究。以期为宫颈癌的诊治和预后判断提供新的指标。方法:
1材料:稳定表达IL-8的宫颈癌细胞株Hela/hIL-8细胞和转染空载体的Hela/pcDNA3.1(+)细胞株均有本室保存。实验动物:无特定病原体(specific pathogen free,SPF)级BALB/C裸小鼠,雌性,4-6周龄,体重16-18g,购自北京协和动物中心。
2皮下移植瘤动物模型的建立使用21只BALB/C遗传背景的雌性裸小鼠作为实验动物,随机分成三组,分别于右后背部皮下注Hela/hIL-8、Hela/pcDNA3.1(+)和Hela三种细胞悬液0.2ml(细胞总数约为5×106个)。
3观察各组裸鼠的肿瘤生长情况和出瘤时间,每周测量肿瘤大小并比较,9周后杀死小鼠取肿瘤标本及肺组织。
4半定量RT-PCR技术:用RT-PCR技术在相同条件下检测各组肿瘤组织IL-8RA及IL-8RB的表达情况,然后进行统计学分析。
5免疫组织化学法:采用SP法,按试剂盒说明书进行操作。分别检测空质粒组,阴性对照组及IL-8组PCNA的表达情况,然后进行统计学分析。
6 HE染色法:检测Hela/hIL-8组、Hela/pcDNA3.1(+)组和Hela组肺转移的发生率。
结果:
1成功建立Hela/hIL-8细胞、Hela/pcDNA3.1(+)细胞和Hela细胞裸鼠皮下移植瘤模型。
2转染IL-8cDNA对裸鼠皮下移植瘤生长的影响:IL-8组成瘤时间为16.00±1.53天,空质粒组成瘤时间为19.90±1.28天,阴性对照组成瘤时间为19.70±1.25天,各组成瘤率均为100%。各组成瘤时间比较有统计学意义(P<0.05)。接种肿瘤细胞后7、8、9周,IL-8组肿瘤生长明显活跃、肿瘤体积也大于空质粒组和阴性对照组,且两两比较有统计学意义(P<0.05)。实验前6周各组肿瘤体积比较无明显差别。
3 RT-PCR结果显示:IL-8组、pcDNA3.1(+)组和阴性对照组均有IL-8RA和IL-8RB的表达,各组之间IL-8RAmRNA、IL-8RBmRNA表达相对系数(Ar)无显著差异(P>0.05)。
4 PCNA免疫组化结果:IL-8组肿瘤组织内阳性表达明显增加,阳性目标平均光密度值明显高于空质粒组和阴性对照组的平均光密度值(P<0.05)。两两比较结果显示,IL-8组与空质粒组,IL-8组与阴性对照组均有明显差异(P<0.05),空质粒组与阴性对照组之间无明显差异(P>0.05)。
5各动物实验组肺组织均未见癌细胞转移。
结论:
1 Hela细胞裸鼠移植瘤可模拟宫颈癌在体内的状态。
2 Hela/hIL-8细胞可显著促进宫颈癌肿瘤组织的增殖。
3 IL-8基因可使PCNA表达上调,并通过此途径对宫颈癌细胞起促进增殖作用。
4 IL-8可能通过与受体IL-8RA及IL-8RB结合的途径促进宫颈癌组织的生长,但IL-8并不能促进其受体高表达。
5 PCNA可能作为一种新的肿瘤标志物应用在宫颈癌的早期筛查、诊断、治疗及预后判断中。
6 IL-8基因有望成为宫颈癌基因治疗的靶点。
Objective: Carcinoma of the uterine cervix is the second commonest female cancer worldwide, The Prevalence lies in first Place in our country (China) [1].The areas of its high occurance are all connected with each other and people who develop it are at a much younger age than before[2]. It become one of the main disease which severely threaten health of women in our country. The genesis and development of uterine cervix cancer is a procedure that become from quantitative change to qualitative alteration and from anamorphosis to mutation. Local infiltration and lymph node metastasis not only influence operation effect but also direct to the prognosis. Lymph node metastasis is the main route of metastasis of uterine cervix cancer,and takes place early. It has been reported that the five-year survival rate of the patients who had no lymph node metastases was 82.2% and the patients who had lymph node metastasis was 50.8%[3].Although the study in the treatment of UCC has continued hundred of years, the result is very striking, five-year survival rate of early UCC have not reach 90%-100%. In recent years, with cell engineering and generic engineering technology development, tumor immunotherapy has been rapidly developed. Cytokine gene therapy become a hot research.
IL-8 is the first chemotatic factor that discovered by Yoshimur[4] in 1987. IL-8 promote the hyperplasia and immigration of tumour cell[5].Along with the investigation in mechanism of IL-8 and acceptors deeply, hinted that IL-8 play an important role in the development of tumer. IL-8 receptors exist in many types of cells,even including some of the cells which did not express IL-8. They mainly include two types: IL-8RA and IL-8RB. PCNA(Proliferating cell Nuclear Antigen) is one of the best known endogenous proliferation markers. PCNA expression appeared to more directly correlate with the presence of proliferating cells. The abnormal expression of PCNA may be involved in the pathogenesis and development of cervical cancer. In recent years, nude mice model transplanted with human cancer has become the main tool of the study of the biological characteristics of cancer and screening of anti-cancer drugs. To get IL-8 transplanted cervical cancer, we establish animal model of transplantated tumor; Expression of IL-8RA and IL-8RB in the cervical tumor tissue of the three groups, was detected by using semiquantitative RT-PCR; The expression of PCNA was examined by S-P immunohistochemical method . In order to provide a new index of diagnosis and treatment and prognosis judgment of cervical cancer, we study the effects of exogenous IL-8 expression on the growth of human cervical cancer transplanted in nude mice and its possible mechanisms.
Methods:
1 Specimens : Stable expression of IL-8 in cervical cancer cell lines Hela/hIL-8 cell、Hela/pcDNA3.1(+) cell and Hela cell are given by Animal Experimental Center of Hebei Medical University. Laboratory animal: SPF (specific pathogen free) level feamale nude mouse, 4-6weeks, 16-18g weight, purchased from Animal Center of Beijing union.
2 Establish animal model of transplantated tumor. Female nude mouse are divided into Hela/hIL-8 group, Hela/pcDNA3.1(+)group and Hela group, and injected diffrent cell suspension 0.2ml(total cellular score is 5×106) into the back of mouse.
3 Observe the time of the tumour appears and the growth of tumour, measure tumor size weekly, kill the mice and get tumour after 9 weeks. The volume of tumour in each group was compared in different time.
4 Semi-quantitative RT-PCR: The present study was performed to detect the expression of IL-8RA and IL-8RB in the cervical tumor tissue of the three groups,then analyzed the results.
5 Immunohistochemistry was performed by using the S-P method. We sued anti-PCNA(1:100 dilution) to detect the expression of PCNA protein in samples, then analyzed the results.
6 HE staining : We used HE staining to detect the incidence of lung metastasis in Hela/hIL-8 group、Hela/pcDNA3.1(+)group and Hela group.
Result:
1 Establish animal model of transplantation tumor successfully by Hela/hIL-8 cells、Hela/pcDNA3.1(+) cells and Hela cells.
2 The effects of exogenous IL-8 expression on the growth of human cervical cancer transplanted in nude mice: Compared with other groups, tumour volume of IL-8 group is much larger than Hela/pcDNA3.1(+)group and Hela group. It have statistical significance(P<0.05). Days of tumour growth of Hela group, empty plasmid group and IL-8 group is 19.70±1.25, 19.90±1.28, 16.00±1.53. Rate of tumor growth is 100%. Tumor volume of Hela/hIL-8 group is much bigger than Hela/pcDNA3.1(+)group and Hela group in 7, 8, 9 week . It have statistical significance(P<0.05). There have no difference in other times.
3 Semi-quantitative RT-PCR: In the present study, we examined the expression of IL-8RAmRNA and IL-8RBmRNA in the Hela/hIL-8 group, Hela/pcDNA3.1(+)group and Hela group. No significant difference was found (P>0.05 ).
4 The immunohistochemical result of PCNA. The PCNA in Hela/hIL-8 group was much higher than other two groups. Light absorption value of PCNA of Hela group, empty plasmid group and IL-8 group are 0.0794±0.0098, 0.0812±0.0100, 0.1072±0.0049. There was statistical significance(P<0.05).
5 Cancer cells couldn’t found in lung in each group.
Conclusion:
1 Nude mice model transplanted with human cancer could simulate the state of cervical cancer in the body .
2 Hela/hIL-8 cells can explicitly promote the proliferation of cervical tumor.
3 IL-8 promote the proliferation of cervical cancer cells through the way of enhancing the express of PCNA.
4 IL-8 promote the growth of cervical cancer may through the way of binding with IL-8 receptor A and B, but it can not let IL-8 receptors express more.
5 PCNA may be used as tumor marker in the diagnosis, treatment and prognostic evaluation.
6 IL-8 gene is expected to become targets of gene therapy for cervical cancer.
引文
1 Waggoner S E. Cervical cancer. Lance, 2003, 361(9376): 2217-2225
2杨玲,皇甫小梅,张思维等.中国20世纪70年代与90年代子宫颈癌死亡率及其变化趋势.中国医学科学院学报,2003, 25(4):386-390
3于冬雁,薛新春.人乳头瘤病毒与宫颈癌的关系.口岸卫生控制,2003, 8(1):40-45
4 Yoshimura T, Matsushima K, Oppenheim J J, et al. Neutrophil chemotactic factor produced by lipolysaccharide (LPS) stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1(IL- 1). J Immunol, 1987, 139(3): 788- 793
5 Inoue K, Slaton JW, Eve BY, et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
6 Murphy C,McGurk M, Pettigrew J, et al. Nonapical and cytop lasmic expression of interleukin - 8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clin Cancer Res, 2005, 11 (11) : 4117 - 4127
7 Tas F, Duranyildiz D, Oguz H, et al. Serum vascular endothelial growth factor (VEGF) and bcl - 2 levels in advanced stage non - small cell lung cancer. Cancer Invest, 2006, 24 (6) : 576 - 580
8 Macri A,VersaciA,Loddo S, et al. Serum levels of interleukin 1beta, in-terleukin 8 and tumour necrosis factor alpha asmarkers of gastric cancer. Biomarkers, 2006, 11 (2) : 184 - 193
9 Lokshin AE,WinansM,LandsittelD, et al. Circulating IL - 8 and anti-IL-8 autoantibody in patients with ovarian cancer. Gynecol Oncol,2006, 102 (2) : 244 - 251
10 Inoue K, Slaton JW, Eve BY, et al Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
11 Kawai T, Suzuki M, Kono S, et al. Proliferating cell nuclear antigen andKi67 in lung carcinoma, correlation with DNA flow cytometric analysis. Cancer, 1994; 74(9): 246
12 Inoue K, Slaton JW, Eve BY, et al Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
13 Li A., Seema D., Michelle L., et a1.IL-8 Directly Enhanced Endothelial Cell Survival,Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis. The Journal of Immunology, 2003,170: 3369-3376
14 Mian BM,Dinney CP,Bermejo CE, et al.Fully human anti-interleukin-8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metallop roteases and nuclear factor-kappa B1Clin Cancer Res, 2003, 19 (8) : 3167-3175
15 Tjiong MY. van der Vange N. ten Kate FJ. Tjong-A-Hung SP. ter Schegget J. Burger MP. Out TA. Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer. Gynecologic Oncology. 1999 ,73(2):285-91
16 Fujimoto J, Sakaguchi H, Aoki I, Tamaya T. Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancer. Cancer Res 2000;60:2632-2635
17吴素慧,解军,李颖.cDNA芯片筛查Ib期子宫颈鳞癌转移相关基因.中华妇产科杂志.2005,40(4):273-275
18 Lakshminarayanan V, Beno DW, Costa RH,et al. Differential regulation of interleukin-8 and intercellular adhesion molecule-1 by H2O2and tumor necrosis factor-alpha in endothelial and epithelial cells. J Biol Chem, 1997; 272(52)∶32910
19 Hoch RC. Schraufstaetter IU,Cochrane CG.In vivo,in vitro,and molculer aspects of interleukin-8 and interleukin-8 receptors. J Lab Clin Med, 1996; 128(2)∶134
20 Zhang W, Chen H. The Study on the Interleukin-8(IL-8). J Biomed Eng,2002; 19(4)∶697-702
21 Richards BL, Eisma RJ, Spiro JD, et al. Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am J Surg, 1997,174(5)∶507-512
22 Dray TG, Hardin NJ, Sofferman RA. Angiogenesis as a prognostic marker in early head and neck cancer. Ann Otol Rhinol Laryngol, 1995, 104(9 Pt 1)∶724-729
23 Brew R,Erikson JS,West DC,et al. Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitm,Cytokine, 2000,12(1):78-85
24 Garciq RL, Lortrera MD, Gown AM. Analysis of prolifera-tive grade using anti-PCNA /cyclinmonoclonal antibodiesinfixed embedded tissue; comparison with flow cytometreicanalysis. Am J Pathol, 1989;134: 733~739
25 Leland H, Michael BK. Cell cycle control and cancer. Science, 1994; 266:1821
26 Dervan PA,Magee HM,Carney DN. Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. AM J Clin pathol, 1992;97(suppll):S21
27侯萌,杨丹,濮德敏等. hTERT、PCNA在人宫颈癌组织中的表达.中国组织化学与细胞化学杂志,2005;14(2):142~146
28朱锋,吕翔,孙虹. PCNA的过度表达在宫颈鳞癌诊断中的临床意义.右江民族医学院学报,2002;24(1):9-10
29 Hoffmann E,Dittrich-Breiholz O,Holtmann H.et al. Multiple control of interleukin-8 gene expression[J]. J Leukac Biol,2002,72(5):847-855.
30 Brat DJ,Bellail AC,Van Meir EG. The role of interleukin-8 and its recap- tors in gliomagenesis and tumoral angiogenesis. Neuro-Oncology. 2005,7(2):122-133
31 Charalambous C,Pen LB,Su YS, et a1. Interleukin-8 differentially regulates migration of tumor-associated and normal human brain endothelial cells. Cancer Res,2005,65(22):10347-10354
1 Dervan PA,Magee HM,Carney DN. Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. AM J Clin pathol, 1992;97(suppll):S21
2 Kawai T, Suzuki M, Kono S, et al. Proliferating cell nuclear antigen and Ki67 in lung carcinoma, correlation with DNA flow cytometric analysis. Cancer, 1994; 74(9): 246
3 Maga G,Hubseher U. Proliferating cell nuclear antigen (PC-NA):A dancer with many partners. Journal of Cell Scienee,2003,116(15): 3051-3060
4 KrishnaT S R,Kong X P,Gary S,et al. Crystal strueture of the eukaryotic DNA polymerase proeessivity faetor PCNA.Cell, 1994,79: 1233-1243
5 Baserga R. Growth regulation of the gene. Cell sci,1991;98(4):433-436
6 Kelman Z. PCNA: structure, functions and interactions. Oncogene, 1997, 14(16):629-640
7 Moarefi I,Jeruzalmi D,Turner J,et al. Crystal strueture of the DNA polymerase proeessivity faetor of T4 baeteriophage. Journal of Moleeular Biology,2000,296:1215-1223
8 Cermick DM, Hall PA. The comexitics of proliferation cell nuclear antigen. Histopathology, 1992,21:591
9吕翔,张丽华,潘心宇.嗜铬细胞瘤临床病理免疫组化及超微结构的研究.浙江肿瘤,1998;4(3):16~17
10 Garciq RL, Lortrera MD, Gown AM. Analysis of proliferative grade using anti- PCNA/cyclinmonoclonal antibodies infixed embedded tissue; comparison with flow cytometreic analysis. AM J Clin pathol, 1989; 134:733~739
11 Waseem N H et al. Monclonal antibody analysis of the proliferating cell nuclear antigen (PCNA) structural conservation and the detection of a nucleolar form. J Cell Sci, 1990;96:121
12 Prelich G,Tan Ck, Kostura M. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature,1987, 326(6112):517-520
13邓志鸿.PCNA在肿瘤病理学上的应用.临床与实验病理学杂志1994;10(4):331
14 Yu CC-W et al. Update on proliferation associated antibodies applicable to formalin fixd paraffin embedded tissue and their clinical applications. Histochem J,1993;25:843
15 Garcia R,Coltrera M, Analysis of proliferative grade using ant-PCNA/cyclin monoclonal antibodies infixed embedded tissues. Am J Pathol, 1989, 134:733
16 Willett C, Warland G,Christopher G,et al. Tumor proliferating in rectal cancer following preoperative irradiation. J Cin Oncol, 1995,13(6):1317
17 Jain S, Filipe M, Hall P, et al. Prognostic value of Proliferating cell nuclear antigen ingastic carcinoma. J Cin Pathol, 1991,13(9):1417
18 Pich A, Chinsa L, Pacani L, et al. Argyrophilic nucieolar organzizer region counts and Proliferating cell nuclear antigenscores are low reliable indicator of survilva in pharyngeal carcinoma. J Cancer Res Clin Oncol, 1992,119(1):106
19 Kawai T,Suzuki M,Kono S,et al.Proliferating cell nuclear antigen and ki-67 in lung carcinoma ,correlation with DNA flow cyctometric analysis.Cancer 1994;74(9):246
20 NgIo,Lai EC,Fan ST,et al.Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma.Cancer 1994;73(9):2268
21 Jain S, Fillip MI, Hall PA, et al. Prognostic value of PCNA in gastric carcinoma. J Clin Pathol, 1991,44:655
22 Hearslve T et al. Proliferating cell nuclear antigen in breast carcinoma :an immuno-histochemical study with correlation to histopathological features and prognostic factors. Virch Arch Int J Pathol, 1994;424(1):39
23 Ding X,Yang J。Hu S,et al. Evaluation of p53,p21wafl,and PCNA in the diagnosis on lung cancer. Zhonghua Liu Xing Bing Xue Za Zhi 2001;22(1):54
24 Xu J, Morris GF. P53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation. Mol Cell Biol, 1999; 19(1): 12-20
25张美琴,等.癌基因、增殖细胞核抗原与宫颈癌放射敏感性和预后的关系.中国癌症杂志,1997;7(4):302~303
26侯萌,杨丹,濮德敏等. hTERT、PCNA在人宫颈癌组织中的表达.中国组织化学与细胞化学杂志,2005;14(2):142~146
27薛月珍,朱吴珍.子宫颈上皮内瘤变及子宫颈鳞癌中增殖细胞核抗原和C-myc基因过度表达及其临床意义.现代妇产科进展, 1997;6(3):204~207
28朱锋,吕翔,孙虹. PCNA的过度表达在宫颈鳞癌诊断中的临床意义.右江民族医学院学报,2002;24(1):9-10
29 Liu Fs,Chen JT,Liu SC,et al.Expression and prognostic significance of proliferating cell nuclear antigen and ki-67 in malignant ovarian germ cell tumors.Chung Hua I Hsuen Tsa Chih Taipei 1999;62(10):695~700
30 Anreder MB,Freeman SM,Merogi A,et al.P53,cerb B2,and PCNA status in benign,proliferative and malignant ovarian surface epithelial neoplasms:a study of 75 cases.Arch Pathot Lab Mde 1999;123(4):310
31银铎,陆景明.卵巢上皮癌检测PCNA的临床意义.中国实用妇科与产科杂志1999;15(2):101
32仲建新,史锦云,施公胜等. PCNA在卵巢上皮性肿瘤中的表达与临床意义的研究.交通医学2001;15(3):296-298
33 Nakopoulou L, Janinis J, Panagos G, et al. The immunohistochemical expression of proliferating call nuclear (PCNA/cyclin) in maliganant and benign epithelial ovarian neoplasms and correlation with prognosis. Eur J. Cancer, 1993, 29A: 1599
34 Gao L, Wilkison N, Hale R, et al. Ovarian epithelial tumors: expression of PCNA. J Pathol, 1992, 168(supple):134A
35赵先兰,李留霞,乔玉环.卵巢上皮性癌p16和PCNA的表达及意义.临床肿瘤杂志2000;5(3):167-169.
36刘君燕,姜常勇,王静元.子宫内膜增生与内膜癌增殖细胞核抗原表达计数相关性研究.卫生职业教育,2005,23(15):143
37 Shang S,Takal N,Nishida M,et al. CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. Int J Mol Med 2003,1l(2):18l
38晴山仁志.抗PCNA(proliferating cell nuclear antigen)抗体在正常子宫内膜、非典型增生子宫内膜细胞、子宫体癌细胞增殖的研究.北海道医学杂志,1994;69:1427
39 Hamel NW, Sebo TJ, Wilson T et al. Prognostic value of P53 and proliferating cell nuclear antigen expression in endometrial carcinoma. Gynecol Onco, 1996, 62: 192
40尹玲,欧玉荣,张洪福. p27、PCNA在子宫内膜增生过长、腺癌中的表达及意义.肿瘤,2003,23(3):209-211
41 Uzunlar AK, Yilmaz F, Bayhan G, et al. Expressions of P53, proliferating cell nuclear antigen (PCNA),and Ki-67 in gestational trophoblastic diseases. Eur J Gynaecol Oncol, 2002,23(1):79-83
42 Kale A, Soylemez F, Ensari A. Expressions of proliferation markers(Ki-67, proliferating cell nuclear antigen (PCNA), and silver-staining nuclear organizer regions) and of P53 tumor protein in gestational trophoblastic disease.Am J Obatet Gynecol,2001,184(4):567-574
43 Ozbillim G,Karaburun SP,Zorlu G, et al. Immunohistochemicl staining properties of PCNA. Ki-67, P53,bata-hCG and HPL in trophoblastic disease. Eur J Gynecol Oncol, 2002,21(2):200-204
44 Tuncer ZS, Vegh GL, Fulop V, et al. Expressions of epidermal growth factor receptor-related family products in gestational trophoblastic disease and normal placenta and its relationship with development of postmolar turner. Gynecol Oncol, 2000,77(3):389-393
45李荷莲,何津.宫颈癌治疗方法对生存质量的影响.中国实用妇科与产科杂志,2003,19(3):142
46 Giuseppe G, Andrea C, Caia G, et al. Proliferating cell nuclear antigen in endometrial carcinoma: pretreatment identification at high-risk aptients. Gynecol Oncol, 1996,61(1):16
47 Ritsuto F, Kentaro T, Manabu K, et al. Decrease in tumor volume and histologic response to introarterial adenocarcinoma. Gynecol Oncol, 1997,65(2):258
48 Kmios MC, Wang S, Borkowski A, et al. Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression. Int J Cancer, 2004,111(3): 415-417
49 Juric G, Zarkovic N, Nola M, et a.l The value of cell proliferation and angiogenesis in the prognostic assessment of ovarian granulose cell tumors. Tumor, 2001, 87(1): 47-53
50 Txujiahshi H,Naranishi A,Matsuda H,et al.Cell proliferation of human bladder tumors determined by BRDURD and Ki-67 immunostaining. J Urol,145(2):846
51 Wolf HK,Dittrich KL,J Histochem Cytochem,1992;40:1269-1273
2杨玲,皇甫小梅,张思维等.中国20世纪70年代与90年代子宫颈癌死亡率及其变化趋势.中国医学科学院学报,2003, 25(4):386-390
3于冬雁,薛新春.人乳头瘤病毒与宫颈癌的关系.口岸卫生控制,2003, 8(1):40-45
4 Yoshimura T, Matsushima K, Oppenheim J J, et al. Neutrophil chemotactic factor produced by lipolysaccharide (LPS) stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1(IL- 1). J Immunol, 1987, 139(3): 788- 793
5 Inoue K, Slaton JW, Eve BY, et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
6 Murphy C,McGurk M, Pettigrew J, et al. Nonapical and cytop lasmic expression of interleukin - 8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clin Cancer Res, 2005, 11 (11) : 4117 - 4127
7 Tas F, Duranyildiz D, Oguz H, et al. Serum vascular endothelial growth factor (VEGF) and bcl - 2 levels in advanced stage non - small cell lung cancer. Cancer Invest, 2006, 24 (6) : 576 - 580
8 Macri A,VersaciA,Loddo S, et al. Serum levels of interleukin 1beta, in-terleukin 8 and tumour necrosis factor alpha asmarkers of gastric cancer. Biomarkers, 2006, 11 (2) : 184 - 193
9 Lokshin AE,WinansM,LandsittelD, et al. Circulating IL - 8 and anti-IL-8 autoantibody in patients with ovarian cancer. Gynecol Oncol,2006, 102 (2) : 244 - 251
10 Inoue K, Slaton JW, Eve BY, et al Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
11 Kawai T, Suzuki M, Kono S, et al. Proliferating cell nuclear antigen andKi67 in lung carcinoma, correlation with DNA flow cytometric analysis. Cancer, 1994; 74(9): 246
12 Inoue K, Slaton JW, Eve BY, et al Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-2119
13 Li A., Seema D., Michelle L., et a1.IL-8 Directly Enhanced Endothelial Cell Survival,Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis. The Journal of Immunology, 2003,170: 3369-3376
14 Mian BM,Dinney CP,Bermejo CE, et al.Fully human anti-interleukin-8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metallop roteases and nuclear factor-kappa B1Clin Cancer Res, 2003, 19 (8) : 3167-3175
15 Tjiong MY. van der Vange N. ten Kate FJ. Tjong-A-Hung SP. ter Schegget J. Burger MP. Out TA. Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer. Gynecologic Oncology. 1999 ,73(2):285-91
16 Fujimoto J, Sakaguchi H, Aoki I, Tamaya T. Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancer. Cancer Res 2000;60:2632-2635
17吴素慧,解军,李颖.cDNA芯片筛查Ib期子宫颈鳞癌转移相关基因.中华妇产科杂志.2005,40(4):273-275
18 Lakshminarayanan V, Beno DW, Costa RH,et al. Differential regulation of interleukin-8 and intercellular adhesion molecule-1 by H2O2and tumor necrosis factor-alpha in endothelial and epithelial cells. J Biol Chem, 1997; 272(52)∶32910
19 Hoch RC. Schraufstaetter IU,Cochrane CG.In vivo,in vitro,and molculer aspects of interleukin-8 and interleukin-8 receptors. J Lab Clin Med, 1996; 128(2)∶134
20 Zhang W, Chen H. The Study on the Interleukin-8(IL-8). J Biomed Eng,2002; 19(4)∶697-702
21 Richards BL, Eisma RJ, Spiro JD, et al. Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am J Surg, 1997,174(5)∶507-512
22 Dray TG, Hardin NJ, Sofferman RA. Angiogenesis as a prognostic marker in early head and neck cancer. Ann Otol Rhinol Laryngol, 1995, 104(9 Pt 1)∶724-729
23 Brew R,Erikson JS,West DC,et al. Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitm,Cytokine, 2000,12(1):78-85
24 Garciq RL, Lortrera MD, Gown AM. Analysis of prolifera-tive grade using anti-PCNA /cyclinmonoclonal antibodiesinfixed embedded tissue; comparison with flow cytometreicanalysis. Am J Pathol, 1989;134: 733~739
25 Leland H, Michael BK. Cell cycle control and cancer. Science, 1994; 266:1821
26 Dervan PA,Magee HM,Carney DN. Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. AM J Clin pathol, 1992;97(suppll):S21
27侯萌,杨丹,濮德敏等. hTERT、PCNA在人宫颈癌组织中的表达.中国组织化学与细胞化学杂志,2005;14(2):142~146
28朱锋,吕翔,孙虹. PCNA的过度表达在宫颈鳞癌诊断中的临床意义.右江民族医学院学报,2002;24(1):9-10
29 Hoffmann E,Dittrich-Breiholz O,Holtmann H.et al. Multiple control of interleukin-8 gene expression[J]. J Leukac Biol,2002,72(5):847-855.
30 Brat DJ,Bellail AC,Van Meir EG. The role of interleukin-8 and its recap- tors in gliomagenesis and tumoral angiogenesis. Neuro-Oncology. 2005,7(2):122-133
31 Charalambous C,Pen LB,Su YS, et a1. Interleukin-8 differentially regulates migration of tumor-associated and normal human brain endothelial cells. Cancer Res,2005,65(22):10347-10354
1 Dervan PA,Magee HM,Carney DN. Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. AM J Clin pathol, 1992;97(suppll):S21
2 Kawai T, Suzuki M, Kono S, et al. Proliferating cell nuclear antigen and Ki67 in lung carcinoma, correlation with DNA flow cytometric analysis. Cancer, 1994; 74(9): 246
3 Maga G,Hubseher U. Proliferating cell nuclear antigen (PC-NA):A dancer with many partners. Journal of Cell Scienee,2003,116(15): 3051-3060
4 KrishnaT S R,Kong X P,Gary S,et al. Crystal strueture of the eukaryotic DNA polymerase proeessivity faetor PCNA.Cell, 1994,79: 1233-1243
5 Baserga R. Growth regulation of the gene. Cell sci,1991;98(4):433-436
6 Kelman Z. PCNA: structure, functions and interactions. Oncogene, 1997, 14(16):629-640
7 Moarefi I,Jeruzalmi D,Turner J,et al. Crystal strueture of the DNA polymerase proeessivity faetor of T4 baeteriophage. Journal of Moleeular Biology,2000,296:1215-1223
8 Cermick DM, Hall PA. The comexitics of proliferation cell nuclear antigen. Histopathology, 1992,21:591
9吕翔,张丽华,潘心宇.嗜铬细胞瘤临床病理免疫组化及超微结构的研究.浙江肿瘤,1998;4(3):16~17
10 Garciq RL, Lortrera MD, Gown AM. Analysis of proliferative grade using anti- PCNA/cyclinmonoclonal antibodies infixed embedded tissue; comparison with flow cytometreic analysis. AM J Clin pathol, 1989; 134:733~739
11 Waseem N H et al. Monclonal antibody analysis of the proliferating cell nuclear antigen (PCNA) structural conservation and the detection of a nucleolar form. J Cell Sci, 1990;96:121
12 Prelich G,Tan Ck, Kostura M. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature,1987, 326(6112):517-520
13邓志鸿.PCNA在肿瘤病理学上的应用.临床与实验病理学杂志1994;10(4):331
14 Yu CC-W et al. Update on proliferation associated antibodies applicable to formalin fixd paraffin embedded tissue and their clinical applications. Histochem J,1993;25:843
15 Garcia R,Coltrera M, Analysis of proliferative grade using ant-PCNA/cyclin monoclonal antibodies infixed embedded tissues. Am J Pathol, 1989, 134:733
16 Willett C, Warland G,Christopher G,et al. Tumor proliferating in rectal cancer following preoperative irradiation. J Cin Oncol, 1995,13(6):1317
17 Jain S, Filipe M, Hall P, et al. Prognostic value of Proliferating cell nuclear antigen ingastic carcinoma. J Cin Pathol, 1991,13(9):1417
18 Pich A, Chinsa L, Pacani L, et al. Argyrophilic nucieolar organzizer region counts and Proliferating cell nuclear antigenscores are low reliable indicator of survilva in pharyngeal carcinoma. J Cancer Res Clin Oncol, 1992,119(1):106
19 Kawai T,Suzuki M,Kono S,et al.Proliferating cell nuclear antigen and ki-67 in lung carcinoma ,correlation with DNA flow cyctometric analysis.Cancer 1994;74(9):246
20 NgIo,Lai EC,Fan ST,et al.Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma.Cancer 1994;73(9):2268
21 Jain S, Fillip MI, Hall PA, et al. Prognostic value of PCNA in gastric carcinoma. J Clin Pathol, 1991,44:655
22 Hearslve T et al. Proliferating cell nuclear antigen in breast carcinoma :an immuno-histochemical study with correlation to histopathological features and prognostic factors. Virch Arch Int J Pathol, 1994;424(1):39
23 Ding X,Yang J。Hu S,et al. Evaluation of p53,p21wafl,and PCNA in the diagnosis on lung cancer. Zhonghua Liu Xing Bing Xue Za Zhi 2001;22(1):54
24 Xu J, Morris GF. P53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation. Mol Cell Biol, 1999; 19(1): 12-20
25张美琴,等.癌基因、增殖细胞核抗原与宫颈癌放射敏感性和预后的关系.中国癌症杂志,1997;7(4):302~303
26侯萌,杨丹,濮德敏等. hTERT、PCNA在人宫颈癌组织中的表达.中国组织化学与细胞化学杂志,2005;14(2):142~146
27薛月珍,朱吴珍.子宫颈上皮内瘤变及子宫颈鳞癌中增殖细胞核抗原和C-myc基因过度表达及其临床意义.现代妇产科进展, 1997;6(3):204~207
28朱锋,吕翔,孙虹. PCNA的过度表达在宫颈鳞癌诊断中的临床意义.右江民族医学院学报,2002;24(1):9-10
29 Liu Fs,Chen JT,Liu SC,et al.Expression and prognostic significance of proliferating cell nuclear antigen and ki-67 in malignant ovarian germ cell tumors.Chung Hua I Hsuen Tsa Chih Taipei 1999;62(10):695~700
30 Anreder MB,Freeman SM,Merogi A,et al.P53,cerb B2,and PCNA status in benign,proliferative and malignant ovarian surface epithelial neoplasms:a study of 75 cases.Arch Pathot Lab Mde 1999;123(4):310
31银铎,陆景明.卵巢上皮癌检测PCNA的临床意义.中国实用妇科与产科杂志1999;15(2):101
32仲建新,史锦云,施公胜等. PCNA在卵巢上皮性肿瘤中的表达与临床意义的研究.交通医学2001;15(3):296-298
33 Nakopoulou L, Janinis J, Panagos G, et al. The immunohistochemical expression of proliferating call nuclear (PCNA/cyclin) in maliganant and benign epithelial ovarian neoplasms and correlation with prognosis. Eur J. Cancer, 1993, 29A: 1599
34 Gao L, Wilkison N, Hale R, et al. Ovarian epithelial tumors: expression of PCNA. J Pathol, 1992, 168(supple):134A
35赵先兰,李留霞,乔玉环.卵巢上皮性癌p16和PCNA的表达及意义.临床肿瘤杂志2000;5(3):167-169.
36刘君燕,姜常勇,王静元.子宫内膜增生与内膜癌增殖细胞核抗原表达计数相关性研究.卫生职业教育,2005,23(15):143
37 Shang S,Takal N,Nishida M,et al. CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. Int J Mol Med 2003,1l(2):18l
38晴山仁志.抗PCNA(proliferating cell nuclear antigen)抗体在正常子宫内膜、非典型增生子宫内膜细胞、子宫体癌细胞增殖的研究.北海道医学杂志,1994;69:1427
39 Hamel NW, Sebo TJ, Wilson T et al. Prognostic value of P53 and proliferating cell nuclear antigen expression in endometrial carcinoma. Gynecol Onco, 1996, 62: 192
40尹玲,欧玉荣,张洪福. p27、PCNA在子宫内膜增生过长、腺癌中的表达及意义.肿瘤,2003,23(3):209-211
41 Uzunlar AK, Yilmaz F, Bayhan G, et al. Expressions of P53, proliferating cell nuclear antigen (PCNA),and Ki-67 in gestational trophoblastic diseases. Eur J Gynaecol Oncol, 2002,23(1):79-83
42 Kale A, Soylemez F, Ensari A. Expressions of proliferation markers(Ki-67, proliferating cell nuclear antigen (PCNA), and silver-staining nuclear organizer regions) and of P53 tumor protein in gestational trophoblastic disease.Am J Obatet Gynecol,2001,184(4):567-574
43 Ozbillim G,Karaburun SP,Zorlu G, et al. Immunohistochemicl staining properties of PCNA. Ki-67, P53,bata-hCG and HPL in trophoblastic disease. Eur J Gynecol Oncol, 2002,21(2):200-204
44 Tuncer ZS, Vegh GL, Fulop V, et al. Expressions of epidermal growth factor receptor-related family products in gestational trophoblastic disease and normal placenta and its relationship with development of postmolar turner. Gynecol Oncol, 2000,77(3):389-393
45李荷莲,何津.宫颈癌治疗方法对生存质量的影响.中国实用妇科与产科杂志,2003,19(3):142
46 Giuseppe G, Andrea C, Caia G, et al. Proliferating cell nuclear antigen in endometrial carcinoma: pretreatment identification at high-risk aptients. Gynecol Oncol, 1996,61(1):16
47 Ritsuto F, Kentaro T, Manabu K, et al. Decrease in tumor volume and histologic response to introarterial adenocarcinoma. Gynecol Oncol, 1997,65(2):258
48 Kmios MC, Wang S, Borkowski A, et al. Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression. Int J Cancer, 2004,111(3): 415-417
49 Juric G, Zarkovic N, Nola M, et a.l The value of cell proliferation and angiogenesis in the prognostic assessment of ovarian granulose cell tumors. Tumor, 2001, 87(1): 47-53
50 Txujiahshi H,Naranishi A,Matsuda H,et al.Cell proliferation of human bladder tumors determined by BRDURD and Ki-67 immunostaining. J Urol,145(2):846
51 Wolf HK,Dittrich KL,J Histochem Cytochem,1992;40:1269-1273