APE1、VEGF在非小细胞肺癌组织中的表达及其与预后的关系
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摘要
目的：
肺癌是人类最常见的恶性肿瘤之一,居所有恶性肿瘤死因的首位,其中超过80%是非小细胞肺癌(non-small cell lung cancer, NSCLC)。近年来,随着基础医学相关方面的发展,运用免疫学及分了生物学方面的新技术在该领域已取得了长足的进步。APE1、VEGF的发现及在肿瘤研究方面的运用,正是这类的体现。人类脱嘌呤核酸内切酶1(apyrimidinic endonuclease 1, APE1)是一种广泛存在于生物体中的多功能核蛋白,它在DNA的碱基切除修复、对转录因子的氧化还原调控和活性氧簇的调控等多个重要的生物学过程中发挥着主要的作用。血管内皮生长因子(vascular endothelial growth factor,VEGF)是肿瘤血管生成中最重要的促血管生成因子,它选择性促使血管内皮细胞进行有丝分裂、刺激内皮细胞增殖,从而促进血管生成；同时,它能增加血管、尤其是微血管的渗透性,使血浆大分子外渗。APE1能调控的多种转录因子包括p53、HIF-α、NF-κB、Fos/Jun(AP-1)等,其中HIF-a通过VEGF依赖途径和’VEGF非依赖途径影响血管生成。本文通过研究APE1和VEGF在非小细胞肺癌中的表达特征,探讨它们的表达与非小细胞肺癌临床病理因素以及与非小细胞肺癌预后的关系。
方法：
本实验收集2004年1月-2005年1月于天津医科大学附属肿瘤医院和武警医学院附属医院接受手术的78例非小细胞肺癌患者的临床资料进行分析,同时收集30例正常肺组织作为对照。采用免疫组织化学SABC法检测78例有完整蜡块标本的患者中APE1、VEGF的表达情况,血管内皮特异标记物CD34标记并计数肿瘤微血管密度(microvessel density,MVD)。应用SPSS17.0统计软件包进行数据处理。
结果：
1.APE1在所有非小细胞肺癌和正常肺组织都有表达,但是其定位有所不同：APE1主要在肺癌细胞的细胞质表达,78例非小细胞肺癌组织中61例(78.2%)呈高表达,17例(21.8%)呈低表达。而APE1在30例正常肺组织中表达较弱,表达率较低6.7%(2/30)。
2.VEGF主要表达于非小细胞肺癌细胞的细胞质,78例非小细胞肺癌组织中50例(64.1%)呈高表达,17例(35.9%)呈低表达。而在30例正常肺组织中无VEGF的表达。
3.APE1表达与吸烟、淋巴结转移关系密切；VEGF表达与肿瘤大小、分化程度和淋巴结转移关系密切；MVD值与肿瘤大小和淋巴结转移关系密切。
4.Kaplan-Meier生存分析显示：肿瘤大小、淋巴结转移、APE1表达及VEGF表达与生存率之间均呈负相关(P＜0.01); COX回归模型分析显示：肿瘤大小、淋巴结转移和APE1表达是影响非小细胞肺癌患者生存率的独立危险因素。
5.APE1、VEGF表达和MVD计数之间存在相关性。
结论：
1.APE1在NSCLC组织表达增强明显高于正常肺组织,表明APE1可能参与了NSCLC的发生。APE1表达与肺癌淋巴结转移有关,表明APE1可能参与了NSCLC的转移。APE1是影响非小细胞肺癌患者生存率的独立危险因素,表明APE1对判断NSCLC的转移和预后有一定帮助。
2.VEGF在NSCLC组织中的表达与肿瘤大小、分化程度和淋巴结转移有关。VEGF也可作为评价肺癌预后的指标。提示VEGF的表达增强与NSCLC的浸润性发展有密切关系。
3.NSCLC组织APE1及VEGF高表达组MVD值均高于低表达组,且APE1、VEGF表达显著相关,提示二者直接或间接地参与了肿瘤血管的生成,与肺癌细胞浸润转移有关。
Objective:
Lung cancer is one of the most common cancer in the world.It is a major course of death form malignant diseases.Over 80 percent is non-small cell lung cancer (NSCLC).Recently,With the development of the immunology and molecular biology,the studies of lung cancer have achieved greatly progresses.The findings and the appliances of APE1(apyrimidinic endonuclease 1) and VEGF(vascular endothelial growth factor) are the signs of these progresses.APE1 is a paradigm of the functional comp lexity of a biological macromoleculel and it plays a central role in DNA base excision repair,redox-dependeent regulation of specific transcrip tional factors and production control of reactive oxygen species.It is also a key enzyme in the base excision repair and in transcriptional modulation against oxidative stress.VEGF takes the major function to stimulate the growth of the tumor and correlated with the tumor's proliferation,invasion and metastasis.Furthermore,VEGF has the function to improve the activity of Endothelial cell's mitosis.APE1 also functions as a major redox-signaling factor to reduce and activate transcription factors such as p53, HIF-a,NF-KB,Fos/Jun(AP-1),and so on.We investigated the altered expression of APE1/ref-1 and VEGF antioxidant systems in lung cancer,to investigate the expression of APE1 and VEGF in NSCLC,and to explore the influence of the two biological factors and other clinical factors on prognosis of NSCLC.
Methods:
Clinic data of 78 inpatienit cases in the Tianjin Medical University Cancer Hospital and the Affiliated Hospital of Armed police for Medical College from January 2004 to January 2005,were retrospectively reviewed.Meanwile,we collect 30 cases of normal lung tissue. Expression of APE1,VEGF and MVD of 78 cases was studied by inununohistoehemistry(Strept Avidin-Biotin-enzyme Complex).The data are analyzed by soft ware SPSS 17.00.
Results:
1.APE1 expressed both in the NSCLC specimens and in the normal lung tissue,but the location is different.It mainly expressed in cytoplasm in the NSCLC specimens,and mainly localized to nucleus in the normal lung tissue.The positive expression rate of APE1 was 78.2%(61/78) in NSCLC.
2.VEGF mainly expressed in cytoplasm in the NSCLC specimens.The positive expression rate of VEGF was 64.1%(50/78) in NSCLC.
3.The Positive expression artes of APE 1 corrlated with the Patinets' and lymph node matastasis;the Positive expression artes of VEGF corrlated with the Patinets'tumer size,differentiation and lymph node matastasis; MVD corrlated with the Patinets'tumer size, and lymph node matastasis.
4.Kaplan-Meier survival analysis suggested that the survival time was significantly related to turner size,lymph node matastasis,expression of APE1 and VEGF,(P< 0.01).Multivariate COX model analysis indicated that turner size,lymphatic metastasis and APE1 expression may be the independent prognostic factor.
5.There were significant correlations with the expression of APE1,VEGF and MVD.
Conclusion:
1.The expression of APE1 low in the normal lung tissue,but high in lung carainoma;The expression of APE1 closely related to lymph node matastasis.APE1 expression may be the independent prognostic factor,which can be a marker of prognosis evaluation.
2. The expression of VEGF is closely related to turner size, differentiation and lymph node matastasis, it can evaluate prognosis.
3.Both APE1 and VEGF expression are positively related to MVD in lung cancer tissues and the close relationships between APE1 and VEGF indieated that they play important roles in the careinogenesis of lung cancer especially in tumor angiogenesis.
肺癌是人类最常见的恶性肿瘤之一,居所有恶性肿瘤死因的首位,其中超过80%是非小细胞肺癌(non-small cell lung cancer, NSCLC)。近年来,随着基础医学相关方面的发展,运用免疫学及分了生物学方面的新技术在该领域已取得了长足的进步。APE1、VEGF的发现及在肿瘤研究方面的运用,正是这类的体现。人类脱嘌呤核酸内切酶1(apyrimidinic endonuclease 1, APE1)是一种广泛存在于生物体中的多功能核蛋白,它在DNA的碱基切除修复、对转录因子的氧化还原调控和活性氧簇的调控等多个重要的生物学过程中发挥着主要的作用。血管内皮生长因子(vascular endothelial growth factor,VEGF)是肿瘤血管生成中最重要的促血管生成因子,它选择性促使血管内皮细胞进行有丝分裂、刺激内皮细胞增殖,从而促进血管生成；同时,它能增加血管、尤其是微血管的渗透性,使血浆大分子外渗。APE1能调控的多种转录因子包括p53、HIF-α、NF-κB、Fos/Jun(AP-1)等,其中HIF-a通过VEGF依赖途径和’VEGF非依赖途径影响血管生成。本文通过研究APE1和VEGF在非小细胞肺癌中的表达特征,探讨它们的表达与非小细胞肺癌临床病理因素以及与非小细胞肺癌预后的关系。
方法：
本实验收集2004年1月-2005年1月于天津医科大学附属肿瘤医院和武警医学院附属医院接受手术的78例非小细胞肺癌患者的临床资料进行分析,同时收集30例正常肺组织作为对照。采用免疫组织化学SABC法检测78例有完整蜡块标本的患者中APE1、VEGF的表达情况,血管内皮特异标记物CD34标记并计数肿瘤微血管密度(microvessel density,MVD)。应用SPSS17.0统计软件包进行数据处理。
结果：
1.APE1在所有非小细胞肺癌和正常肺组织都有表达,但是其定位有所不同：APE1主要在肺癌细胞的细胞质表达,78例非小细胞肺癌组织中61例(78.2%)呈高表达,17例(21.8%)呈低表达。而APE1在30例正常肺组织中表达较弱,表达率较低6.7%(2/30)。
2.VEGF主要表达于非小细胞肺癌细胞的细胞质,78例非小细胞肺癌组织中50例(64.1%)呈高表达,17例(35.9%)呈低表达。而在30例正常肺组织中无VEGF的表达。
3.APE1表达与吸烟、淋巴结转移关系密切；VEGF表达与肿瘤大小、分化程度和淋巴结转移关系密切；MVD值与肿瘤大小和淋巴结转移关系密切。
4.Kaplan-Meier生存分析显示：肿瘤大小、淋巴结转移、APE1表达及VEGF表达与生存率之间均呈负相关(P＜0.01); COX回归模型分析显示：肿瘤大小、淋巴结转移和APE1表达是影响非小细胞肺癌患者生存率的独立危险因素。
5.APE1、VEGF表达和MVD计数之间存在相关性。
结论：
1.APE1在NSCLC组织表达增强明显高于正常肺组织,表明APE1可能参与了NSCLC的发生。APE1表达与肺癌淋巴结转移有关,表明APE1可能参与了NSCLC的转移。APE1是影响非小细胞肺癌患者生存率的独立危险因素,表明APE1对判断NSCLC的转移和预后有一定帮助。
2.VEGF在NSCLC组织中的表达与肿瘤大小、分化程度和淋巴结转移有关。VEGF也可作为评价肺癌预后的指标。提示VEGF的表达增强与NSCLC的浸润性发展有密切关系。
3.NSCLC组织APE1及VEGF高表达组MVD值均高于低表达组,且APE1、VEGF表达显著相关,提示二者直接或间接地参与了肿瘤血管的生成,与肺癌细胞浸润转移有关。
Objective:
Lung cancer is one of the most common cancer in the world.It is a major course of death form malignant diseases.Over 80 percent is non-small cell lung cancer (NSCLC).Recently,With the development of the immunology and molecular biology,the studies of lung cancer have achieved greatly progresses.The findings and the appliances of APE1(apyrimidinic endonuclease 1) and VEGF(vascular endothelial growth factor) are the signs of these progresses.APE1 is a paradigm of the functional comp lexity of a biological macromoleculel and it plays a central role in DNA base excision repair,redox-dependeent regulation of specific transcrip tional factors and production control of reactive oxygen species.It is also a key enzyme in the base excision repair and in transcriptional modulation against oxidative stress.VEGF takes the major function to stimulate the growth of the tumor and correlated with the tumor's proliferation,invasion and metastasis.Furthermore,VEGF has the function to improve the activity of Endothelial cell's mitosis.APE1 also functions as a major redox-signaling factor to reduce and activate transcription factors such as p53, HIF-a,NF-KB,Fos/Jun(AP-1),and so on.We investigated the altered expression of APE1/ref-1 and VEGF antioxidant systems in lung cancer,to investigate the expression of APE1 and VEGF in NSCLC,and to explore the influence of the two biological factors and other clinical factors on prognosis of NSCLC.
Methods:
Clinic data of 78 inpatienit cases in the Tianjin Medical University Cancer Hospital and the Affiliated Hospital of Armed police for Medical College from January 2004 to January 2005,were retrospectively reviewed.Meanwile,we collect 30 cases of normal lung tissue. Expression of APE1,VEGF and MVD of 78 cases was studied by inununohistoehemistry(Strept Avidin-Biotin-enzyme Complex).The data are analyzed by soft ware SPSS 17.00.
Results:
1.APE1 expressed both in the NSCLC specimens and in the normal lung tissue,but the location is different.It mainly expressed in cytoplasm in the NSCLC specimens,and mainly localized to nucleus in the normal lung tissue.The positive expression rate of APE1 was 78.2%(61/78) in NSCLC.
2.VEGF mainly expressed in cytoplasm in the NSCLC specimens.The positive expression rate of VEGF was 64.1%(50/78) in NSCLC.
3.The Positive expression artes of APE 1 corrlated with the Patinets' and lymph node matastasis;the Positive expression artes of VEGF corrlated with the Patinets'tumer size,differentiation and lymph node matastasis; MVD corrlated with the Patinets'tumer size, and lymph node matastasis.
4.Kaplan-Meier survival analysis suggested that the survival time was significantly related to turner size,lymph node matastasis,expression of APE1 and VEGF,(P< 0.01).Multivariate COX model analysis indicated that turner size,lymphatic metastasis and APE1 expression may be the independent prognostic factor.
5.There were significant correlations with the expression of APE1,VEGF and MVD.
Conclusion:
1.The expression of APE1 low in the normal lung tissue,but high in lung carainoma;The expression of APE1 closely related to lymph node matastasis.APE1 expression may be the independent prognostic factor,which can be a marker of prognosis evaluation.
2. The expression of VEGF is closely related to turner size, differentiation and lymph node matastasis, it can evaluate prognosis.
3.Both APE1 and VEGF expression are positively related to MVD in lung cancer tissues and the close relationships between APE1 and VEGF indieated that they play important roles in the careinogenesis of lung cancer especially in tumor angiogenesis.
引文
[1]FerlayJ,BrayF,PisaniP,et al.GLOBOCAN2002:Cancerineidence,mortality and Prevalence worldwide,Version2.0.IARCCaneerBase No.5.Lyon:IARC Press,2004.
[2]Li LD, Zhang SW,LU FZ,et al. Analysis of variation trend and short term detection of Chinese malignant term mortality during twenty years[J].Chin J Oncol,1997,19(1):3-9.
[3]Jiang N, Wang X, Yang Y, et al. Advances in mitotic inhibitors for cancer treatment[J].Mini Rev Med Chem,2006,6(8):885-895.
[4]Sung JS, Demple B. Roles of base excision repair subpathways in correcting oxidized abasic sites in DNA[J]. FEBS J,2006,273(8):1620-1629.
[5]Xanthoudakis S, Curran T. Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity[J].EMBO J,1992,11(2):653-665.
[6]Sweasy JB,Lang T, DiMaio D. Is base excision repair a tumor suppressor mechanism? [J].Ceii Cycie,2006,5(3):250-259.
[7]Evans AR, Limp-Foster M, Kelley MR. Going APE over ref-1 [J].Mutat Res,2000,461(2):83-108.
[8]Wong D, DeMott MS, Demple B. Modulation of the 3'--＞5'-exonuclease activity of human apurinic endonuclease (Apel) by its 5'-incised Abasic DNA product[J].J Biol Chem,2003,278(38):36242-36249.
[9]Puglisi F, Barbone F, Tell G,et al. Prognostic role of Ape/Ref-1 subcellular expression in stage Ⅰ-Ⅲ breast carcinomas[J].Oncol Rep,2002,9(1):11-17.
[10]Puglisi F, Aprile G, Minisini AM, et al. Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas[J].Anticancer Res, 2001,21(6A):4041-4049.
[11]Ouellet V, Le Page C, Guyot MC,et al. SET complex in serous epithelial ovarian cancer[J].Int J Cancer,2006,119(9):2119-2126.
[12]Zienolddiny S, Campa D, Lind H, et al. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer[J].Carcinogenesis,2006,27(3):560-567.
[13]Tell G, Damante G, Caldwell D, et al. The intracellular localization of APE1/Ref-1:more than a passive phenomenon? [J].Antioxid Redox Signal, 2005,7(3-4):367-384.
[14]Petrova TV, Makinen T, Alitalo K. Signaling via vascular endothelial growth factor receptors[J].Exp Cell Res,1999,253(1):117-130.
[15]Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions[J].Clin Sci (Lond),2005,109(3):227-241.
[16]岳培彬,杨晓明.细胞生长因子和人类肿瘤.见詹启敏主编.分子肿瘤学.北京：人民卫生出版社,2005.188-224.
[17]杨玲,李连弟,陈育德,等.中国2000年及2005年恶性肿瘤发病死亡的估计与预测[J].中国卫生统计,2005,22(4)：218-221.
[18]Folkman J.shing Y.Angiogenesis[J].J Biol Chem,1992,267:10931-10934.
[19]Varey AH, Rennel ES, Qiu Y,et al.VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma:balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy[J]. Br J Cancer.2008,98(8):1366-1379.
[20]Korpanty G, Smyth E, Sullivan LA, et al. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway[J].Exp Biol Med (Maywood),2010,235(1):3-9.
[21]WEY js,FAN F,GRAY MJ,et al.Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines[J].Cancer,2005,104(2):427-438.
[22]VIEIRA JM,SANTOS SC.ESPADINHA C,et al.Expression of vaseular endothelial growth factor (VEGF)and its receptors in thyroid carcinomas offollicular origin:a potential autocrine loop [J].Eur J Endocrinol,2005,153(5):701-709.
[23]LACAL PM,RUFFINI F,PAGANI E,et al.An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of humanmelanoma cells[J].IntJOncol,2005,27(6):1625-1632.
[24]Tamura M,Ohta Y,Kajita T,et al.Plasma VEGF concentration can predict the turner angiogenic capacity in non-small cell lung cancer[J].Oncol Rep,2001,8(5):1097-1102.
[25]WEIDNER N.Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors [J].Breast Cancer ResTreat,1995,36(2):169-180.
[26]Al-Attar A,Gossage L,Fareed KR,et al.Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian,gastro-oesophageal and pancreatico-biliary cancers[J].Br J Cancer,2010,102(4):704-709.
[27]Wang D, Zhong ZY, Li MX, et al. Vector-based Apel small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo[J].Cancer Sc;,2007,98(12):1993-2001.
[28]Yang ZZ, Chen XH, Wang D. Experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE!-silencing RNA expression vector[J].Clin Lymphoma Myeloma,2007,7(4):296-304.
[29]David M,Wilson III.Small molecule inhibitors of DNA repair nuclease activities of APE1[J].Cell.Mol.Life Sci,2010,67(21):3621-3631.
[30]Kakolyris S, Kaklamanis L, Giatromanolaki A, et al. Exp ression and subcellular locaLization of human AP endonuclease 1 (HAP1/Ref21)protein:a basis for its role in human disease [J].Histopathology,1998,33 (6):561-569.
[31]Gros L,Ishchenko AA,Ide H,et al.The major human AP endonuclease(APE1) is involved in the nucleotide incision repair pathway[J].Nucleic Acids Res,2004,32(1):73.
[32]Fishel ML,Kelley MR.The DNA base excision repair protein APE1/Ref-1 as a therapeutic and chemopreventive target[J].Molecular Aspects of Med,2007,8(3-4):375.
[33]Rachel Abbotts, Srinivasan Madhusudan.Human AP endonuclease 1 (APE1): From mechanistic insights to druggable target in cancer[J].Cancer Treatment Reviews,2010,36(5):425-435.
[34]Furudoi A, Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma[J].Oncology,2002,62 (2):157-166.
[35]Parsons J L, Dianova I I, Dianov G L. APE1 is the major 3'phosphoglycolate activity in human cell extracts [J].NucleicAcids Res,2004,32 (12):3531-3536.
[36]WangD,Meihua L,Mark K R. Human apurinic endonuclease 1(APE1) exp ressiong and p rognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 exp ression inhibition[J].MolCancer Ther,2004,3(6):679-686.
[37]Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor exp ression at the deepest invasive site of advanced colorectal carcinoma [J].Oncology,2003,64(1):61-73.
[38]Zou GM,Karikari C,Kab Y,et al.The Apel/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells:therapeutic implications in tumor angiogenesis[J].J Cell Physiol.2009,219(1):209-218.
[39]Kakolyris S, Kaklamanis L, Engels K, et al. Human AP endonuclease 1 (HAP1) p rotein expression in breast cancer correlates with lymph node status and angiogenesis [J].Br J Cancer,1998,77(7):1169-1173.
[40]Luo M,Delaplane S,Jiang A,et al.Role of the multifunctional DNA repair and redox signaling protein Apel/Ref-1 in cancer and endothelial cells:small-molecule inhibition of the redox function of Apel[J].Antioxid Redox Signal,2008,10(11):1853-1867.
[41]Ziel KA, Campbell CC, Wilson GL, et al.Ref-1/Ape is critical for formation of the hypoxia-inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene[J].FASEB J,2004,18(9):986-988.
[42]Jackson AL, Zhou B, Kim WY.HIF,hypoxia and the role of angiogenesis in non-small cell lung cancer [J]. Expert Opin Ther Targets,2010,14(10):1047-1057.
[43]陈连生,王东,张云嵩,等.DNA损伤修复基因APE1表达与非小细胞肺癌 术后治疗及预后关系的研究[J].重庆医学,2007,36(19)：1915-1917.
[44]Dae Goon Yoo, Yun Jeong Song, Eun Jung Cho,et al.Alteration of APE1/ref-1 expression in non-small cell lung cancer:The implications of impaired extracellular superoxide dismutase and catalase antioxidant systems [J].Lung Cancer,2008,60(2):277-284.
[45]Tanner B,Grimme S,Schiffer I,et al.Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas[J].Gynecol Oncol,2004,92(2):568.
[46]Iwasaki A,Kuwahara M,Yoshinaga Y,et al.Basic fibroblast growth factor(bFGF) and vascular endothelial growth factor(VEGF) level,as prognostic indicators in NSCLC[J].Eur J Cardiothorac Surg,2004,25(3):443-448.
[47]朱志华,戎铁华,曾灿光,等.Ⅰ-Ⅱ期非小细胞肺癌组织中VEGF的表达和微血管密度与预后的关系[J].癌症,2005,24(7)：865-869.
[48]Tanaka F,Oyanagi H,Takenaka K,et al.Glomeruloid microvascular proliferation is superior to intratumoral microvessel density as a prognostic marker in non-small cell lung cancer[J].Cancer Res,2003,63(20):6791-6794.
[49]Mineo TC,Ambrogi V,Baldi A,et al.Prognostic impact of VEGF,CD31,CD34 and CD 105 expression and tumour vessel invasion after radical surgery for ⅠB-ⅡA non-small cell lung cancer[J].J Clin Pathol,2004,57(6):591-597.
[50]吕喜英,张秀芹,李青山.P-gp、P53和VEGF在非小细胞肺癌中的表达及临床意义[J].陕西医学杂志,2006,35(1)：24-27.
[51]Agachan B, Kucukhuseyin O, Aksoy P,et al.Apurinic/apyrimidinic endonuclease (APE1) gene polymorphisms and lung cancer risk in relation to tobacco smoking[J].Anticancer Res June,2009,29(6):2417-2420.
[52]Yoo DG, Song YJ, Cho EJ, et al. Alteration of APE1/ref-1 expression in non-small cell lung cancer:the implications of impaired extracellular superoxide dismutase and catalase antioxidant systems[J].Lung Cancer,2008,60(2):277-284.
[53]李宏云,贾宝辉,秦超,等.血管内皮细胞生长因子在非小细胞肺癌中的表达[J].实用癌症杂志,2005,20(2)：131-134.
[54]张云嵩,范士志,王东,等APE1在非小细胞肺癌中的表达特点及其与预后的关系[J].第三军医大学学报,2007,29(9)：776-778.
[55]Ozbudak IH, Ozbilim G, Kucukosmanoglu I,et al.Vascular endothelial growth factor expression and neovascularization in non-small cell lung carcinoma[J].Int J Surg Pathol,2009,17(5):390-395.
[56]Wang D, Xiang DB, Yang XQ, et al.APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE 1 enhances the activity of cisplatin in A549 cells. [J],Lung Cancer,2009,66(3):298-304.
[57]Puglisi F, Aprile G, Minisini AM, et al.Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas [J].Anticancer Res, 2001,21(6A):4041-4049.
[58]Di Maso V, Avellini C, Croce LS,et al. Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma:possible prognostic significance[J].Molecular Medicine,2007,13(1-2):89-96.
[59]Sak SC, Harnden P, Johnston CF, APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer[J]. Clinical Cancer Research,2005,11(17):6205-6211.
[60]张颖,工东,辛晓燕,等APE1在卵巢上皮性癌中的表达及其临床意义[J].第四军医大学学报,2008,29(19)：1803-1806.
[61]Yanlin Jiang, Shaoyu Zhou, George E.Sandusky,Reduced Expression of DNA Repair and Redox Signaling Protein APE1/Ref-1 Impairs Human Pancreatic Cancer Cell Survival,Proliferation, and Cell Cycle Progression[J].Cancer Invest,2010,28(9):885-895.
[62]Deng Q, Sheng L, Su D, et al.Genetic polymorphisms in ATM, ERCC1, APE1 and iASPP genes and lung cancer risk in a population of southeast China[J].Medical Oncology,2010,Mar 31.
[63]Gianluca Tell,Damiano Fantini,Franco Quadrifoglio.Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment[J].Cell. Mol. Life Sci,2010,67(21):3589-3608.
[64]Ying Zhang, Jian Wang.Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factorl(APE/Refl)[J].Chin J Cancer,2010,29(3):333-339.
[65]Rohrabaugh SL,Hangoc G,Kelley MR,et al.Mad2 haploinsufficiency protects hematopoietic progenitor cells subjected to cell-cycle stress in vivo and to inhibition of redox function of Apel/Ref-1 in vitro[J].Exp Hematol,2011,39(4):415-423.
[66]Naidu MD, Mason JM, Pica RV, et al.Radiation resistance in glioma cells determined by DNA damage repair activity of Apel/Ref-1 [J].J Radiat Res (Tokyo),2010,51(4):393-404.
[67]Yang JL, Tadokoro T, Keijzers G, et al.Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1[J]. J Biol Chem,2010,285(36):28191-28199.
[68]Stetler RA, Gao Y, Zukin RS,et al.Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia[J]. Proc Natl Acad Sci U S A,2010,107(7):3204-3209.
[1]Xanthoudakis S, Curran T.Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity[J].EMBO J, 1992,11(2):653-665.
[2]Robson C N, Hickson I D.Isolation of cDNA clones encoding ahuman apurinic/apyrimidinic endonuclease that corrects DNA re-pair and mutagenesis defects in E. coli xth (exonucleaselⅡ) mutants[J]. Nucleic Acids Res,1991,19(20):5519-5523.
[3]Sweasy JB, Lang T, DiMaio D.Is base excision repair a tumor suppressor mechanism?[J].Cell Cycle,2006,5(3):250-259.
[4]Kakolyris S,Kaklamanis L,Giatromanolaki A,et al.Expression and subcellular localization of human AP endonuclease 1(APE1/Ref-1) protein:a basis for its role in human disease[J].Histopathology,1998,33(6):561-569.
[5]Mol CD, Hosfield DJ, Tainer JA,et al.Abasic site recognition by two apurinic/apyrimidinic endonuclease families in DNA base excision repair:the 3' ends justify the means[J].Mutat Res,2000,460(3-4):211-229.
[6]Flaherty D M,Monick M M,Hunninghake G W.AP Endonuclcascs and the Many-Functions of Ref-1[J].Am J Respir Cell Mol Biol,2001,25(6):664-667.
[7]Gaiddon C,Moorthy N C,Prives C.Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo[J].EMBO J,1999,18(20):5609-5621.
[8]Hanson S,Kim E,Deppert W.Redox factor 1(Ref-1) ehancesspecific DNA binding of p53 by promoting p53 tetramerization[J].Oncogene,2005,24(9):1641-1647.
[9]Guan Z,Basi D,Li Q,et al.Loss of redox factor 1 decreases NF-kappaB activity and increases susceptibility of endothelial cells to apoptosis. Arterioscler [J].Arterioscler Thromb Vase Biol,2005,25(1):96-101.
[10]Ziel K A,Campbell C C,Wilson G L,et al. Ref-1/Ape is critical for formation of the hypoxia-inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene[J].FASEB J,2004,18(9):986-988.
[11]Kawase M, Fujimura M,Morita, Fujimura Y,et al.Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats:implication of the failure of DNA repair in neuronal apoptosis[J].Stroke,1999,30:441-449.
[12]Walton M,Lawlor P,Sirimanne E,et al.Loss of Ref21 protein expression precedes DNA fragmentation in apoptotic neurons[J]. Brain Res Mol Brain Res,1997,44:167-170.
[13]Robertson KA, Hill DP,Xu Y,et al.Down2regulation of apurinic/apyrimidinic endonuclease expresion is associated with the induction of apoptosis in differentiating myeloid leukemia cells[J].Cell Growth Differ,1997,8:443-449.
[14]Chan PH,Kawase M,Murakami K,et al.Overexpression of SOD! in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion[J].J Neurosci,1998,18:82-92.
[15]Puglisi F,Barbone F,Tell G,et al.Prognostic role of Ape/Ref-1 subcellular expression in stage Ⅰ-Ⅲ breast carcinomas[J].Oncol Rep,2002,9(l):11-17.
[16]Ding S Z,O'Hara A M,Denning T L,et al.Helicobacter pylori and H2O2increase AP endonuclease-1/redox factor-1 expression in human gastric epithelial cells[J]. Gastroenterology,2004,127(3):845-858.
[17]Tell G,Pellizzari L,Pucillo C,et al.TSH controls Rcf-1 nucleartranslation in thyroid cells[J]. J Mol Endocrinol,2000,24(3):383-390.
[18]Walker L J,Robson C N,Black E,et al.Identification of residues in the human DNA. repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding[J].Mol Cell Biol,1993,13(9):5370-5376.
[19]Khomenko T,Deng X,Jadus M R,et al.Effect of cysteamine on redox-sensitive thiol-containing proteins in the duodenal mucosa. Biochem Biophys Res Commun[J],2003,309(4):910-916.
[20]Raffoul J J,Cabelof D C,Nakamura J,et al.Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair[J].J Biol Chem,2004,279(18):18425-18433.
[21]Puglisi F, Aprile G, Minisini AM, et al.Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas. Anticancer Res,2001, 21(6A):4041-4049.
[22]Ouellet V, Le Page C, Guyot MC, et al.SET complex in serous epithelial ovarian cancer[J].Int J Cancer,2006,119(9):2119-2126.
[23]Zienolddiny S, Campa D, Lind H, et al.Polymorphisms of DNA repair genes and risk of non-small cell lung cancer[J].Carcinogenesis,2006,27(3):560-567.
[24]Tell G, Damante G, Caldwell D, et al.The intracellular localization of APE1/Ref-1:more than a passive phenomenon?[J].Antioxid Redox Signal, 2005,7(3-4):367-384.
[25]Kakolyris S,Kaklamanis L,Engels K,et al.Human apurinic endonuclease 1 expression in a colorectal adenoma-carcinoma sequence[J].Cancer Res,1997,57(9):1794-1797.
[26]Sak SC, Harnden P, Johnston CF, et al.APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer[J].Clin Cancer Res,2005,11 (17):6205-6211.
[27]Bobola MS, Finn LS, Ellenbogen RG, et al.Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors[J].Clin Cancer Res,2005,11(20):7405-7414.
[28]Robertson KA, Bullock HA, Xu Y, et al.Altered expression of Apel/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation[J].Cancer Res,2001,61(5):2220-2225.
[29]Silber JR, Bobola MS, Blank A, et al.The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress[J].Clin Cancer Res,2002,8(9):3008-3018.
[30]Luo M, Kelley MR.Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone[J].Anticancer Res,2004,24(4):2127-2134.
[31]Chang-Claude J, Popanda O, Tan XL, et al. Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in the breast cancer patients[J].Clin Cancer Res,2005, 11(13):4802-4809.
[32]Wang D, Luo M, Kelley MR.Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE 1 expression inhibition[J].Mol Cancer Ther,2004,3(6):679-686.
[33]王东,仲召阳,李增鹏APE1 siRNA表达载体的构建及其对骨肉瘤细胞APE1的表达抑制作用[J].第三军医大学学报,2006,28(2)：97-100.
[34]Wang D, Zhong ZY, Li MX, et al.Vector-based Apel small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo[J].Cancer Sci,2007,98(12):1993-2001.
[35]Lau J P,Weatherdon K L,Skalski V,et al. Effects of gemcit-abine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides[J].Br Jancer,2004,91(6):1166-1173.
[36]Moore D H,Michael H,Tritt R,et al.Alterations in the expression of the DNA repair/redox enzyme APE/ref-1 in epithelial ovarian cancers[J].Clin Cancer Res,2000,6(2):602-609.
[37]Tanner B,Grimme S,Schiffer I,et al.Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas[J].Gynccol Oncol,2004,92(2):568-577.
[38]Freitas S,Moore D H,Michael H, et al.Studies of apurinic/apyrimidinic endonuclease/ref-1 expression in epithelial ovarian cancer:correlations with tumor progression and platinum resistance[J].Clin Cancer Res,2003,9(13):4689-4694.
[39]吕嘉春,何敏,廖永德,等.氧化/还原因子ref-1在肺癌组织中的细胞定位表达与8-OH-dG的关系[J].肿瘤,2004,24(1)：35-37.
[40]Koukourakis M I,Giatromanolaki A, Kakolyris S,et al.Nuclear expression of human apurinic/apyrimidinic endonuclease (APE1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome[J].Int J Radiat Oncol Biol Phys,2001,50(1):27-36.
[41]WangD,Meihua L,Mark K R.Human apurinic endonuclease 1(APE1) exp ressiong and p rognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 exp ression inhibition[J].MolCancer Ther,2004,3 (6):679-686.
[42]Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor exp ression at the deepest invasive site of advanced colorectal carcinoma[J].Oncology,2003,64(1):61-73.
[43]Luo M,Delaplane S,Jiang A,et al.Role of the multifunctional DNA repair and redox signaling protein Ape1/Ref-1 in cancer and endothelial cells:small-molecule inhibition of the redox function of Ape1[J].Antioxid Redox Signal,2008,10(11):1853-1867.
[44]Zou GM,Karikari C,Kab Y,et al.The Apel/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells:therapeutic implications in tumor angiogenesis[J].J Cell Physiol,2009,219(1):209-218.
[2]Li LD, Zhang SW,LU FZ,et al. Analysis of variation trend and short term detection of Chinese malignant term mortality during twenty years[J].Chin J Oncol,1997,19(1):3-9.
[3]Jiang N, Wang X, Yang Y, et al. Advances in mitotic inhibitors for cancer treatment[J].Mini Rev Med Chem,2006,6(8):885-895.
[4]Sung JS, Demple B. Roles of base excision repair subpathways in correcting oxidized abasic sites in DNA[J]. FEBS J,2006,273(8):1620-1629.
[5]Xanthoudakis S, Curran T. Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity[J].EMBO J,1992,11(2):653-665.
[6]Sweasy JB,Lang T, DiMaio D. Is base excision repair a tumor suppressor mechanism? [J].Ceii Cycie,2006,5(3):250-259.
[7]Evans AR, Limp-Foster M, Kelley MR. Going APE over ref-1 [J].Mutat Res,2000,461(2):83-108.
[8]Wong D, DeMott MS, Demple B. Modulation of the 3'--＞5'-exonuclease activity of human apurinic endonuclease (Apel) by its 5'-incised Abasic DNA product[J].J Biol Chem,2003,278(38):36242-36249.
[9]Puglisi F, Barbone F, Tell G,et al. Prognostic role of Ape/Ref-1 subcellular expression in stage Ⅰ-Ⅲ breast carcinomas[J].Oncol Rep,2002,9(1):11-17.
[10]Puglisi F, Aprile G, Minisini AM, et al. Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas[J].Anticancer Res, 2001,21(6A):4041-4049.
[11]Ouellet V, Le Page C, Guyot MC,et al. SET complex in serous epithelial ovarian cancer[J].Int J Cancer,2006,119(9):2119-2126.
[12]Zienolddiny S, Campa D, Lind H, et al. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer[J].Carcinogenesis,2006,27(3):560-567.
[13]Tell G, Damante G, Caldwell D, et al. The intracellular localization of APE1/Ref-1:more than a passive phenomenon? [J].Antioxid Redox Signal, 2005,7(3-4):367-384.
[14]Petrova TV, Makinen T, Alitalo K. Signaling via vascular endothelial growth factor receptors[J].Exp Cell Res,1999,253(1):117-130.
[15]Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions[J].Clin Sci (Lond),2005,109(3):227-241.
[16]岳培彬,杨晓明.细胞生长因子和人类肿瘤.见詹启敏主编.分子肿瘤学.北京：人民卫生出版社,2005.188-224.
[17]杨玲,李连弟,陈育德,等.中国2000年及2005年恶性肿瘤发病死亡的估计与预测[J].中国卫生统计,2005,22(4)：218-221.
[18]Folkman J.shing Y.Angiogenesis[J].J Biol Chem,1992,267:10931-10934.
[19]Varey AH, Rennel ES, Qiu Y,et al.VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma:balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy[J]. Br J Cancer.2008,98(8):1366-1379.
[20]Korpanty G, Smyth E, Sullivan LA, et al. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway[J].Exp Biol Med (Maywood),2010,235(1):3-9.
[21]WEY js,FAN F,GRAY MJ,et al.Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines[J].Cancer,2005,104(2):427-438.
[22]VIEIRA JM,SANTOS SC.ESPADINHA C,et al.Expression of vaseular endothelial growth factor (VEGF)and its receptors in thyroid carcinomas offollicular origin:a potential autocrine loop [J].Eur J Endocrinol,2005,153(5):701-709.
[23]LACAL PM,RUFFINI F,PAGANI E,et al.An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of humanmelanoma cells[J].IntJOncol,2005,27(6):1625-1632.
[24]Tamura M,Ohta Y,Kajita T,et al.Plasma VEGF concentration can predict the turner angiogenic capacity in non-small cell lung cancer[J].Oncol Rep,2001,8(5):1097-1102.
[25]WEIDNER N.Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors [J].Breast Cancer ResTreat,1995,36(2):169-180.
[26]Al-Attar A,Gossage L,Fareed KR,et al.Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian,gastro-oesophageal and pancreatico-biliary cancers[J].Br J Cancer,2010,102(4):704-709.
[27]Wang D, Zhong ZY, Li MX, et al. Vector-based Apel small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo[J].Cancer Sc;,2007,98(12):1993-2001.
[28]Yang ZZ, Chen XH, Wang D. Experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE!-silencing RNA expression vector[J].Clin Lymphoma Myeloma,2007,7(4):296-304.
[29]David M,Wilson III.Small molecule inhibitors of DNA repair nuclease activities of APE1[J].Cell.Mol.Life Sci,2010,67(21):3621-3631.
[30]Kakolyris S, Kaklamanis L, Giatromanolaki A, et al. Exp ression and subcellular locaLization of human AP endonuclease 1 (HAP1/Ref21)protein:a basis for its role in human disease [J].Histopathology,1998,33 (6):561-569.
[31]Gros L,Ishchenko AA,Ide H,et al.The major human AP endonuclease(APE1) is involved in the nucleotide incision repair pathway[J].Nucleic Acids Res,2004,32(1):73.
[32]Fishel ML,Kelley MR.The DNA base excision repair protein APE1/Ref-1 as a therapeutic and chemopreventive target[J].Molecular Aspects of Med,2007,8(3-4):375.
[33]Rachel Abbotts, Srinivasan Madhusudan.Human AP endonuclease 1 (APE1): From mechanistic insights to druggable target in cancer[J].Cancer Treatment Reviews,2010,36(5):425-435.
[34]Furudoi A, Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma[J].Oncology,2002,62 (2):157-166.
[35]Parsons J L, Dianova I I, Dianov G L. APE1 is the major 3'phosphoglycolate activity in human cell extracts [J].NucleicAcids Res,2004,32 (12):3531-3536.
[36]WangD,Meihua L,Mark K R. Human apurinic endonuclease 1(APE1) exp ressiong and p rognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 exp ression inhibition[J].MolCancer Ther,2004,3(6):679-686.
[37]Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor exp ression at the deepest invasive site of advanced colorectal carcinoma [J].Oncology,2003,64(1):61-73.
[38]Zou GM,Karikari C,Kab Y,et al.The Apel/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells:therapeutic implications in tumor angiogenesis[J].J Cell Physiol.2009,219(1):209-218.
[39]Kakolyris S, Kaklamanis L, Engels K, et al. Human AP endonuclease 1 (HAP1) p rotein expression in breast cancer correlates with lymph node status and angiogenesis [J].Br J Cancer,1998,77(7):1169-1173.
[40]Luo M,Delaplane S,Jiang A,et al.Role of the multifunctional DNA repair and redox signaling protein Apel/Ref-1 in cancer and endothelial cells:small-molecule inhibition of the redox function of Apel[J].Antioxid Redox Signal,2008,10(11):1853-1867.
[41]Ziel KA, Campbell CC, Wilson GL, et al.Ref-1/Ape is critical for formation of the hypoxia-inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene[J].FASEB J,2004,18(9):986-988.
[42]Jackson AL, Zhou B, Kim WY.HIF,hypoxia and the role of angiogenesis in non-small cell lung cancer [J]. Expert Opin Ther Targets,2010,14(10):1047-1057.
[43]陈连生,王东,张云嵩,等.DNA损伤修复基因APE1表达与非小细胞肺癌 术后治疗及预后关系的研究[J].重庆医学,2007,36(19)：1915-1917.
[44]Dae Goon Yoo, Yun Jeong Song, Eun Jung Cho,et al.Alteration of APE1/ref-1 expression in non-small cell lung cancer:The implications of impaired extracellular superoxide dismutase and catalase antioxidant systems [J].Lung Cancer,2008,60(2):277-284.
[45]Tanner B,Grimme S,Schiffer I,et al.Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas[J].Gynecol Oncol,2004,92(2):568.
[46]Iwasaki A,Kuwahara M,Yoshinaga Y,et al.Basic fibroblast growth factor(bFGF) and vascular endothelial growth factor(VEGF) level,as prognostic indicators in NSCLC[J].Eur J Cardiothorac Surg,2004,25(3):443-448.
[47]朱志华,戎铁华,曾灿光,等.Ⅰ-Ⅱ期非小细胞肺癌组织中VEGF的表达和微血管密度与预后的关系[J].癌症,2005,24(7)：865-869.
[48]Tanaka F,Oyanagi H,Takenaka K,et al.Glomeruloid microvascular proliferation is superior to intratumoral microvessel density as a prognostic marker in non-small cell lung cancer[J].Cancer Res,2003,63(20):6791-6794.
[49]Mineo TC,Ambrogi V,Baldi A,et al.Prognostic impact of VEGF,CD31,CD34 and CD 105 expression and tumour vessel invasion after radical surgery for ⅠB-ⅡA non-small cell lung cancer[J].J Clin Pathol,2004,57(6):591-597.
[50]吕喜英,张秀芹,李青山.P-gp、P53和VEGF在非小细胞肺癌中的表达及临床意义[J].陕西医学杂志,2006,35(1)：24-27.
[51]Agachan B, Kucukhuseyin O, Aksoy P,et al.Apurinic/apyrimidinic endonuclease (APE1) gene polymorphisms and lung cancer risk in relation to tobacco smoking[J].Anticancer Res June,2009,29(6):2417-2420.
[52]Yoo DG, Song YJ, Cho EJ, et al. Alteration of APE1/ref-1 expression in non-small cell lung cancer:the implications of impaired extracellular superoxide dismutase and catalase antioxidant systems[J].Lung Cancer,2008,60(2):277-284.
[53]李宏云,贾宝辉,秦超,等.血管内皮细胞生长因子在非小细胞肺癌中的表达[J].实用癌症杂志,2005,20(2)：131-134.
[54]张云嵩,范士志,王东,等APE1在非小细胞肺癌中的表达特点及其与预后的关系[J].第三军医大学学报,2007,29(9)：776-778.
[55]Ozbudak IH, Ozbilim G, Kucukosmanoglu I,et al.Vascular endothelial growth factor expression and neovascularization in non-small cell lung carcinoma[J].Int J Surg Pathol,2009,17(5):390-395.
[56]Wang D, Xiang DB, Yang XQ, et al.APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE 1 enhances the activity of cisplatin in A549 cells. [J],Lung Cancer,2009,66(3):298-304.
[57]Puglisi F, Aprile G, Minisini AM, et al.Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas [J].Anticancer Res, 2001,21(6A):4041-4049.
[58]Di Maso V, Avellini C, Croce LS,et al. Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma:possible prognostic significance[J].Molecular Medicine,2007,13(1-2):89-96.
[59]Sak SC, Harnden P, Johnston CF, APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer[J]. Clinical Cancer Research,2005,11(17):6205-6211.
[60]张颖,工东,辛晓燕,等APE1在卵巢上皮性癌中的表达及其临床意义[J].第四军医大学学报,2008,29(19)：1803-1806.
[61]Yanlin Jiang, Shaoyu Zhou, George E.Sandusky,Reduced Expression of DNA Repair and Redox Signaling Protein APE1/Ref-1 Impairs Human Pancreatic Cancer Cell Survival,Proliferation, and Cell Cycle Progression[J].Cancer Invest,2010,28(9):885-895.
[62]Deng Q, Sheng L, Su D, et al.Genetic polymorphisms in ATM, ERCC1, APE1 and iASPP genes and lung cancer risk in a population of southeast China[J].Medical Oncology,2010,Mar 31.
[63]Gianluca Tell,Damiano Fantini,Franco Quadrifoglio.Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment[J].Cell. Mol. Life Sci,2010,67(21):3589-3608.
[64]Ying Zhang, Jian Wang.Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factorl(APE/Refl)[J].Chin J Cancer,2010,29(3):333-339.
[65]Rohrabaugh SL,Hangoc G,Kelley MR,et al.Mad2 haploinsufficiency protects hematopoietic progenitor cells subjected to cell-cycle stress in vivo and to inhibition of redox function of Apel/Ref-1 in vitro[J].Exp Hematol,2011,39(4):415-423.
[66]Naidu MD, Mason JM, Pica RV, et al.Radiation resistance in glioma cells determined by DNA damage repair activity of Apel/Ref-1 [J].J Radiat Res (Tokyo),2010,51(4):393-404.
[67]Yang JL, Tadokoro T, Keijzers G, et al.Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1[J]. J Biol Chem,2010,285(36):28191-28199.
[68]Stetler RA, Gao Y, Zukin RS,et al.Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia[J]. Proc Natl Acad Sci U S A,2010,107(7):3204-3209.
[1]Xanthoudakis S, Curran T.Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity[J].EMBO J, 1992,11(2):653-665.
[2]Robson C N, Hickson I D.Isolation of cDNA clones encoding ahuman apurinic/apyrimidinic endonuclease that corrects DNA re-pair and mutagenesis defects in E. coli xth (exonucleaselⅡ) mutants[J]. Nucleic Acids Res,1991,19(20):5519-5523.
[3]Sweasy JB, Lang T, DiMaio D.Is base excision repair a tumor suppressor mechanism?[J].Cell Cycle,2006,5(3):250-259.
[4]Kakolyris S,Kaklamanis L,Giatromanolaki A,et al.Expression and subcellular localization of human AP endonuclease 1(APE1/Ref-1) protein:a basis for its role in human disease[J].Histopathology,1998,33(6):561-569.
[5]Mol CD, Hosfield DJ, Tainer JA,et al.Abasic site recognition by two apurinic/apyrimidinic endonuclease families in DNA base excision repair:the 3' ends justify the means[J].Mutat Res,2000,460(3-4):211-229.
[6]Flaherty D M,Monick M M,Hunninghake G W.AP Endonuclcascs and the Many-Functions of Ref-1[J].Am J Respir Cell Mol Biol,2001,25(6):664-667.
[7]Gaiddon C,Moorthy N C,Prives C.Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo[J].EMBO J,1999,18(20):5609-5621.
[8]Hanson S,Kim E,Deppert W.Redox factor 1(Ref-1) ehancesspecific DNA binding of p53 by promoting p53 tetramerization[J].Oncogene,2005,24(9):1641-1647.
[9]Guan Z,Basi D,Li Q,et al.Loss of redox factor 1 decreases NF-kappaB activity and increases susceptibility of endothelial cells to apoptosis. Arterioscler [J].Arterioscler Thromb Vase Biol,2005,25(1):96-101.
[10]Ziel K A,Campbell C C,Wilson G L,et al. Ref-1/Ape is critical for formation of the hypoxia-inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene[J].FASEB J,2004,18(9):986-988.
[11]Kawase M, Fujimura M,Morita, Fujimura Y,et al.Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats:implication of the failure of DNA repair in neuronal apoptosis[J].Stroke,1999,30:441-449.
[12]Walton M,Lawlor P,Sirimanne E,et al.Loss of Ref21 protein expression precedes DNA fragmentation in apoptotic neurons[J]. Brain Res Mol Brain Res,1997,44:167-170.
[13]Robertson KA, Hill DP,Xu Y,et al.Down2regulation of apurinic/apyrimidinic endonuclease expresion is associated with the induction of apoptosis in differentiating myeloid leukemia cells[J].Cell Growth Differ,1997,8:443-449.
[14]Chan PH,Kawase M,Murakami K,et al.Overexpression of SOD! in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion[J].J Neurosci,1998,18:82-92.
[15]Puglisi F,Barbone F,Tell G,et al.Prognostic role of Ape/Ref-1 subcellular expression in stage Ⅰ-Ⅲ breast carcinomas[J].Oncol Rep,2002,9(l):11-17.
[16]Ding S Z,O'Hara A M,Denning T L,et al.Helicobacter pylori and H2O2increase AP endonuclease-1/redox factor-1 expression in human gastric epithelial cells[J]. Gastroenterology,2004,127(3):845-858.
[17]Tell G,Pellizzari L,Pucillo C,et al.TSH controls Rcf-1 nucleartranslation in thyroid cells[J]. J Mol Endocrinol,2000,24(3):383-390.
[18]Walker L J,Robson C N,Black E,et al.Identification of residues in the human DNA. repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding[J].Mol Cell Biol,1993,13(9):5370-5376.
[19]Khomenko T,Deng X,Jadus M R,et al.Effect of cysteamine on redox-sensitive thiol-containing proteins in the duodenal mucosa. Biochem Biophys Res Commun[J],2003,309(4):910-916.
[20]Raffoul J J,Cabelof D C,Nakamura J,et al.Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair[J].J Biol Chem,2004,279(18):18425-18433.
[21]Puglisi F, Aprile G, Minisini AM, et al.Prognostic significance of Apel/ref-1 subcellular localization in non-small cell lung carcinomas. Anticancer Res,2001, 21(6A):4041-4049.
[22]Ouellet V, Le Page C, Guyot MC, et al.SET complex in serous epithelial ovarian cancer[J].Int J Cancer,2006,119(9):2119-2126.
[23]Zienolddiny S, Campa D, Lind H, et al.Polymorphisms of DNA repair genes and risk of non-small cell lung cancer[J].Carcinogenesis,2006,27(3):560-567.
[24]Tell G, Damante G, Caldwell D, et al.The intracellular localization of APE1/Ref-1:more than a passive phenomenon?[J].Antioxid Redox Signal, 2005,7(3-4):367-384.
[25]Kakolyris S,Kaklamanis L,Engels K,et al.Human apurinic endonuclease 1 expression in a colorectal adenoma-carcinoma sequence[J].Cancer Res,1997,57(9):1794-1797.
[26]Sak SC, Harnden P, Johnston CF, et al.APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer[J].Clin Cancer Res,2005,11 (17):6205-6211.
[27]Bobola MS, Finn LS, Ellenbogen RG, et al.Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors[J].Clin Cancer Res,2005,11(20):7405-7414.
[28]Robertson KA, Bullock HA, Xu Y, et al.Altered expression of Apel/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation[J].Cancer Res,2001,61(5):2220-2225.
[29]Silber JR, Bobola MS, Blank A, et al.The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress[J].Clin Cancer Res,2002,8(9):3008-3018.
[30]Luo M, Kelley MR.Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone[J].Anticancer Res,2004,24(4):2127-2134.
[31]Chang-Claude J, Popanda O, Tan XL, et al. Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in the breast cancer patients[J].Clin Cancer Res,2005, 11(13):4802-4809.
[32]Wang D, Luo M, Kelley MR.Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE 1 expression inhibition[J].Mol Cancer Ther,2004,3(6):679-686.
[33]王东,仲召阳,李增鹏APE1 siRNA表达载体的构建及其对骨肉瘤细胞APE1的表达抑制作用[J].第三军医大学学报,2006,28(2)：97-100.
[34]Wang D, Zhong ZY, Li MX, et al.Vector-based Apel small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo[J].Cancer Sci,2007,98(12):1993-2001.
[35]Lau J P,Weatherdon K L,Skalski V,et al. Effects of gemcit-abine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides[J].Br Jancer,2004,91(6):1166-1173.
[36]Moore D H,Michael H,Tritt R,et al.Alterations in the expression of the DNA repair/redox enzyme APE/ref-1 in epithelial ovarian cancers[J].Clin Cancer Res,2000,6(2):602-609.
[37]Tanner B,Grimme S,Schiffer I,et al.Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas[J].Gynccol Oncol,2004,92(2):568-577.
[38]Freitas S,Moore D H,Michael H, et al.Studies of apurinic/apyrimidinic endonuclease/ref-1 expression in epithelial ovarian cancer:correlations with tumor progression and platinum resistance[J].Clin Cancer Res,2003,9(13):4689-4694.
[39]吕嘉春,何敏,廖永德,等.氧化/还原因子ref-1在肺癌组织中的细胞定位表达与8-OH-dG的关系[J].肿瘤,2004,24(1)：35-37.
[40]Koukourakis M I,Giatromanolaki A, Kakolyris S,et al.Nuclear expression of human apurinic/apyrimidinic endonuclease (APE1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome[J].Int J Radiat Oncol Biol Phys,2001,50(1):27-36.
[41]WangD,Meihua L,Mark K R.Human apurinic endonuclease 1(APE1) exp ressiong and p rognostic significance in osteosarcoma:enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 exp ression inhibition[J].MolCancer Ther,2004,3 (6):679-686.
[42]Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor exp ression at the deepest invasive site of advanced colorectal carcinoma[J].Oncology,2003,64(1):61-73.
[43]Luo M,Delaplane S,Jiang A,et al.Role of the multifunctional DNA repair and redox signaling protein Ape1/Ref-1 in cancer and endothelial cells:small-molecule inhibition of the redox function of Ape1[J].Antioxid Redox Signal,2008,10(11):1853-1867.
[44]Zou GM,Karikari C,Kab Y,et al.The Apel/Ref-1 redox antagonist E3330 inhibits the growth of tumor endothelium and endothelial progenitor cells:therapeutic implications in tumor angiogenesis[J].J Cell Physiol,2009,219(1):209-218.