食管鳞癌组织中c-fos，c-jun及PCNA的表达及临床病理意义
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摘要
目的：食管癌是我国最常见的恶性肿瘤之一,在我国食管癌的死亡率居恶性肿瘤的第四位,通过长期细胞学、内窥镜活检及手术切除标本等资料研究证实,人食管粘膜上皮的癌变是一个长期的、多阶段与进行性发展的过程。食管癌的癌变机制与细胞的增殖、分化、凋亡调控失常密切相关,多种癌基因及肿瘤抑制基因参与了其发生发展的过程。有促进作用。目前,原癌基因的生理功能愈来愈引起重视,c-fos和c-jun是编码核蛋白的癌基因,属于立早基因的成员,此类基因受到多种刺激后立即表达,产生转录因子,调控其他基因的转录及表达,调节正常细胞的生长、发育和分化,并且与肿瘤分级、临床分期及浸润转移有关。国内外的研究亦表明PCNA已成为恶性肿瘤增殖期细胞的有效标志物,在肝、胃、乳腺和大肠等肿瘤研究中发现,PCNA的表达与肿瘤分级、临床分期及浸润转移有关。本研究检测原癌基因c-fos, c-jun和PCNA在原发性食管鳞状细胞癌的表达情况,探讨其临床病理学意义及两者与食管鳞状细胞癌的发生发展的关系。方法：选取2004年1月-2007年1月于新疆医科大学附属第二附属医院病理科经手术切除及活检存档的蜡块,其中采用免疫组化染色SP法,检测60例食管鳞状细胞癌、20例重度上皮内瘤变和10例正常食管粘膜组织标本中c-fos,c-jun和PCNA的表达。结果：(1)60例食管癌组织,20例重度上皮内瘤变和10例正常食管粘膜组织标本中c-fos的阳性表达率分别为56%(51/60),75%(15/20)和0,差异有统计学意义(P<0.05),c-jun的阳性表达率分别为38%(23/60),55%(11/20)和10%(1/10),差异有统计学意义(P<0.05),而PCNA的阳性表达率分别为70%(42/60),50%(10/20)和10%(1/10),差异有统计学意义(P<0.05)。(2)c-fos和c-jun在高分化食管癌中的表达率显著高于中、低分化癌(P<0.01)；无淋巴结转移者表达率高于有淋巴结转移者,临床分期Ⅰ-Ⅱ表达率高于Ⅲ-Ⅳ期(P<0.05)。而PCNA的表达相反。(3)在食管鳞状细胞癌中,c-fos与c-jun的蛋白表达情况的Spearman等级相关系数为0.399,具有统计学差异(P<0.05)。(4)c-fos, c-jun和PCNA术前活检组织和术后病理组织表达无统计学差异(P>0.05)。结论：c-fos, c-jun和PCNA的过表达可能均参与了食管鳞状细胞癌的发生发展过程,并可能作为监测肿瘤恶性程度和诊断的指标。
Objective:Esophageal carcinoma is a kind of common maglignant tumor in china.It was the fourth in the death rate of malignant tumor in our country.Themost.The research has shown tha the carcerrization of epidermis of mueous membrane of People's esophagus is along-temr, multistage and progressing process of development. the cancerization mechanism of esophageal carcinoma is closely related to the proliferation, differentiation and disorder of decease and regulation & control of cells.Many kinds of cancer genes and tumor cheeking genes take part in the occurrence & development of it. The hysiology function of proto oncogene causing various,incitement and more c-fos and c-jun are the cancer genes which code to check nuclear protein.belong to the early gene this kind of gens is subjected to immediately express by various incitement and produce to transcript factor.This kind of gene adjust to contro ltranseription and expresstion of other geneses and regulate the growth, development and division of normal cell. And have shown that the expressions of c-fos and c-jun are related to the classification of tumrors, clinical stages and the soakage & metasastis.The research of both home and abroad has also shown thatpoliferating cell nuclear natigen(PCNA) is an effectiven symbol of the malingantTumor cells in the period of proliferation.The studies of livesr, stomach, galactophore and intestinum crassmu have shown that the expressions of PCNA are related to the classification of tumrors, clinical stages and the soakage & metasastis.To investigate the expression of c-fos,c-jun and PCNA inprimar esophageal squamous cellcarcinoma and to evaluate whether these Alterations could provide clinical significant informations. Methods:Select wax lumps were cutted off by 2004 at the xinjiang medieinedepartment University the second affiliated Hospital,The expression of c-fos, c-jun and PCNA was studied by StrePtavidin Peroxidase(SP) immunohisto chemical methodwas used to detect the expressions of c-fos,c-jun and PCNA and to analyse the correlation between them and different clinical pathological features in 60 cases of esophageal squamous cell carcinoma, in 20 cases of abnormal and in 10 cases of normal esophageal tissues.Results:(1) The positive frequency of c-fos in 60 cases of esophageal squamous cell carcinoma, in 20 cases of abnormal and in 10 cases of normal esophageal tissues was respectively 56%(51/60),75%(15/20)and 0, The group had significant difference (P<0.05). The positive frequency of c-jun was respectively 38%(23/60),55 %(11/20)和10%(1/10),The group had significant difference (P<0.05).But the positive frequency of PCNA was respectively 70%(42/60),50%(10/20) and 10%(1/10) The group had significant difference (P<0.05).(2) The positive ratio of c-fos, c-jun and PCNA proteinwas significantly higher in thewell differentiated and moderately differentiated esophageal carcinomas than in the poorly differentiated esophageal carcinomas(P<0.05). The esophageal carcinomas with lymph node metastasis expressed c-fos, c-jun and PCNA protein more markedly than those without lymphnode metastasis(P<0.05). (3) In carcinoma samples, the expression of c-fos protein was Positively correlated with that of c-jun(spearman rho 0.399, P<0.05). (4) the expression of c-fos,c-jun and PCNA at the preoperative biopsy and afteroperative pathology tissue were no significant relationship with either clinical stage (P>0.05).Conclusions:The overexpression of c-fos, c-jun and PCNA could serve as an important index in the aspect of invasiveness and metastasis in esophageal squamous cell carcinoma,and might be used as valuable molecular markers for the tumor progression and diagnose.
Objective:Esophageal carcinoma is a kind of common maglignant tumor in china.It was the fourth in the death rate of malignant tumor in our country.Themost.The research has shown tha the carcerrization of epidermis of mueous membrane of People's esophagus is along-temr, multistage and progressing process of development. the cancerization mechanism of esophageal carcinoma is closely related to the proliferation, differentiation and disorder of decease and regulation & control of cells.Many kinds of cancer genes and tumor cheeking genes take part in the occurrence & development of it. The hysiology function of proto oncogene causing various,incitement and more c-fos and c-jun are the cancer genes which code to check nuclear protein.belong to the early gene this kind of gens is subjected to immediately express by various incitement and produce to transcript factor.This kind of gene adjust to contro ltranseription and expresstion of other geneses and regulate the growth, development and division of normal cell. And have shown that the expressions of c-fos and c-jun are related to the classification of tumrors, clinical stages and the soakage & metasastis.The research of both home and abroad has also shown thatpoliferating cell nuclear natigen(PCNA) is an effectiven symbol of the malingantTumor cells in the period of proliferation.The studies of livesr, stomach, galactophore and intestinum crassmu have shown that the expressions of PCNA are related to the classification of tumrors, clinical stages and the soakage & metasastis.To investigate the expression of c-fos,c-jun and PCNA inprimar esophageal squamous cellcarcinoma and to evaluate whether these Alterations could provide clinical significant informations. Methods:Select wax lumps were cutted off by 2004 at the xinjiang medieinedepartment University the second affiliated Hospital,The expression of c-fos, c-jun and PCNA was studied by StrePtavidin Peroxidase(SP) immunohisto chemical methodwas used to detect the expressions of c-fos,c-jun and PCNA and to analyse the correlation between them and different clinical pathological features in 60 cases of esophageal squamous cell carcinoma, in 20 cases of abnormal and in 10 cases of normal esophageal tissues.Results:(1) The positive frequency of c-fos in 60 cases of esophageal squamous cell carcinoma, in 20 cases of abnormal and in 10 cases of normal esophageal tissues was respectively 56%(51/60),75%(15/20)and 0, The group had significant difference (P<0.05). The positive frequency of c-jun was respectively 38%(23/60),55 %(11/20)和10%(1/10),The group had significant difference (P<0.05).But the positive frequency of PCNA was respectively 70%(42/60),50%(10/20) and 10%(1/10) The group had significant difference (P<0.05).(2) The positive ratio of c-fos, c-jun and PCNA proteinwas significantly higher in thewell differentiated and moderately differentiated esophageal carcinomas than in the poorly differentiated esophageal carcinomas(P<0.05). The esophageal carcinomas with lymph node metastasis expressed c-fos, c-jun and PCNA protein more markedly than those without lymphnode metastasis(P<0.05). (3) In carcinoma samples, the expression of c-fos protein was Positively correlated with that of c-jun(spearman rho 0.399, P<0.05). (4) the expression of c-fos,c-jun and PCNA at the preoperative biopsy and afteroperative pathology tissue were no significant relationship with either clinical stage (P>0.05).Conclusions:The overexpression of c-fos, c-jun and PCNA could serve as an important index in the aspect of invasiveness and metastasis in esophageal squamous cell carcinoma,and might be used as valuable molecular markers for the tumor progression and diagnose.
引文
[1]张曙光等转录因子c-jun在食道癌中的表达及其与临床病理的关系[J]现代肿瘤医学2007,15,1089-1092
[2]Coia LR, Sauter ER.Esophageal cnaee[J] Curr Probl Cancer,1994,18(4):189-247
[3]Blot WJ, Devesa SS, Kneller RW, et al.Rising incidence of adenocarcinoma of the Esophagus and gastric cardia. [J] JAMA,1991,265(10):1287-1259
[4]Karakosta A, Golias Ch, CharalaboPoulos A, et al.Genetic models of human Cancer as a multistep proeess.Paradign models of coloreetal caneer, breast caneer, and chronic myelogenous and acute lymphoblastic leukaemia. [J] ExP Clin Cancer Res.2005, 24(4):505-14.
[5]Wittmann T,Wilm M,Karsenti E,et al.TPX2,a novel xenopus MAP in volved in spindle pole organization[J].J Cell Biol,2000,149:1405-1418.
[6]Hussain S, killbeyA, Gillespie DA.Vjun represses c-jun Protooneogene expression in vivo Through atetradecanoylphoro acethate responsive element in the Promoter. [J]Cell Growth Diffe,1998,9:677-686.
[7]Joehum W, David J P, Elliott C, et al Inereased formation and osteoselerosis in mice Overepressing the transcription factor Fra [J].NatMed,2000,6(9):950-984.
[8]Lake Bakaer G, Mazzoeeoli V, Ruffini L.Digital Imag analysis of the distribution of Proliferating cell nuelear antigen in hepatitis C virusrelated chronic hepatitis, cirrhosis, and hepatocellal carcinoma [J].Dig Dis Sci,2002,47:1644-1648.
[9]赖启明,石一复.子宫平滑肌肿瘤细胞增殖活性的研究[J]中华肿瘤杂志,2001,23：485-486.
[10]吴文新,张祥宏,严霞,等.大肠腺瘤癌变过程中p-catenin、p53和增殖细胞抗原表达的研究[J]中华肿瘤杂志,2002,24：264-267.
[11]许庆中,李岩松,朱荷根.大肠癌p53蛋白、PCNA和CEA的表达与淋巴结转移关系[J).华人消化杂志,1998,6(3)：244-246.
[12]ainS,Filipe MI,Hall PA,et,al. Application of proliferating cell Nuclear antigen(PCNA) immunostain in gastric carcinoma [J].Pathol,1990,161 (4):3511
[13]OkunoY, Nismhura Y, Kashu 1, et al.Prognostic values of proliferating cell nuelear Antigen (PCNA) and Ki-67 forradiotherapy of oesophaggeal squmaous cell careinoma. [J] Cancer,1999,80(2):387-395
[14]张丽珍,程炳权,杨伟志.PCNA及mn23的表达与食管鳞状细胞癌放射敏感性及预后的相关性研究[J]中华放射肿瘤学杂志,2001,10(4)：239-242
[15]Aoatomaa S, LipponenP,Syrjanen K.Prognostic Value of cell Proliferatino in berast Cnacer as determined by porliefration cell nulear antigen(PCNA) immonostaing. [J]Anticnacer Res.1992; 12(9):1281
[16]IshidaT,Knaeko S, Akazawa K et al.Proliefration cell nuelear antigen expression and argyroPhilic nucleoar organizer region as fectors influencing Prognosis of sugrieally treated lung cancer Pations [J]Caneer Res,1993:53(20):5000-5003
[17]Sonini Y Virkajarvi N, Lehto VP, et al.Hepatoeellular careinomas with a high Proliferation index and a low degree of a poptosis and necrosi are assoeiated with a Shortened survival.[J] Cancer,1996,73(9):1025-1030
[18]Maeda T,Chung Y,Onoda N,etal.Proliefration cell nuelear antigen antigen labelingInde of preoperative biopsy speeimens in gastric careinoma with speeial reference to Prognosis [J] Cancer,1994,73(3):525-533
[19]Mnagham DC, Rowlands DC.Expression of proliefarting cell nuelear antigen(PCNA) In gastric carcinoma:no edivence for prognostic value. [J] Clin pathol,1994, 47(s):437-510
[20]Stemley R.Hamilton Laur A.Pathology and Genetics of Tumours of the Digestive System [M] Lyon 2000:3-4
[21]HaoXP, Pretlow TG, Rao JS,et al. Beta-catenin expression is altered in human colonic aberrant crypt foci [J]. Cancer Res,2001,61:8085-8088.
[22]Passegue E, Wagner EF.JunB suppresses cell Proliferation by transeriptional activation of p16 expression. EMBOJ,2000,19:2969-2979.
[23]冀群升章静波c-fos原癌基因的研究进展[J]国外医学分子生物学分册1994(15)4：152-156
[24]Suhardja A, Kovacs K, Rutka J.Role of transcription factors in the pathogenesis Of pitultary adenomas:a review [J]Neurooncol,2001Dec:55(3):185-193.
[25]Dunn C, W iltshire C, MacLaren A,et al. Molecularmechanism and biological functions of c-Jun N-terminal kinase signaling via the c-Jun transcription factor [J]. CellSigna,l 2002,14:585-593.
[26]VogtPK. Jun, the oncoprotein [J]. Oncogene,2001,20:2365-2677.
[27]VogtPK. Jun, the oncoprotein[J]. Oncogene,2001,20:2365-2677.
[28]Mechta-Grigoriou F, Gerald D, YanivM. The mammalian Jun proteins:redundancy and specificity[J]. Oncogene,2001,20:2378-2389.
[29]Szabo E, RiffeME, Steinberg SM,et al. Altered cJUN expression:an early event in human lung carcinogenesis[J]. Cancer Res,1996,56:305-315.
[30]YamanishiK, Inazawa J, Liew FM,etal. Structure of the gene for human transglutaminase [J]. BiolChem,1992,267:17858-17863.
[31]OyaM, MikamiS, MizunoR,etal. C-jun activation in acquire cystic kidney disease and renal cell carcinoma[J]. Jurol 2005,174:726.
[32]Han H J,Yoon B C, Lee, S H,et al.Ginsenosides inhibit EGF.induced proliferation of renal proximal tubule cells via decrease of c-fos and c-jun gene expression in vitro[J]Planta-Med.2002,68(11):971-914
[33]张式暖等食管癌中癌基因产物c-fos,c-jun的表达及意义[J]潍坊医学院学报,2007,29(2)：143-144
[34]李海,李维鑫,颜鸣等C-fos和C-jun蛋白在鳞状细胞皮损中的表达及意义[J]现代实用医学,2004,16(9)：527-528.
[35]刘萍等瘤发生发展过程中AP-1活化的研究[J]南京医科大学学报,2004,24(1)：28-29.
[36]李为民等肺癌与转录因子c-jun, c-fos, AP-1 [J]国外医学临床生物学与检验学分册 1999(20)5：217-219
[37]Kurkip,Ogata K,Tan E.M Tan E.M.Monoclonal antibies to proliferating cell nuclear antigen(PCNA)/cyclin as probes for proliferating cells by immuno -fluorence microscopy and flow cytometry [J]Immunol-Metheds,1988,109(1):49.
[38]HallP.A,Levison DA,Woods AL,et al. Proliferating cell nuclear antigen in paraffin section:an index of cell proliferation with evidence of deregulated expression in some neoplasms [J] Pathol,1990,162:285.
[39]蔡家新,童坦君.细胞周期蛋白[J]生理科学进展,1994,25(4)351.
[40]Baserga R. Growth regulation of the PCNA gene [J] cell Sci 1991,98:433.
[41]郑春鹏,傅俊惠,刘敦序,等.食管癌nm23基因和PCNA的表达及其意义[J]中国实用外科杂志,2003,23(5)：279.
[42]陶仪声.食管鳞状细胞癌增殖细胞核抗原表达178例分析[J]蚌埠医学院学报,1997,22(3)：141.
[43]Hall PA,Levison DA,Woods AL,et al.Proliferating cellnuclear antigen (PCNA) immunolocalization in paraffin sections.An index of cell proliferation withevidence of deregulated expression in some neoplasms [J] Path,1990,162(3):185
[44]Edwards J, Krishna NS, Mukherjee et al.The role of c-Jun and c-fos expression in androgen-independent prostate cancer.[J]Pathol.2004Oet:204(2):153-8.
[1]张曙光等转录因子c-jun在食道癌中的表达及其与临床病理的关系[J]现代肿瘤医学2007,15,1089-1092
[2]杨海军等内窥镜诊断或可疑早期食管癌265例活检病理分析[J]肿瘤研究与临床2007,19：705-706。
[3]蔡英敏,王美钠,马小亚.镇静剂量异丙酚对大鼠脑缺血再灌注损伤保护作用的形态学研究[J]西安医科大学学报,2001,22：3
[4]Eriksson O, Pollesello P, Saris NEI. Inhibition of Lipidperoxidation in isolated rat Liver mitoehondria by the general anaesthetic propofo [J] Biochum Phammeol,1992, 44:391
[5]Morgan JI,Currml T. Stimulus transcription coupling in the nervous system involv-ement of the inducible protooneogenelos and jun. [J] Rev Neurosci 1991,14:421
[6]Janknecht R. Regulation of the c-fospromoter [J] Immunobiology,1995,1R 193: 137
[7]Sheng M. Greenberg ME. The regulation and function of c-fos other immediate early genes in the nervous system [J] Neuron,1990,4:447
[8]王晓明,韩济生原癌基因与核内第三信使.神经科学纲要[M]北京医科大学,中国协和医科大学联合出版社,1993,273
[9]09 Foregin Medical Science of Pathophysiology and Clinical Foregin Medical Science of Pathophysiology and Clinical Medicine [J] Medicine,1998,18:358-361
[10]韩济生.神经科学纲要[M]北京医科大学,中国协和医科大学联合出版社,1993,535-552
[11]Morgan JI, Curran T, lnmaediate early gone:ten year on [J]Trends Non-rosei,1995, 18:66
[12]Bohmann D, Bos TJ, Admon A.et al.Human Proto-oneogene c-jun eneodes a DNA binding Protein with struetural and functional ProPerties of transcription factor AP-1.CA94720 [J] Seienee,1987,238(4832):1386-1392.
[13]Kazue H, Peter A, Michelle M.Le B.e tal.Strueture and chromosomal Loealization of the funetional intronless human JUN Protooneogene, Proc.Nati.Aead [J] Sci, USA 1988,85:9148-9152.
[14]LiuY, Lu C, Shen Q, et al.AP-1 blockade in breast cancer cells Causes cell cycle arrest by suppressing G1:cyclin expression and Redueing cyclin-dependent kinase aetivity[J]oncogene.2004,23(50):8238-8246.
[15]Vleugel M.Greijer A.Bos R.et al. c-jun aetivation is assoeiated With Proliferation and angiogenesis ininvasive breast caneer [J]Human Pathology,37(6):668-674.
[16]olm M, Kaick G v, Mattern J.Analysis of c-fos, c-jun, c-erbBI, c-erbB2 and c-myc in Primary lung carcinomas and their lymph node metastases [J] Clin.ExP Metastasis, 1994,12:329-334.
[17]Yamit Hezi A, Plaksin D, Eisenbaeh L.fos and c-jun Overexpression in malignant cells reduces their tumorigeniec and Metastatic Potential, and affeets their MHC class I gene expression [J] Oneogene.1994,9(4):1065-1079.
[18]张式暖,王亚利,戚文明,等.子宫颈癌中癌基因产物C-fos、c-jun的表达及意义[J]解剖学杂志2001,24(6)：552-553.
[19]余东海,周四维,章慧平,等.CK20及c-jun在膀胱肿瘤的表达和临床意义[J]临床泌尿外科杂志,2005,20(5)：288-290.
[20]王志强,黄杰,林慧庆,等.癌基因。C-fos和。C-jun与非小细胞肺癌临病理特征的相关性研究[J]肿瘤防治研究,2004,31(5)：284-285.
[21]Wu MY, Zhuang CX, Yang HX, et al.ExPression of Egr-1, C-fos and cyclin D1 in esophageal cancer and its precursors:An imtnunohistochemical and in situ hybridization study [J] World J Gastroenterol,2004,10:476-480
[22]Wu Ming yao, Wu Xianying, Shen jian Expression of c-fos, c-jun oncogen
Produets in esophageal careinoma [J] Clin Exp pathol 1998:14(2)125-127
[23]Kelman.z.PCNA:structure,funetions and interaetions [J] Oneogene.1997 Febl3: 14(6):629-40.
[24]Baserga R.Growth regulation of the PCNA gene [J] CellSei.1991:98 (4):433-436.
[25]Prelich G, Kostura M, Marshak DR, et al.The cell-cycle regulated Prolifcrating cell nuclea rantigen is required for SV40 DNA replieation invitro[J] Nature 1987 2-8:326(6112):471
[26]Kelman Z, Hurwitz J.Protein-PCNA interaetions:aDNA scnning mechanism Trends [J] Bioehem Sei.1998;23(7):236-8.
[27]Xu J, Morris GF.P53 mediate dregulation of Proli ferating cell nuelear Antigen expression in cells exposed toionizing radiation [J] MolCellBiol.1999:19(1):12-20
[28]Cayrol C, Knibiehler M, Dueonunun B.PZI binding to PCNA causes G1 and G2 cell cycl carrestin P53-defieient cells.oneogene.1998 22:16(3):311-20.
[29]ains, FiliPe Ml, Hall PA, et al.APPlieation of Proliferating cell nuclea rantigen (PCNA) immunostain in gastrie careinoma[J].J Pathol,1990,161(4):3511
[30]Lake Z Bakaar G, Mazzoeeoli V, RuffiniL.Digital imageanalysis of the distribution of Proliferating cell nuelear antigeninhe Patitis Cvirus- related chronie hepatitis, cirrhosis, and hePatic cell ularcarei nomal[J] DigDisSei,2002,47:1644-1648.
[31]李鸣,于茂生,靳凤烁,等.联合应用C-karas, C-myC反义寡聚脱氧核普酸对膀胱癌细胞生长增长的抑制作用[J].中华外科杂志,1996,34(1)：7-9.
[32]许庆中,李岩松,朱荷根.大肠癌p53蛋白、PCNA和CEA的表达与淋巴结转移的关系[J]华人消化杂志,1998,6(3)：244-246.
[33]王顺文,高青,王王龙环氧化酶-2的表达与食管癌细胞增殖和凋亡的关系[J]. 重庆医科大学学报,2004,29(5)：597-600.
[34]谷化平,尚培中,刘艳茹CD44V6和PCNA在食管癌中的表达及相关性研究[J].肿瘤防治杂志,2003,10(2)：140-142.
[35]陶仪声,承泽农,武世伍等.食管癌旁上皮p53及增殖细胞核抗原的表达[J].蚌埠医学院学报,2003,27(3)：189-191.
[36]Mori M, Mimori K, Sadanaga N, et al.PolyPoideareinoma of the esophagus [J].JpnJCaneerRes,1994;85:1131-1136.
[37]Morisaki Y, Shima S, Yoshizumi Y, et al.PCNA inununo staining combined With AgNOR stainingineso Phageals quamous eell eareinomatoidentify patients with apoorprognosis[J].SurgToday,1995:25:389-395.
[38]赵志毅,张明,涂响安等.细胞凋亡、增殖、DNA倍体和相关基因Fas、bax和bcl-2在食管癌中的表达和临床意义[J].中国肿瘤临床与康复,2001,8(5)：6-9.
[39]胡庆军,周力,车筑平增殖细胞核抗原在食管癌中的表达及其临床意义[J]贵阳医学院学报,2001,26(4)：292-293.
[2]Coia LR, Sauter ER.Esophageal cnaee[J] Curr Probl Cancer,1994,18(4):189-247
[3]Blot WJ, Devesa SS, Kneller RW, et al.Rising incidence of adenocarcinoma of the Esophagus and gastric cardia. [J] JAMA,1991,265(10):1287-1259
[4]Karakosta A, Golias Ch, CharalaboPoulos A, et al.Genetic models of human Cancer as a multistep proeess.Paradign models of coloreetal caneer, breast caneer, and chronic myelogenous and acute lymphoblastic leukaemia. [J] ExP Clin Cancer Res.2005, 24(4):505-14.
[5]Wittmann T,Wilm M,Karsenti E,et al.TPX2,a novel xenopus MAP in volved in spindle pole organization[J].J Cell Biol,2000,149:1405-1418.
[6]Hussain S, killbeyA, Gillespie DA.Vjun represses c-jun Protooneogene expression in vivo Through atetradecanoylphoro acethate responsive element in the Promoter. [J]Cell Growth Diffe,1998,9:677-686.
[7]Joehum W, David J P, Elliott C, et al Inereased formation and osteoselerosis in mice Overepressing the transcription factor Fra [J].NatMed,2000,6(9):950-984.
[8]Lake Bakaer G, Mazzoeeoli V, Ruffini L.Digital Imag analysis of the distribution of Proliferating cell nuelear antigen in hepatitis C virusrelated chronic hepatitis, cirrhosis, and hepatocellal carcinoma [J].Dig Dis Sci,2002,47:1644-1648.
[9]赖启明,石一复.子宫平滑肌肿瘤细胞增殖活性的研究[J]中华肿瘤杂志,2001,23：485-486.
[10]吴文新,张祥宏,严霞,等.大肠腺瘤癌变过程中p-catenin、p53和增殖细胞抗原表达的研究[J]中华肿瘤杂志,2002,24：264-267.
[11]许庆中,李岩松,朱荷根.大肠癌p53蛋白、PCNA和CEA的表达与淋巴结转移关系[J).华人消化杂志,1998,6(3)：244-246.
[12]ainS,Filipe MI,Hall PA,et,al. Application of proliferating cell Nuclear antigen(PCNA) immunostain in gastric carcinoma [J].Pathol,1990,161 (4):3511
[13]OkunoY, Nismhura Y, Kashu 1, et al.Prognostic values of proliferating cell nuelear Antigen (PCNA) and Ki-67 forradiotherapy of oesophaggeal squmaous cell careinoma. [J] Cancer,1999,80(2):387-395
[14]张丽珍,程炳权,杨伟志.PCNA及mn23的表达与食管鳞状细胞癌放射敏感性及预后的相关性研究[J]中华放射肿瘤学杂志,2001,10(4)：239-242
[15]Aoatomaa S, LipponenP,Syrjanen K.Prognostic Value of cell Proliferatino in berast Cnacer as determined by porliefration cell nulear antigen(PCNA) immonostaing. [J]Anticnacer Res.1992; 12(9):1281
[16]IshidaT,Knaeko S, Akazawa K et al.Proliefration cell nuelear antigen expression and argyroPhilic nucleoar organizer region as fectors influencing Prognosis of sugrieally treated lung cancer Pations [J]Caneer Res,1993:53(20):5000-5003
[17]Sonini Y Virkajarvi N, Lehto VP, et al.Hepatoeellular careinomas with a high Proliferation index and a low degree of a poptosis and necrosi are assoeiated with a Shortened survival.[J] Cancer,1996,73(9):1025-1030
[18]Maeda T,Chung Y,Onoda N,etal.Proliefration cell nuelear antigen antigen labelingInde of preoperative biopsy speeimens in gastric careinoma with speeial reference to Prognosis [J] Cancer,1994,73(3):525-533
[19]Mnagham DC, Rowlands DC.Expression of proliefarting cell nuelear antigen(PCNA) In gastric carcinoma:no edivence for prognostic value. [J] Clin pathol,1994, 47(s):437-510
[20]Stemley R.Hamilton Laur A.Pathology and Genetics of Tumours of the Digestive System [M] Lyon 2000:3-4
[21]HaoXP, Pretlow TG, Rao JS,et al. Beta-catenin expression is altered in human colonic aberrant crypt foci [J]. Cancer Res,2001,61:8085-8088.
[22]Passegue E, Wagner EF.JunB suppresses cell Proliferation by transeriptional activation of p16 expression. EMBOJ,2000,19:2969-2979.
[23]冀群升章静波c-fos原癌基因的研究进展[J]国外医学分子生物学分册1994(15)4：152-156
[24]Suhardja A, Kovacs K, Rutka J.Role of transcription factors in the pathogenesis Of pitultary adenomas:a review [J]Neurooncol,2001Dec:55(3):185-193.
[25]Dunn C, W iltshire C, MacLaren A,et al. Molecularmechanism and biological functions of c-Jun N-terminal kinase signaling via the c-Jun transcription factor [J]. CellSigna,l 2002,14:585-593.
[26]VogtPK. Jun, the oncoprotein [J]. Oncogene,2001,20:2365-2677.
[27]VogtPK. Jun, the oncoprotein[J]. Oncogene,2001,20:2365-2677.
[28]Mechta-Grigoriou F, Gerald D, YanivM. The mammalian Jun proteins:redundancy and specificity[J]. Oncogene,2001,20:2378-2389.
[29]Szabo E, RiffeME, Steinberg SM,et al. Altered cJUN expression:an early event in human lung carcinogenesis[J]. Cancer Res,1996,56:305-315.
[30]YamanishiK, Inazawa J, Liew FM,etal. Structure of the gene for human transglutaminase [J]. BiolChem,1992,267:17858-17863.
[31]OyaM, MikamiS, MizunoR,etal. C-jun activation in acquire cystic kidney disease and renal cell carcinoma[J]. Jurol 2005,174:726.
[32]Han H J,Yoon B C, Lee, S H,et al.Ginsenosides inhibit EGF.induced proliferation of renal proximal tubule cells via decrease of c-fos and c-jun gene expression in vitro[J]Planta-Med.2002,68(11):971-914
[33]张式暖等食管癌中癌基因产物c-fos,c-jun的表达及意义[J]潍坊医学院学报,2007,29(2)：143-144
[34]李海,李维鑫,颜鸣等C-fos和C-jun蛋白在鳞状细胞皮损中的表达及意义[J]现代实用医学,2004,16(9)：527-528.
[35]刘萍等瘤发生发展过程中AP-1活化的研究[J]南京医科大学学报,2004,24(1)：28-29.
[36]李为民等肺癌与转录因子c-jun, c-fos, AP-1 [J]国外医学临床生物学与检验学分册 1999(20)5：217-219
[37]Kurkip,Ogata K,Tan E.M Tan E.M.Monoclonal antibies to proliferating cell nuclear antigen(PCNA)/cyclin as probes for proliferating cells by immuno -fluorence microscopy and flow cytometry [J]Immunol-Metheds,1988,109(1):49.
[38]HallP.A,Levison DA,Woods AL,et al. Proliferating cell nuclear antigen in paraffin section:an index of cell proliferation with evidence of deregulated expression in some neoplasms [J] Pathol,1990,162:285.
[39]蔡家新,童坦君.细胞周期蛋白[J]生理科学进展,1994,25(4)351.
[40]Baserga R. Growth regulation of the PCNA gene [J] cell Sci 1991,98:433.
[41]郑春鹏,傅俊惠,刘敦序,等.食管癌nm23基因和PCNA的表达及其意义[J]中国实用外科杂志,2003,23(5)：279.
[42]陶仪声.食管鳞状细胞癌增殖细胞核抗原表达178例分析[J]蚌埠医学院学报,1997,22(3)：141.
[43]Hall PA,Levison DA,Woods AL,et al.Proliferating cellnuclear antigen (PCNA) immunolocalization in paraffin sections.An index of cell proliferation withevidence of deregulated expression in some neoplasms [J] Path,1990,162(3):185
[44]Edwards J, Krishna NS, Mukherjee et al.The role of c-Jun and c-fos expression in androgen-independent prostate cancer.[J]Pathol.2004Oet:204(2):153-8.
[1]张曙光等转录因子c-jun在食道癌中的表达及其与临床病理的关系[J]现代肿瘤医学2007,15,1089-1092
[2]杨海军等内窥镜诊断或可疑早期食管癌265例活检病理分析[J]肿瘤研究与临床2007,19：705-706。
[3]蔡英敏,王美钠,马小亚.镇静剂量异丙酚对大鼠脑缺血再灌注损伤保护作用的形态学研究[J]西安医科大学学报,2001,22：3
[4]Eriksson O, Pollesello P, Saris NEI. Inhibition of Lipidperoxidation in isolated rat Liver mitoehondria by the general anaesthetic propofo [J] Biochum Phammeol,1992, 44:391
[5]Morgan JI,Currml T. Stimulus transcription coupling in the nervous system involv-ement of the inducible protooneogenelos and jun. [J] Rev Neurosci 1991,14:421
[6]Janknecht R. Regulation of the c-fospromoter [J] Immunobiology,1995,1R 193: 137
[7]Sheng M. Greenberg ME. The regulation and function of c-fos other immediate early genes in the nervous system [J] Neuron,1990,4:447
[8]王晓明,韩济生原癌基因与核内第三信使.神经科学纲要[M]北京医科大学,中国协和医科大学联合出版社,1993,273
[9]09 Foregin Medical Science of Pathophysiology and Clinical Foregin Medical Science of Pathophysiology and Clinical Medicine [J] Medicine,1998,18:358-361
[10]韩济生.神经科学纲要[M]北京医科大学,中国协和医科大学联合出版社,1993,535-552
[11]Morgan JI, Curran T, lnmaediate early gone:ten year on [J]Trends Non-rosei,1995, 18:66
[12]Bohmann D, Bos TJ, Admon A.et al.Human Proto-oneogene c-jun eneodes a DNA binding Protein with struetural and functional ProPerties of transcription factor AP-1.CA94720 [J] Seienee,1987,238(4832):1386-1392.
[13]Kazue H, Peter A, Michelle M.Le B.e tal.Strueture and chromosomal Loealization of the funetional intronless human JUN Protooneogene, Proc.Nati.Aead [J] Sci, USA 1988,85:9148-9152.
[14]LiuY, Lu C, Shen Q, et al.AP-1 blockade in breast cancer cells Causes cell cycle arrest by suppressing G1:cyclin expression and Redueing cyclin-dependent kinase aetivity[J]oncogene.2004,23(50):8238-8246.
[15]Vleugel M.Greijer A.Bos R.et al. c-jun aetivation is assoeiated With Proliferation and angiogenesis ininvasive breast caneer [J]Human Pathology,37(6):668-674.
[16]olm M, Kaick G v, Mattern J.Analysis of c-fos, c-jun, c-erbBI, c-erbB2 and c-myc in Primary lung carcinomas and their lymph node metastases [J] Clin.ExP Metastasis, 1994,12:329-334.
[17]Yamit Hezi A, Plaksin D, Eisenbaeh L.fos and c-jun Overexpression in malignant cells reduces their tumorigeniec and Metastatic Potential, and affeets their MHC class I gene expression [J] Oneogene.1994,9(4):1065-1079.
[18]张式暖,王亚利,戚文明,等.子宫颈癌中癌基因产物C-fos、c-jun的表达及意义[J]解剖学杂志2001,24(6)：552-553.
[19]余东海,周四维,章慧平,等.CK20及c-jun在膀胱肿瘤的表达和临床意义[J]临床泌尿外科杂志,2005,20(5)：288-290.
[20]王志强,黄杰,林慧庆,等.癌基因。C-fos和。C-jun与非小细胞肺癌临病理特征的相关性研究[J]肿瘤防治研究,2004,31(5)：284-285.
[21]Wu MY, Zhuang CX, Yang HX, et al.ExPression of Egr-1, C-fos and cyclin D1 in esophageal cancer and its precursors:An imtnunohistochemical and in situ hybridization study [J] World J Gastroenterol,2004,10:476-480
[22]Wu Ming yao, Wu Xianying, Shen jian Expression of c-fos, c-jun oncogen
Produets in esophageal careinoma [J] Clin Exp pathol 1998:14(2)125-127
[23]Kelman.z.PCNA:structure,funetions and interaetions [J] Oneogene.1997 Febl3: 14(6):629-40.
[24]Baserga R.Growth regulation of the PCNA gene [J] CellSei.1991:98 (4):433-436.
[25]Prelich G, Kostura M, Marshak DR, et al.The cell-cycle regulated Prolifcrating cell nuclea rantigen is required for SV40 DNA replieation invitro[J] Nature 1987 2-8:326(6112):471
[26]Kelman Z, Hurwitz J.Protein-PCNA interaetions:aDNA scnning mechanism Trends [J] Bioehem Sei.1998;23(7):236-8.
[27]Xu J, Morris GF.P53 mediate dregulation of Proli ferating cell nuelear Antigen expression in cells exposed toionizing radiation [J] MolCellBiol.1999:19(1):12-20
[28]Cayrol C, Knibiehler M, Dueonunun B.PZI binding to PCNA causes G1 and G2 cell cycl carrestin P53-defieient cells.oneogene.1998 22:16(3):311-20.
[29]ains, FiliPe Ml, Hall PA, et al.APPlieation of Proliferating cell nuclea rantigen (PCNA) immunostain in gastrie careinoma[J].J Pathol,1990,161(4):3511
[30]Lake Z Bakaar G, Mazzoeeoli V, RuffiniL.Digital imageanalysis of the distribution of Proliferating cell nuelear antigeninhe Patitis Cvirus- related chronie hepatitis, cirrhosis, and hePatic cell ularcarei nomal[J] DigDisSei,2002,47:1644-1648.
[31]李鸣,于茂生,靳凤烁,等.联合应用C-karas, C-myC反义寡聚脱氧核普酸对膀胱癌细胞生长增长的抑制作用[J].中华外科杂志,1996,34(1)：7-9.
[32]许庆中,李岩松,朱荷根.大肠癌p53蛋白、PCNA和CEA的表达与淋巴结转移的关系[J]华人消化杂志,1998,6(3)：244-246.
[33]王顺文,高青,王王龙环氧化酶-2的表达与食管癌细胞增殖和凋亡的关系[J]. 重庆医科大学学报,2004,29(5)：597-600.
[34]谷化平,尚培中,刘艳茹CD44V6和PCNA在食管癌中的表达及相关性研究[J].肿瘤防治杂志,2003,10(2)：140-142.
[35]陶仪声,承泽农,武世伍等.食管癌旁上皮p53及增殖细胞核抗原的表达[J].蚌埠医学院学报,2003,27(3)：189-191.
[36]Mori M, Mimori K, Sadanaga N, et al.PolyPoideareinoma of the esophagus [J].JpnJCaneerRes,1994;85:1131-1136.
[37]Morisaki Y, Shima S, Yoshizumi Y, et al.PCNA inununo staining combined With AgNOR stainingineso Phageals quamous eell eareinomatoidentify patients with apoorprognosis[J].SurgToday,1995:25:389-395.
[38]赵志毅,张明,涂响安等.细胞凋亡、增殖、DNA倍体和相关基因Fas、bax和bcl-2在食管癌中的表达和临床意义[J].中国肿瘤临床与康复,2001,8(5)：6-9.
[39]胡庆军,周力,车筑平增殖细胞核抗原在食管癌中的表达及其临床意义[J]贵阳医学院学报,2001,26(4)：292-293.