Beclin1、P53与肺癌恶性度及疗效预后的相关性研究
|
摘要
目的：本文旨在通过定量检测肺组织中Beclinl和P53表达水平,分析自噬蛋白Beclinl与凋亡蛋白P53在肺癌发生发展中的作用,研究二者之间及其与肺癌临床病理分期的关系、为肺癌早期诊断提供新的思路和实验依据。
方法：选取外科手术或纤维支气管镜肺组织56例,依据2003年UICC公布的肺癌TNM分期标准同时结合临床、胸部CT、X线检查、纤维支气管镜检查、胸部CT、腹部CT、或B超等将入选病例进行分组：其中Ⅰ期5例,Ⅱ期10例,Ⅲ期(ⅢA+ⅢB)26例,Ⅳ期9例,各组年龄、性别等控制情况基本匹配。组织病理学分级按2003年UICC标准：G16例,G214例,G319例。并取6例癌旁组织或者病理确诊为正常组织作为对照组织。采用流式细胞术检测和分析不同病理分期以及不同临床分期肺癌组织中Beclin1、P53的表达水平,对该表达情况与对应的分期进行样本均数两两对比式统计学分析,并设立正常肺组织对照组。
结果：
肺癌组织P53蛋白表达百分率：肿瘤患者(63.96±9.43)%显著高于正常对照组(24.90±4.68)%的表达百分率,t＝49.46,p<0.05；肿瘤转移者显著高于未转移者,p<0.05；并且P53蛋白表达随患者临床分期和病理分级的增加而逐渐增高。
Beclin1蛋白检出率的变化规律与P53蛋白检出率的变化相反：肿瘤患者Beclin1蛋白(31.72±20.53)%显著低于正常对照组(92.26±4.51)%的表达百分率,t=35.84,p<0.05；该指标百分表达率随患者临床分期和病理分级的增加而逐渐降低。
Beclin1蛋白与P53蛋白两者相关性分析,Beclin1与P53的蛋白表达率呈负相关,r=-0.848,p<0.05。
结论：Beclin1与P53的检测可以作为肺癌诊断的参考指标,并可提示肺癌的恶性度情况,为肺癌病人的预后估计提供客观理论依据,多源信息的联合检测为肺癌个性化治疗提供了依据。肺癌患者瘤组织细胞Beclin1与P53蛋白表达水平与肺癌临床分子生物学行为的关系密切,同时揭示自噬蛋白与凋亡蛋白在肺癌发生发展中的相互作用,为肿瘤发生的病因学提供实验室依据。
Objective
The paper aims to analyze the roles of autophagy protein Beclin1 and the apoptotic protein P53 in the process of lung cancer by detecting the expression levels of Beclinl and P53 in the lung tissue quantitatively. And the paper researches the relationship between Beclinl and P53 and the pathological stages of lung cancer, in order to provide new ideas and experimental evidence for the early diagnosis of lung cancer.
Methods
Fifty-six cases of lung tissue which underwent surgery or fiberoptic bronchoscope were enrolled in the study. According to staging standards of the lung cancer TNM published in 2003 by UICC and the clinical manifestations, CT on the chest, X-ray examination, bronchoscopy, abdominal CT, and type-B ultrasonic diagnosis, we divided the cases into many groups among the selected 50 cases:there are 5 cases of in Stage 1,10 cases in Stage II,26 cases in StageⅢ(ⅢA+ⅢB),9 cases in StageⅣ. The age, gender and other conditions in each group were basically matched. The histopathological classification was based on the criteria of 2003 UICC:7 instances of G1,19 instances of G2,24 instances of G3. And then, selecting other six cases of the cancer tissue which are diagnosed as normal tissue for comparison. By detecting and analyzing the expression levels of Beclinl and P53 of the lung cancer tissues in different pathological and clinical stages with flow cytometry, the present research tries to analyze the samples statistically and compare the results with the normal lung tissue.
Results
The percentage ofP53 protein expression of the cancer patients (63.96±9.43) %was significantly higher than the normal control group (24.90±4.68)%, t= 49.46, p<0.05; tumor metastasis were significantly higher than those without metastasis, p<0.05; and P53 protein expression is gradually increasing with the clinical stage and the pathological grade (p<0.05). Beclin1 protein detection rate was opposite to P53 protein detection rate:Beclinl protein of the cancer patients was (31.72±20.53)%, which was significantly lower than the normal control group (92.26±4.51)%, t=35.84,;p<0.05; the index was gradually reducing with the clinical stage and the pathological grade (p<0.05). Beclin1 protein was correlated toP53 protein, and the expression of Beclin1 and that of P53 was negatively correlated, r=-0.848,p<0.05.
Conclusion
The combined detection of Beclin1 andP53 can be used as indicators to the lung cancer and provide the evidence for prognosis of malignant efficacy and prognosis of the lung cancer. The expression levels of Beclin1 and P53 is closely related to the development of the lung cancer, the declining of the autophagy effect and the antiapoptotic enhancement of the cells coexist in the process of the tumor cell, thus, raising the macrophages ability becomes another alternative for the cancer therapy.
方法：选取外科手术或纤维支气管镜肺组织56例,依据2003年UICC公布的肺癌TNM分期标准同时结合临床、胸部CT、X线检查、纤维支气管镜检查、胸部CT、腹部CT、或B超等将入选病例进行分组：其中Ⅰ期5例,Ⅱ期10例,Ⅲ期(ⅢA+ⅢB)26例,Ⅳ期9例,各组年龄、性别等控制情况基本匹配。组织病理学分级按2003年UICC标准：G16例,G214例,G319例。并取6例癌旁组织或者病理确诊为正常组织作为对照组织。采用流式细胞术检测和分析不同病理分期以及不同临床分期肺癌组织中Beclin1、P53的表达水平,对该表达情况与对应的分期进行样本均数两两对比式统计学分析,并设立正常肺组织对照组。
结果：
肺癌组织P53蛋白表达百分率：肿瘤患者(63.96±9.43)%显著高于正常对照组(24.90±4.68)%的表达百分率,t＝49.46,p<0.05；肿瘤转移者显著高于未转移者,p<0.05；并且P53蛋白表达随患者临床分期和病理分级的增加而逐渐增高。
Beclin1蛋白检出率的变化规律与P53蛋白检出率的变化相反：肿瘤患者Beclin1蛋白(31.72±20.53)%显著低于正常对照组(92.26±4.51)%的表达百分率,t=35.84,p<0.05；该指标百分表达率随患者临床分期和病理分级的增加而逐渐降低。
Beclin1蛋白与P53蛋白两者相关性分析,Beclin1与P53的蛋白表达率呈负相关,r=-0.848,p<0.05。
结论：Beclin1与P53的检测可以作为肺癌诊断的参考指标,并可提示肺癌的恶性度情况,为肺癌病人的预后估计提供客观理论依据,多源信息的联合检测为肺癌个性化治疗提供了依据。肺癌患者瘤组织细胞Beclin1与P53蛋白表达水平与肺癌临床分子生物学行为的关系密切,同时揭示自噬蛋白与凋亡蛋白在肺癌发生发展中的相互作用,为肿瘤发生的病因学提供实验室依据。
Objective
The paper aims to analyze the roles of autophagy protein Beclin1 and the apoptotic protein P53 in the process of lung cancer by detecting the expression levels of Beclinl and P53 in the lung tissue quantitatively. And the paper researches the relationship between Beclinl and P53 and the pathological stages of lung cancer, in order to provide new ideas and experimental evidence for the early diagnosis of lung cancer.
Methods
Fifty-six cases of lung tissue which underwent surgery or fiberoptic bronchoscope were enrolled in the study. According to staging standards of the lung cancer TNM published in 2003 by UICC and the clinical manifestations, CT on the chest, X-ray examination, bronchoscopy, abdominal CT, and type-B ultrasonic diagnosis, we divided the cases into many groups among the selected 50 cases:there are 5 cases of in Stage 1,10 cases in Stage II,26 cases in StageⅢ(ⅢA+ⅢB),9 cases in StageⅣ. The age, gender and other conditions in each group were basically matched. The histopathological classification was based on the criteria of 2003 UICC:7 instances of G1,19 instances of G2,24 instances of G3. And then, selecting other six cases of the cancer tissue which are diagnosed as normal tissue for comparison. By detecting and analyzing the expression levels of Beclinl and P53 of the lung cancer tissues in different pathological and clinical stages with flow cytometry, the present research tries to analyze the samples statistically and compare the results with the normal lung tissue.
Results
The percentage ofP53 protein expression of the cancer patients (63.96±9.43) %was significantly higher than the normal control group (24.90±4.68)%, t= 49.46, p<0.05; tumor metastasis were significantly higher than those without metastasis, p<0.05; and P53 protein expression is gradually increasing with the clinical stage and the pathological grade (p<0.05). Beclin1 protein detection rate was opposite to P53 protein detection rate:Beclinl protein of the cancer patients was (31.72±20.53)%, which was significantly lower than the normal control group (92.26±4.51)%, t=35.84,;p<0.05; the index was gradually reducing with the clinical stage and the pathological grade (p<0.05). Beclin1 protein was correlated toP53 protein, and the expression of Beclin1 and that of P53 was negatively correlated, r=-0.848,p<0.05.
Conclusion
The combined detection of Beclin1 andP53 can be used as indicators to the lung cancer and provide the evidence for prognosis of malignant efficacy and prognosis of the lung cancer. The expression levels of Beclin1 and P53 is closely related to the development of the lung cancer, the declining of the autophagy effect and the antiapoptotic enhancement of the cells coexist in the process of the tumor cell, thus, raising the macrophages ability becomes another alternative for the cancer therapy.
引文
[1]GuessousI,Gornuz J,Paceaud F.Lung cancer gcreening:current situation and perspective[J].Swiss Med Wkly,2007.137(21-22):304-311.
[2]Bursch W.The autophagosomal-lysosomal compartmentin programmed cell death.Cell Death and Differen-tiation, [J]. J 2001,8(6):545-548
[3]Uchiyama Y.Autophagic cell death and its execu-tion by lysosomal cathepsins.Archives of Histolo-gy and Cytology[J]. J,2001,64(3):233-24
[4]Gorski DJ,Chittaranjan S,Pleasance E D,et al.A SAGE approach to discovery of genes of genes involved in autophagic cell death.Current biology:CB, [J]. J 2003,13(4):358-363
[5]Camougrand N,Grelaud-Coq A,Marza E,et al.The product of the UTH1 gene,required for Bax-in-duced cell death in yeast,is involved in the re-sponse to rapamycin.Molecular Microbiology, [J]. J 2003,47(2):495-506
[6]Kinch G,Hoffman K L,Rodrigues E M,et al.Steroid-triggered programmed cell death of amotoneuron is autophagic and involves structural changes in mitochondria.The Journal of Compara-tive Neurology, [J]. J 2003,457(4):384-403
[7]Bursch-W:Ellinger-A:Kienzl-H.Torok-L:Pandey-S:Sikorska-M:Walker-R:Hermann-RS Aetive cell death indueed by the anti-estrogens tamoxifen and ICI 164 384 in human mamary carcinoma cells (MCF-7)in culture:the role of autophagy.Careinogenesis.[J].J 1996Aug:17(8):1595-1607
[8].Hammond-EM:Brunet-CL:Johnson-GD:Parkhill-J:Milner-AE:Brady-G:Gregory-CD:Grand-RJHomologybetweenahumanaPoPtosissPeeifieProteinandtheProduetofAPGSageneinvolvedi nautoPhagyinyeast.FEBS-Lett. [J]. J 1998APr3:425(3):391-5
[9]Mizushima N, Yamamoto A, Hatano M, et al. Dissection ofautophagosome formation using Apg5-deficient mouse embry-onic stem cells[J]. J Cell Biol,2001,152(4):657-668.
[10]Toth S, Nagy K, Palfia Z,et al. Cellular autophagic capacitychanges during azaserine-induced tumour progression in the ratpancreas. Up regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregationalong with malignant transformation [J]. Cell Tissue Res,2002,309(3):409-416.
[11]Yue Z,Jin S,Yang C,et al.Beclinl,an autophagy gene essen-tial for early embryonic development, is a haploinsufficienttumor suppressor[J].Proc Natl Acad Sci USA,2003,100(25): 15077-15082.
[12]Futreal PA,Marks JR,Marks JR, et al. Detection of frequentallelic loss on proximal chromosome 17q in sporadic breast car-cinoma using microsatellite length polymorphisms[J]. CancerRes,1992,52(9):2624-2627.
[13]H Saito, J Inazawa, S Saito, et al. Detailed deletion mappingof chromosome 17q in ovarian and breast cancers:2-cM region on 17q21.3often and commonly deleted in tumors[J]. Cance Res,1993,53(14):3382-3385.
[14]Gao X, Zacharek A, Salkowski A, et al. Loss of heterozygosi-ty of the BRCA1and other loci on chromosome17q in human prostate cancer[J]. Cancer Res,1995,55(19):1002-1005.
[15]Cuervo AM, Dice JF, Knecht E. et al. A receptor for the se-lective uptake and degradation of proteins by lysosomes[J].Science,1996,273(26):501-503
[16]刘全,王建军,潘永成,孟利峰,詹曦,郑庆丰,等.Beclinl在非小细胞肺癌中的表达及临床意义.肿瘤防治研究,[J]2008；35(3)：184-187.
[17]Lee CC,Yqn qmoto S W an buchiH,et al.Cyclin Dl overexpression in rat wolstage bladdr carcinogen is and itsrelationship with onco-genes tumor expressor genes and cell proliferation [J].Cancer Res1997,57(6):4765-4776.
[18]GoodellV,Salazar LQUrban N,et al. Antibody immunity to the p53 oncogenic protein is a prognostic indicator inovarian cancer J Clin HY 2006,24;762-768
[19]王自正,王书奎,翁慎毅,等.肿瘤转移抑制基因蛋白在不同恶性肿瘤组织中表达的检测[J].实用癌症杂志,2003,18(5)：4471-4473.
[20]Lechpammer M,Lukac j,Lechpammer S, et al.Humoral immune reponse to p53 correlates with clinical course in colorectal cancer patients duing adjuvant chemotherapy. Int J Colorectal Dis,2004,19:114-120.
[1]Gorski DJ,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003; 13(4):358-362.
[2]Tan EM, Zhang J.Autoantibodies to tumor-associated antigens:reporters from the immune system. Immunol Rev,2008,222:328-340.
[3]胡野凌志强,单小云编著军事医学科学出版社 7-80121-273-8 2002／08／01 11 16583.
[4]Gadducci A, Ferdeghini M, Buttitta F, et al.Assessment of the prognostic relevance of serum anti-p53 antibodies in epithelial ovarian cancer. Gynecol Oncol,1999,72:76-81.
[5]Tang R, Ko MC,Wang JY, et al.Humoral response to p53 in human colorectal tumors:a prospective study of 1,209 patients. Int J Cancer,2001,94:859-863.
[6]Lubin R,Zalcman G, Bouchet L, et al. Serum p53 antibodies as ealy markes of lung cancer. Nat Med,1995,1:701-702。
[7]Lokshin RA,ZaKeri Z..Apoptosis,autophagy, and more.Int J Bochem Cell Biol,2004;36(12):2405-2419.
[8]Kerr J F R,Wyllie A H, Currie A R. Apoptosis:a basic biological phenomenon with wide-anging implications in lissue kinetics [J]
[9]Thor A D,Moor D H,Edgertor SM, et al. Accumulation of p53 tumor suppressor gene protein:A Independependent MARK-ER OF prongnosis in breast cancer.J Nat cancer inst,1992,84:845.
[10]Harris CC,Hollstein M, Clinical implications of the p53 tumor suppressor gene. N Engl J Med,1993,329:1318.
[11]姜彦多,何安光,朱继江,等。肺癌P53蛋白表达的免疫组织化学研究。中国医科大学学报,J 1995,24：451.
[12]Lechpammer M,Lukac j,Lechpammer S, et al.Humoral immune reponse to p53 correlates with clinical course in colorectal cancer patients duing adjuvant chemotherapy. Int J Colorectal Dis,2004,19:114-120.
[13]Komiya T,Hirashima T,Kawase I Clinical significance of p53 in non-small-lung cancer[J].Oncol REP,1996,6(1):19-28.
[14]LiggettWH Jr, SidranskyD. Role of the p16 tumor suppressorgene in cancer [J]. JClin Onco,l 1998,16(3):1197.
[15]Kim SK, Ro JY, Kemp BL,et al. Identification of three distinct tumor suppressor loci on the short arm of chromsome 9 in small cell lung cancer[J].CancerRes,1997,57:400.
[16]Lokshin RA,ZaKeri Z..Apoptosis,autophagy, and more.Int J Bochem Cell Biol,2004; 36(12):2405-2419.
[17]KlionskyDJ.autophagy.Current Biology,2005;15(8):282-283.
[18]MizushimaN,HaraT,Intracellular quality control by autophagy:how does autophagy prevent neurdegeneration?Autophagy,2006;2(4):302-304.
[19]Yu L,Lenardo MJ,Baehreche EH.Autophagy and caspases:a new cell death program.Cell Cycle,2004;3(9):1124-1126.
[20]Codogno P,Meijer AJ.Autophagy and signaling:their role in cell suvival and cell death.Cell Death & Differentiation,2005;12(2):1509-1518.
[21]Aita, V.M.et al. Cloning and genomic structure of beclin 1,a candiate tumor suppressor gene on chromosome 17q21.Genommics,1999,59,59-65
[22]王赞宏,彭芝兰,段振玲,等。自噬基因Beclin1在宫颈癌中的表达及其临床意义。四川大学学报(医学版),2006；37(6)：860-863.
[23]康凯夫,王晓蔚,陈小伍,谭光明,康子婧,等。Beclin1在原发性肝细胞癌中的表达及其临床意义。南方医科大学学报2009；29(1)：151-153.
[24]刘全,王建军,潘永成,孟利峰,詹曦,郑庆丰,等.Beclin1在非小细胞肺癌中的表达及临床意义.肿瘤防治研究,2008；35(3)：184-187.
[25]Arico S,Petiot A,Bauvy C,et al.The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phos-phatidylinositol3-kinase/protein kinase B pathway [J]. J Biol Chem,2001,276(38),35243-35246.
[26]Weinmann A S, Bartley S M, Zhang T, et al.Use of Chroma-tin Immunoprecipitation To Clone Novel E2F Target Promot-ers[J]. Mol Cell Biol,2001,21(20),6820-6832.
[27]Nevins JR. The Rb/E2F pathway and cancer[J]. Hum MGenet,2001,10(7),699-703.
[28]FuruyaD,Tsuji N,Yagihashi A,et al.Beclinlaugmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9activity[J]. Exp Cell Res,2005,307(1):26-40.
[29]Yue Z, Jin S, Yang C,et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.Proc Natl Acad Sci USA,2003,100(25):15077-15082.
[30]KoneriK,GoiT, HironoY,et al.Beclinl gene inhibits tumor growth in colon cancer cell lines [J].Anticance Res,2007,27:1453-1457.
[31]何才姑,朴英杰,胡莲美,等 受体介导内吞和自噬同凋亡的关系。第一军医大学学报,2003,23(10)：1025-1027。
[32]Furuya D, T suji N.Beclinl augmented cis-diamminedichloroplatinum inducedapoptosis via enhancing caspase-9activity Experimental Cell Research,2005;307(1):26-40.
[33]Pattingre S,LevineB.Bcl-2 inhibition of autophagy:a new route to cancer? Cancer Research,2006;66(6):2885-2888.
[34]Ogier-Denis E,Codogno p.Autophagy; a barrier or an adaptive response to cancer.B iochim A cta,2003,1603; 113-128.
[35]CuervoAM.Autophagy in sickness and in health.trenda Cell Biol,2004,14:70-77.
[36]Gozuacik D,Kimchi A.Autophagy as a cell death and tumor suppressor mechanism.Oncogene,2004,23:2891-2906.
[37]Liang XH, Kleeman LK,J iangHH, et al. Protection against fatal Sindbis virus encephaitis by beclin, a novel Bcl-2-interacting protein-J Virol,1998,72:8586-8589.
[38]Aita VM,Liang XH,Murty VV,et al.Cloning and genomic organization of beclinl,acandidate tumn orsuppessor gene on chromosome 17q21..Genomics,1999,59:59-65.
[39]Chapman CJ,Murray A, M celveen JE,et al.Autoantibodies in lung cancer: possibilities for early detection and subsequent cure.Thorax,2008,63:228-23.
[40]Lechpammer M,Lukac J,Lechpammer S,et al.Humoal immune reponse to p53 corelates with clinical course in colorectal cancer patients during adjuvant chemotherapy.Int J Colorectal Dis,2004,19:114-120.
[41]Cai HY,Wang XH,Tian Y,et al.Changes of serum p53 antibodies and clinical significance of adiotherapy for esophageal squamous cell carcinoma.World J Gastroenterol,2008,14:4082-4086.
[2]Bursch W.The autophagosomal-lysosomal compartmentin programmed cell death.Cell Death and Differen-tiation, [J]. J 2001,8(6):545-548
[3]Uchiyama Y.Autophagic cell death and its execu-tion by lysosomal cathepsins.Archives of Histolo-gy and Cytology[J]. J,2001,64(3):233-24
[4]Gorski DJ,Chittaranjan S,Pleasance E D,et al.A SAGE approach to discovery of genes of genes involved in autophagic cell death.Current biology:CB, [J]. J 2003,13(4):358-363
[5]Camougrand N,Grelaud-Coq A,Marza E,et al.The product of the UTH1 gene,required for Bax-in-duced cell death in yeast,is involved in the re-sponse to rapamycin.Molecular Microbiology, [J]. J 2003,47(2):495-506
[6]Kinch G,Hoffman K L,Rodrigues E M,et al.Steroid-triggered programmed cell death of amotoneuron is autophagic and involves structural changes in mitochondria.The Journal of Compara-tive Neurology, [J]. J 2003,457(4):384-403
[7]Bursch-W:Ellinger-A:Kienzl-H.Torok-L:Pandey-S:Sikorska-M:Walker-R:Hermann-RS Aetive cell death indueed by the anti-estrogens tamoxifen and ICI 164 384 in human mamary carcinoma cells (MCF-7)in culture:the role of autophagy.Careinogenesis.[J].J 1996Aug:17(8):1595-1607
[8].Hammond-EM:Brunet-CL:Johnson-GD:Parkhill-J:Milner-AE:Brady-G:Gregory-CD:Grand-RJHomologybetweenahumanaPoPtosissPeeifieProteinandtheProduetofAPGSageneinvolvedi nautoPhagyinyeast.FEBS-Lett. [J]. J 1998APr3:425(3):391-5
[9]Mizushima N, Yamamoto A, Hatano M, et al. Dissection ofautophagosome formation using Apg5-deficient mouse embry-onic stem cells[J]. J Cell Biol,2001,152(4):657-668.
[10]Toth S, Nagy K, Palfia Z,et al. Cellular autophagic capacitychanges during azaserine-induced tumour progression in the ratpancreas. Up regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregationalong with malignant transformation [J]. Cell Tissue Res,2002,309(3):409-416.
[11]Yue Z,Jin S,Yang C,et al.Beclinl,an autophagy gene essen-tial for early embryonic development, is a haploinsufficienttumor suppressor[J].Proc Natl Acad Sci USA,2003,100(25): 15077-15082.
[12]Futreal PA,Marks JR,Marks JR, et al. Detection of frequentallelic loss on proximal chromosome 17q in sporadic breast car-cinoma using microsatellite length polymorphisms[J]. CancerRes,1992,52(9):2624-2627.
[13]H Saito, J Inazawa, S Saito, et al. Detailed deletion mappingof chromosome 17q in ovarian and breast cancers:2-cM region on 17q21.3often and commonly deleted in tumors[J]. Cance Res,1993,53(14):3382-3385.
[14]Gao X, Zacharek A, Salkowski A, et al. Loss of heterozygosi-ty of the BRCA1and other loci on chromosome17q in human prostate cancer[J]. Cancer Res,1995,55(19):1002-1005.
[15]Cuervo AM, Dice JF, Knecht E. et al. A receptor for the se-lective uptake and degradation of proteins by lysosomes[J].Science,1996,273(26):501-503
[16]刘全,王建军,潘永成,孟利峰,詹曦,郑庆丰,等.Beclinl在非小细胞肺癌中的表达及临床意义.肿瘤防治研究,[J]2008；35(3)：184-187.
[17]Lee CC,Yqn qmoto S W an buchiH,et al.Cyclin Dl overexpression in rat wolstage bladdr carcinogen is and itsrelationship with onco-genes tumor expressor genes and cell proliferation [J].Cancer Res1997,57(6):4765-4776.
[18]GoodellV,Salazar LQUrban N,et al. Antibody immunity to the p53 oncogenic protein is a prognostic indicator inovarian cancer J Clin HY 2006,24;762-768
[19]王自正,王书奎,翁慎毅,等.肿瘤转移抑制基因蛋白在不同恶性肿瘤组织中表达的检测[J].实用癌症杂志,2003,18(5)：4471-4473.
[20]Lechpammer M,Lukac j,Lechpammer S, et al.Humoral immune reponse to p53 correlates with clinical course in colorectal cancer patients duing adjuvant chemotherapy. Int J Colorectal Dis,2004,19:114-120.
[1]Gorski DJ,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003; 13(4):358-362.
[2]Tan EM, Zhang J.Autoantibodies to tumor-associated antigens:reporters from the immune system. Immunol Rev,2008,222:328-340.
[3]胡野凌志强,单小云编著军事医学科学出版社 7-80121-273-8 2002／08／01 11 16583.
[4]Gadducci A, Ferdeghini M, Buttitta F, et al.Assessment of the prognostic relevance of serum anti-p53 antibodies in epithelial ovarian cancer. Gynecol Oncol,1999,72:76-81.
[5]Tang R, Ko MC,Wang JY, et al.Humoral response to p53 in human colorectal tumors:a prospective study of 1,209 patients. Int J Cancer,2001,94:859-863.
[6]Lubin R,Zalcman G, Bouchet L, et al. Serum p53 antibodies as ealy markes of lung cancer. Nat Med,1995,1:701-702。
[7]Lokshin RA,ZaKeri Z..Apoptosis,autophagy, and more.Int J Bochem Cell Biol,2004;36(12):2405-2419.
[8]Kerr J F R,Wyllie A H, Currie A R. Apoptosis:a basic biological phenomenon with wide-anging implications in lissue kinetics [J]
[9]Thor A D,Moor D H,Edgertor SM, et al. Accumulation of p53 tumor suppressor gene protein:A Independependent MARK-ER OF prongnosis in breast cancer.J Nat cancer inst,1992,84:845.
[10]Harris CC,Hollstein M, Clinical implications of the p53 tumor suppressor gene. N Engl J Med,1993,329:1318.
[11]姜彦多,何安光,朱继江,等。肺癌P53蛋白表达的免疫组织化学研究。中国医科大学学报,J 1995,24：451.
[12]Lechpammer M,Lukac j,Lechpammer S, et al.Humoral immune reponse to p53 correlates with clinical course in colorectal cancer patients duing adjuvant chemotherapy. Int J Colorectal Dis,2004,19:114-120.
[13]Komiya T,Hirashima T,Kawase I Clinical significance of p53 in non-small-lung cancer[J].Oncol REP,1996,6(1):19-28.
[14]LiggettWH Jr, SidranskyD. Role of the p16 tumor suppressorgene in cancer [J]. JClin Onco,l 1998,16(3):1197.
[15]Kim SK, Ro JY, Kemp BL,et al. Identification of three distinct tumor suppressor loci on the short arm of chromsome 9 in small cell lung cancer[J].CancerRes,1997,57:400.
[16]Lokshin RA,ZaKeri Z..Apoptosis,autophagy, and more.Int J Bochem Cell Biol,2004; 36(12):2405-2419.
[17]KlionskyDJ.autophagy.Current Biology,2005;15(8):282-283.
[18]MizushimaN,HaraT,Intracellular quality control by autophagy:how does autophagy prevent neurdegeneration?Autophagy,2006;2(4):302-304.
[19]Yu L,Lenardo MJ,Baehreche EH.Autophagy and caspases:a new cell death program.Cell Cycle,2004;3(9):1124-1126.
[20]Codogno P,Meijer AJ.Autophagy and signaling:their role in cell suvival and cell death.Cell Death & Differentiation,2005;12(2):1509-1518.
[21]Aita, V.M.et al. Cloning and genomic structure of beclin 1,a candiate tumor suppressor gene on chromosome 17q21.Genommics,1999,59,59-65
[22]王赞宏,彭芝兰,段振玲,等。自噬基因Beclin1在宫颈癌中的表达及其临床意义。四川大学学报(医学版),2006；37(6)：860-863.
[23]康凯夫,王晓蔚,陈小伍,谭光明,康子婧,等。Beclin1在原发性肝细胞癌中的表达及其临床意义。南方医科大学学报2009；29(1)：151-153.
[24]刘全,王建军,潘永成,孟利峰,詹曦,郑庆丰,等.Beclin1在非小细胞肺癌中的表达及临床意义.肿瘤防治研究,2008；35(3)：184-187.
[25]Arico S,Petiot A,Bauvy C,et al.The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phos-phatidylinositol3-kinase/protein kinase B pathway [J]. J Biol Chem,2001,276(38),35243-35246.
[26]Weinmann A S, Bartley S M, Zhang T, et al.Use of Chroma-tin Immunoprecipitation To Clone Novel E2F Target Promot-ers[J]. Mol Cell Biol,2001,21(20),6820-6832.
[27]Nevins JR. The Rb/E2F pathway and cancer[J]. Hum MGenet,2001,10(7),699-703.
[28]FuruyaD,Tsuji N,Yagihashi A,et al.Beclinlaugmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9activity[J]. Exp Cell Res,2005,307(1):26-40.
[29]Yue Z, Jin S, Yang C,et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.Proc Natl Acad Sci USA,2003,100(25):15077-15082.
[30]KoneriK,GoiT, HironoY,et al.Beclinl gene inhibits tumor growth in colon cancer cell lines [J].Anticance Res,2007,27:1453-1457.
[31]何才姑,朴英杰,胡莲美,等 受体介导内吞和自噬同凋亡的关系。第一军医大学学报,2003,23(10)：1025-1027。
[32]Furuya D, T suji N.Beclinl augmented cis-diamminedichloroplatinum inducedapoptosis via enhancing caspase-9activity Experimental Cell Research,2005;307(1):26-40.
[33]Pattingre S,LevineB.Bcl-2 inhibition of autophagy:a new route to cancer? Cancer Research,2006;66(6):2885-2888.
[34]Ogier-Denis E,Codogno p.Autophagy; a barrier or an adaptive response to cancer.B iochim A cta,2003,1603; 113-128.
[35]CuervoAM.Autophagy in sickness and in health.trenda Cell Biol,2004,14:70-77.
[36]Gozuacik D,Kimchi A.Autophagy as a cell death and tumor suppressor mechanism.Oncogene,2004,23:2891-2906.
[37]Liang XH, Kleeman LK,J iangHH, et al. Protection against fatal Sindbis virus encephaitis by beclin, a novel Bcl-2-interacting protein-J Virol,1998,72:8586-8589.
[38]Aita VM,Liang XH,Murty VV,et al.Cloning and genomic organization of beclinl,acandidate tumn orsuppessor gene on chromosome 17q21..Genomics,1999,59:59-65.
[39]Chapman CJ,Murray A, M celveen JE,et al.Autoantibodies in lung cancer: possibilities for early detection and subsequent cure.Thorax,2008,63:228-23.
[40]Lechpammer M,Lukac J,Lechpammer S,et al.Humoal immune reponse to p53 corelates with clinical course in colorectal cancer patients during adjuvant chemotherapy.Int J Colorectal Dis,2004,19:114-120.
[41]Cai HY,Wang XH,Tian Y,et al.Changes of serum p53 antibodies and clinical significance of adiotherapy for esophageal squamous cell carcinoma.World J Gastroenterol,2008,14:4082-4086.