P57～（kip2）、PCNA在膀胱移行细胞癌中的表达及意义
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摘要
目的:研究细胞周期蛋白依赖性激酶抑制因子 p57kip2、增殖细胞核抗原(PCNA)在膀胱移行细胞癌(Bladder transitional cell carcinoma,BTCC)中的表达及其相关性,以探讨其在膀胱癌的发生、发展中所起的作用及预后的关系。
方法:选取重庆医科大学附属第一医院泌尿外科 1994—1997年 膀 胱 移 行 细 胞 癌 标 本 50 例 。 运 用 免 疫 组 织 化 学 方 法(EliVisionTMplus 二步法)检测标本中 p57kip2、PCNA 的表达情况,综合分析两者在膀胱移行细胞癌中的表达情况及其相关性。
结果:p57kip2和 PCNA 在本组研究的 50 例标本中均有不同程度的表达。p57kip2 阳性表达率在膀胱移行细胞癌组织中为46%(23/50),显著低于正常膀胱粘膜组织 78.57% (11/14()p<0.05),并与膀胱移行细胞癌组织病理分级﹑生存率显著相关(p<0.05),但与临床分期无关(p>0.05)。PCNA 阳性表达率在膀胱移行细胞癌组织中为 60%(30/50),显著高于正常膀胱粘膜组织的 0%(0/14) (p<0.01),并与膀胱移行细胞癌组织病理分级,临床分期和生存率显著相关(p<0.05)。p57kip2和 PCNA 的表达呈负相关(p<0.01)。
结论:1.p57kip2低表达和 PCNA 过度表达,可能参与膀胱肿瘤的诱发。
2.p57kip2 与膀胱肿瘤的病理分级、患者生存率均有显著相关,但与临床分期无关,提示 p57kip2可反映膀胱移行细胞癌细胞分化状态及恶性程度的一种指标,而与肿瘤浸润深度无明显关系。p57kip2低表达可以作为不良预后的一个参考指标。PCNA 与膀胱肿瘤的病
Objective: TO study expressions and correlations of p57kip2、PCNA in bladder transitional cell carcinoma(BTCC)and discuss their significance in carcinogenesis and progression of BTCC cancer,as well as their relations with angiogenesis and prognosis.
Methods: Fifty specimens of BTCC between 1994 and 1997 at the department of Urology,the First Affiliated Hospital Chongqing Medical University,in the study group.The expressions of p57kip2 and PCNA were tested by immunohistochemical method(EliVisionTMplus). The results were reciprocally analyzed and compared with angiogenesis and prognosis.
Results: p57kip2 and PCNA positive stained were a greater or lesser degree detected in all of the 50 cases.Positive rate of p57kip2 in BTCC was 46%,which was significant lower than 78.57% in normal bladder muscosa.(χ2=4.660,P <0.05),p57kip2 expression correlated remarkably with both grade and survival(χ2=8.592,P<0.05;χ2=4.546,P<0.05), but did not correlate clinical stage(χ2=0.573,P>0.05);positive rate of PCNA in BTCC was 60 %(30/50),which was significant higher than 0%(0/14)in normal bladder muscosa(χ2=15.812, p <0.01),PCNA expression correlated remarkably with both grade ,stage and survival(P<0.05)there was a highly significant inverse correlation between the expression of p57kip2 and PCNA(r=-0.443,P <0.01)
Conclusion: l. The low express of p57kip2 and overexpression of PCNA are closely related to tumorigenesis of bladder cancer.
2. p57kip2 expression correlated remarkably with both grade and survival,but did not correlate clinical stage,indicating that p57kip2 is related to the differentiation and malignant degree of bladder cancer,not related to tumor infiltration,it has a poor prognosis.PCNA expression correlated remarkably with both grade ,stage and survival, indicating PCNA are related to the differentiation and progression of bladder cancer and it might be useful prognosistic markers in bladder carcinoma.
3.There was a negative correlation between the expression rate of p57kip2 and PCNA in bladder cancer, indicating that they have synergism in the happening and development of bladder cancer.At the same time they may have some feedback loop in progression of bladder cancer.
方法:选取重庆医科大学附属第一医院泌尿外科 1994—1997年 膀 胱 移 行 细 胞 癌 标 本 50 例 。 运 用 免 疫 组 织 化 学 方 法(EliVisionTMplus 二步法)检测标本中 p57kip2、PCNA 的表达情况,综合分析两者在膀胱移行细胞癌中的表达情况及其相关性。
结果:p57kip2和 PCNA 在本组研究的 50 例标本中均有不同程度的表达。p57kip2 阳性表达率在膀胱移行细胞癌组织中为46%(23/50),显著低于正常膀胱粘膜组织 78.57% (11/14()p<0.05),并与膀胱移行细胞癌组织病理分级﹑生存率显著相关(p<0.05),但与临床分期无关(p>0.05)。PCNA 阳性表达率在膀胱移行细胞癌组织中为 60%(30/50),显著高于正常膀胱粘膜组织的 0%(0/14) (p<0.01),并与膀胱移行细胞癌组织病理分级,临床分期和生存率显著相关(p<0.05)。p57kip2和 PCNA 的表达呈负相关(p<0.01)。
结论:1.p57kip2低表达和 PCNA 过度表达,可能参与膀胱肿瘤的诱发。
2.p57kip2 与膀胱肿瘤的病理分级、患者生存率均有显著相关,但与临床分期无关,提示 p57kip2可反映膀胱移行细胞癌细胞分化状态及恶性程度的一种指标,而与肿瘤浸润深度无明显关系。p57kip2低表达可以作为不良预后的一个参考指标。PCNA 与膀胱肿瘤的病
Objective: TO study expressions and correlations of p57kip2、PCNA in bladder transitional cell carcinoma(BTCC)and discuss their significance in carcinogenesis and progression of BTCC cancer,as well as their relations with angiogenesis and prognosis.
Methods: Fifty specimens of BTCC between 1994 and 1997 at the department of Urology,the First Affiliated Hospital Chongqing Medical University,in the study group.The expressions of p57kip2 and PCNA were tested by immunohistochemical method(EliVisionTMplus). The results were reciprocally analyzed and compared with angiogenesis and prognosis.
Results: p57kip2 and PCNA positive stained were a greater or lesser degree detected in all of the 50 cases.Positive rate of p57kip2 in BTCC was 46%,which was significant lower than 78.57% in normal bladder muscosa.(χ2=4.660,P <0.05),p57kip2 expression correlated remarkably with both grade and survival(χ2=8.592,P<0.05;χ2=4.546,P<0.05), but did not correlate clinical stage(χ2=0.573,P>0.05);positive rate of PCNA in BTCC was 60 %(30/50),which was significant higher than 0%(0/14)in normal bladder muscosa(χ2=15.812, p <0.01),PCNA expression correlated remarkably with both grade ,stage and survival(P<0.05)there was a highly significant inverse correlation between the expression of p57kip2 and PCNA(r=-0.443,P <0.01)
Conclusion: l. The low express of p57kip2 and overexpression of PCNA are closely related to tumorigenesis of bladder cancer.
2. p57kip2 expression correlated remarkably with both grade and survival,but did not correlate clinical stage,indicating that p57kip2 is related to the differentiation and malignant degree of bladder cancer,not related to tumor infiltration,it has a poor prognosis.PCNA expression correlated remarkably with both grade ,stage and survival, indicating PCNA are related to the differentiation and progression of bladder cancer and it might be useful prognosistic markers in bladder carcinoma.
3.There was a negative correlation between the expression rate of p57kip2 and PCNA in bladder cancer, indicating that they have synergism in the happening and development of bladder cancer.At the same time they may have some feedback loop in progression of bladder cancer.
引文
[1]周荣祥,程继义.泌尿男生殖系肿瘤[M].北京:人民卫生出版社,2001,246.
[2]Balasubramanian S,Ahmad N,Jeedigunta S,et al.Alterations in cell cycle regulation in mouse skin tumors[J].Biochem Biophys Res Commun,1998, 243(3):744-748.
[3] Nurse P.Ordering S phase and M phase in the cell cycle[J].Cell. 1994,79(4):547-50.
[4]Hunter T,Pines J.Cyclins and cancer.II:Cyclin D and CDK inhibitors come of age[J].Cell.1994,79(4):573-582.
[5]Kelman Z.PCNA:structure functions and interactions[J].Oncogene 1997,14: 629-640
[6]Norbury C,Nurse P.Animal cell cycles and their control[J].Annu Rev Biochem.1992, 61:441-470..
[7]Kamb A,Gruis NA,Weaver-Feldhaus J,et al. A cell cycle regulator potentially involved in genesis of many tumor types[J].Science.1994 ,264(5157):436-440.
[8]Grana X,Reddy EP.Cell cycle control in mammalian cells:role of cyclins,cyclin dependent kinases(CDKs),growth suppressor genes and cyclin-dependent kinase inhibitors(CKIs)[J].Oncogene.1995,11(2):211-219.
[9]Sherr CJ.G1 phase progression:cycling on cue[J].Cell.1994,79(4):551-555.
[10]Sherr CJ.Cancer cell cycles[J].Science.1996,274(5293):1672-1677.
[11]Kamb A.Cell-cycle regulators and cancer[J].Trends Genet.1995,11(4):136-140.
[12]Clurman BE,Roberts JM.Cell cycle and cancer[J].J Natl Cancer Inst. 1995,87(20):1499-1501.
[13]Matsuoka S,Edwards MC,Bai C,et al.p57KIP2,a structurally distinct member of the p21CIP1 Cdk inhibitor family,is a candidate tumor suppressor gene[J].Genes Dev.1995,9(6):650-662.
[14]Reid LH,Crider-Miller SJ, West A, et al.Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms'tumor assay[J].Cancer Res. 1996,56(6):1214-1218.
[15]Tokino T,Urano T,Furuhata T,et al.Characterization of the human p57KIP2 gene: alternative splicing,insertion/deletion polymorphisms in VNTR sequences in the coding region,and mutational analysis[J].Hum Genet.1996 ,97(5):625-631.
[16]Lee MH,Reynisdottir I,Massague J.et al.Cloning of p57KIP2,a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution[J].Genes Dev.1995 ,9(6):639-649.
[17]Watanabe H,Pan ZQ,Schreiber-Agus N,et al.Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen[J].Proc Natl Acad Sci U S A.1998,95(4):1392-1397.
[18]Leibovitch MP,Kannengiesser C,Leibovitch SA.Signal-induced ubiquitination of p57kip2 is independent of the C-terminal consensus Cdk phosphorylation site[J].FEBS Lett 2003,543:125-128.
[19]Zhang P,Liegeois NJ,Wong C,et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome[J]. Nature.1997,387(6629):151-158.
[20]Matsuoka S,Thompson JS,Edwards MC,et al. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor,p57KIP2,on chromosome 11p15[J].Proc Natl Acad Sci U S A. 1996,93(7):3026-3030.
[21]Hall JG. Genomic imprinting:review and relevance to human diseases[J].Am J Hum Genet.1990,46(5):857-873.
[22]Kondo M,Matsuoka S,Uchida K,et al.Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5[J].Oncogene. 1996,12(6):1365-1368.
[23]Tsuoka S,Thompson JS,Edwards,et al.Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor,p57KIP2,on chromosome 11p15[J]. Proc-Natl-Acad-Sci-U-S-A.1996,93(7):3026-3030.
[24]Zhang P,Liegeois NJ,Wong C, et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome [J].Nature 1997, 387:151-158.
[25]Oya M,Schulz WA.Decreased expression of p57(KIP2)mRNA in human bladder cancer[J].Br J Cancer, 2000,83(5):626-631.
[26]Sui L,Dong,Y, Ohno M,et al.Expression of p57kip2 and its clinical relevance in epithelial ovarian tumors[J].Anticancer-Res.2002,22(6A):3191-3196.
[27]Ito Y,Takeda T,Sasaki Y,et al.Expression of p57/Kip2 protein in extrahepatic bile duct carcinoma and intrahepatic cholangiocellular carcinoma[J].Liver. 2002,22(2):145-149.
[28]Ito Y,Yoshida H,Nakano K,et al.Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues[J].Int J Mol Med.2002,9(4):373-376.
[29]Liang B,Wang S,Yang X,et al.Expressions of cyclin E,cyclin dependent kinase 2 and p57(KIP2)in human gastric cancer[J].Chin Med J (Engl).2003,116(1):20-23.
[30]Nijjar T,Wigington D,Garbe JC,et al.p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells[J].Cancer Res.1999,59(20):5112-5118.
[31]Reid LH,Crider-Miller SJ,West A,et al.Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms'tumor assay[J].Cancer Res. 1996,56(6):1214-1218.
[32]Li JQ, Wu F, Usuki H, et al. Loss of p57KIP2 is associated with colorectal carcinogenesis[J]. Int J Oncol. 2003,23(6):1537-1543.
[33]Almendral JM,Huebsch D,Blundell PA,et al.Cloning and sequence of the human nuclear protein cyclin:homology with DNA-binding proteins[J].Proc Natl Acad Sci U S A.1987,84(6):1575-1579.
[34]Mathews MB,Bernstein RM,Franza BR,et al.Identity of the proliferating cell nuclear antigen and cyclin[J].Nature.1984,309(5966):374-376.
[35]Ottavio L,Chang CD,Rizzo MG,et al.Importance of introns in the growth regulation of mRNA levels of the proliferating cell nuclear antigen gene[J]. Mol-Cell-Biol. 1990,10(1):303-309.
[36]Suzuka I,Daidoji H,Matsuoka M,et al.Gene for proliferating-cell nuclear antigen(DNA polymerase delta auxiliary protein)is present in both mammalian and higher plant genomes[J].Proc-Natl-Acad-Sci-U-S-A.1989,86(9):3189-3193.
[37]Reilly DR,Crawford AM,Miller LK,et al.Viral proliferating cell nuclear antigen[J].Nature.1989,337(6208):606.
[38]Almendral JM,Huebsch D,Blundell PA,et al.Cloning and sequence of the human nuclear protein cyclin:homology with DNA-binding proteins[J]. Proc-Natl-Acad- Sci-U-S-A.1987,84(6):1575-1579.
[39]Miyachi K,Fritzler MJ,Tan EM.et al.Autoantibody to a nuclear antigen in proliferating cells[J].J Immunol.978,121(6):2228-2234.
[40]Kelman Z,et al.PCNA:structure,functions and interactions[J].Oncogene. 1997,14(6): 629-640.
[41]Ottavio L,Chang CD,Rizzo MG,et al.The promoter of the proliferating cell nuclear antigen(PCNA)gene is active in serum-derived cells.Biochem Biophys Res Commun[J].1990,169(2):509-516.
[42]Prelich G,Kostura M,Marshak DR,et al.The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro[J].Nature. 1987,326(6112):471-475.
[43]Kelman Z,Hurwitz J.Protein-PCNA interactions:a DNA-scanning mechanism[J].Trends Biochem Sci.1998,23(7):236-238.
[44]Xu J,Morris GF.p53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation[J].Mol Cell Biol.1999,19(1):12-20.
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[53]Nakai S,Masaki T,Shiratori Y,et al.Expression of p57(KIP2) in hepatocellular carcinoma:relationship between tumor differentiation and patient survival[J].Int J Oncol.2002 , 20(4):769-775.
[54]Yue H,Zhang N,Feng XL,et al.Relationship between expression of p57(kip2), cyclin E protein,PCNA,and clinicopathological factors in human pancreatic cancer[J].Ai Zheng.2003,22(7):705-709.
[55]Yue H,Na YL,Feng XL,et al.Expression of p57kip2,Rb protein and PCNA and their relationships with clinicopathology in human pancreatic cancer[J].World J Gastroenterol.2003,9(2):377-380.
[2]Balasubramanian S,Ahmad N,Jeedigunta S,et al.Alterations in cell cycle regulation in mouse skin tumors[J].Biochem Biophys Res Commun,1998, 243(3):744-748.
[3] Nurse P.Ordering S phase and M phase in the cell cycle[J].Cell. 1994,79(4):547-50.
[4]Hunter T,Pines J.Cyclins and cancer.II:Cyclin D and CDK inhibitors come of age[J].Cell.1994,79(4):573-582.
[5]Kelman Z.PCNA:structure functions and interactions[J].Oncogene 1997,14: 629-640
[6]Norbury C,Nurse P.Animal cell cycles and their control[J].Annu Rev Biochem.1992, 61:441-470..
[7]Kamb A,Gruis NA,Weaver-Feldhaus J,et al. A cell cycle regulator potentially involved in genesis of many tumor types[J].Science.1994 ,264(5157):436-440.
[8]Grana X,Reddy EP.Cell cycle control in mammalian cells:role of cyclins,cyclin dependent kinases(CDKs),growth suppressor genes and cyclin-dependent kinase inhibitors(CKIs)[J].Oncogene.1995,11(2):211-219.
[9]Sherr CJ.G1 phase progression:cycling on cue[J].Cell.1994,79(4):551-555.
[10]Sherr CJ.Cancer cell cycles[J].Science.1996,274(5293):1672-1677.
[11]Kamb A.Cell-cycle regulators and cancer[J].Trends Genet.1995,11(4):136-140.
[12]Clurman BE,Roberts JM.Cell cycle and cancer[J].J Natl Cancer Inst. 1995,87(20):1499-1501.
[13]Matsuoka S,Edwards MC,Bai C,et al.p57KIP2,a structurally distinct member of the p21CIP1 Cdk inhibitor family,is a candidate tumor suppressor gene[J].Genes Dev.1995,9(6):650-662.
[14]Reid LH,Crider-Miller SJ, West A, et al.Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms'tumor assay[J].Cancer Res. 1996,56(6):1214-1218.
[15]Tokino T,Urano T,Furuhata T,et al.Characterization of the human p57KIP2 gene: alternative splicing,insertion/deletion polymorphisms in VNTR sequences in the coding region,and mutational analysis[J].Hum Genet.1996 ,97(5):625-631.
[16]Lee MH,Reynisdottir I,Massague J.et al.Cloning of p57KIP2,a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution[J].Genes Dev.1995 ,9(6):639-649.
[17]Watanabe H,Pan ZQ,Schreiber-Agus N,et al.Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen[J].Proc Natl Acad Sci U S A.1998,95(4):1392-1397.
[18]Leibovitch MP,Kannengiesser C,Leibovitch SA.Signal-induced ubiquitination of p57kip2 is independent of the C-terminal consensus Cdk phosphorylation site[J].FEBS Lett 2003,543:125-128.
[19]Zhang P,Liegeois NJ,Wong C,et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome[J]. Nature.1997,387(6629):151-158.
[20]Matsuoka S,Thompson JS,Edwards MC,et al. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor,p57KIP2,on chromosome 11p15[J].Proc Natl Acad Sci U S A. 1996,93(7):3026-3030.
[21]Hall JG. Genomic imprinting:review and relevance to human diseases[J].Am J Hum Genet.1990,46(5):857-873.
[22]Kondo M,Matsuoka S,Uchida K,et al.Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5[J].Oncogene. 1996,12(6):1365-1368.
[23]Tsuoka S,Thompson JS,Edwards,et al.Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor,p57KIP2,on chromosome 11p15[J]. Proc-Natl-Acad-Sci-U-S-A.1996,93(7):3026-3030.
[24]Zhang P,Liegeois NJ,Wong C, et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome [J].Nature 1997, 387:151-158.
[25]Oya M,Schulz WA.Decreased expression of p57(KIP2)mRNA in human bladder cancer[J].Br J Cancer, 2000,83(5):626-631.
[26]Sui L,Dong,Y, Ohno M,et al.Expression of p57kip2 and its clinical relevance in epithelial ovarian tumors[J].Anticancer-Res.2002,22(6A):3191-3196.
[27]Ito Y,Takeda T,Sasaki Y,et al.Expression of p57/Kip2 protein in extrahepatic bile duct carcinoma and intrahepatic cholangiocellular carcinoma[J].Liver. 2002,22(2):145-149.
[28]Ito Y,Yoshida H,Nakano K,et al.Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues[J].Int J Mol Med.2002,9(4):373-376.
[29]Liang B,Wang S,Yang X,et al.Expressions of cyclin E,cyclin dependent kinase 2 and p57(KIP2)in human gastric cancer[J].Chin Med J (Engl).2003,116(1):20-23.
[30]Nijjar T,Wigington D,Garbe JC,et al.p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells[J].Cancer Res.1999,59(20):5112-5118.
[31]Reid LH,Crider-Miller SJ,West A,et al.Genomic organization of the human p57KIP2 gene and its analysis in the G401 Wilms'tumor assay[J].Cancer Res. 1996,56(6):1214-1218.
[32]Li JQ, Wu F, Usuki H, et al. Loss of p57KIP2 is associated with colorectal carcinogenesis[J]. Int J Oncol. 2003,23(6):1537-1543.
[33]Almendral JM,Huebsch D,Blundell PA,et al.Cloning and sequence of the human nuclear protein cyclin:homology with DNA-binding proteins[J].Proc Natl Acad Sci U S A.1987,84(6):1575-1579.
[34]Mathews MB,Bernstein RM,Franza BR,et al.Identity of the proliferating cell nuclear antigen and cyclin[J].Nature.1984,309(5966):374-376.
[35]Ottavio L,Chang CD,Rizzo MG,et al.Importance of introns in the growth regulation of mRNA levels of the proliferating cell nuclear antigen gene[J]. Mol-Cell-Biol. 1990,10(1):303-309.
[36]Suzuka I,Daidoji H,Matsuoka M,et al.Gene for proliferating-cell nuclear antigen(DNA polymerase delta auxiliary protein)is present in both mammalian and higher plant genomes[J].Proc-Natl-Acad-Sci-U-S-A.1989,86(9):3189-3193.
[37]Reilly DR,Crawford AM,Miller LK,et al.Viral proliferating cell nuclear antigen[J].Nature.1989,337(6208):606.
[38]Almendral JM,Huebsch D,Blundell PA,et al.Cloning and sequence of the human nuclear protein cyclin:homology with DNA-binding proteins[J]. Proc-Natl-Acad- Sci-U-S-A.1987,84(6):1575-1579.
[39]Miyachi K,Fritzler MJ,Tan EM.et al.Autoantibody to a nuclear antigen in proliferating cells[J].J Immunol.978,121(6):2228-2234.
[40]Kelman Z,et al.PCNA:structure,functions and interactions[J].Oncogene. 1997,14(6): 629-640.
[41]Ottavio L,Chang CD,Rizzo MG,et al.The promoter of the proliferating cell nuclear antigen(PCNA)gene is active in serum-derived cells.Biochem Biophys Res Commun[J].1990,169(2):509-516.
[42]Prelich G,Kostura M,Marshak DR,et al.The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro[J].Nature. 1987,326(6112):471-475.
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