P27～（kip1）蛋白在肾母细胞瘤中的表达及其意义
摘要
目的 研究P27~(kip1)蛋白在肾母细胞瘤中的表达，并探讨其与预后及临床病理学特征之间的关系。肾母细胞瘤(Nephroblastoma)或称肾胚瘤，又称Wilms瘤，是婴幼儿最常见的恶性实体瘤之一，罕见于成人。应用手术、放疗及化疗的综合措施，使20-30年代死亡率高达80％变为目前存活率高达80％以上。诊断时年龄最多见于1-3岁，90％病例见于7岁以前，平均年龄是3.1岁。肿瘤可能起源于后肾胚基的不正常分化，它可以遗传的或非遗传形式出现，若属遗传形式，则肿瘤发生的更早，更易为双侧及多中心形式。所有双侧肾母细胞瘤及15-20％的单侧病变与遗传有关。
临床上对于肿瘤的治疗常采用手术加化疗、放疗的综合治疗，何种病儿术后需要行何种辅助治疗、治疗剂量及时间的长短，主要是依据临床分期、病理类型以及淋巴结的状况。但是临床上有的患儿分期早、无淋巴结转移，但预后却不佳。因此，肾母细胞瘤的预后除与其发病早晚及其肿瘤大小有关外，主要与其肿瘤的生物学特性有关。为了判断恶性肿瘤的生物学特征，国内外学者目前都在致力于研究能够预测恶性肿瘤病人预
山妞盯民月呼，气学
毛凡创七学，勺之翻仑岁忆2以〕2
后的生物学指标，目的是更合理地应用综合治疗的方法，提高
病人的生存期。P27tip，是新近发现的一种抑癌基因，主要通过对
CDK的抑制作用，阻断细胞周期从G;到S期的转换，阻断细
胞增殖和肿瘤的形成。P27kin，基因蛋白在各种分化不同的肿瘤
组织中表达不同，被认为是肿瘤独立的标志物。
方法应用特异而敏感的免疫组织化学S一方法对44例肾
母细胞瘤的P27kinl蛋白的表达水平进行了检测，并分析了其与临
床病理学特征和预后的关系，从而探讨其在肾母细胞瘤发生、发
展中的作用，同时对本组病人进行随访，了解P27kivl蛋白与肾母
细胞瘤预后的关系。用Cox回归模型作单因素和多因素预后分
析。
结果P27饰，蛋白在肾、母细胞瘤中高表达率为
65 .91%(29/44)，低表达率为34.090/ofl5/44)，p27“p‘的低表达与
肾母细胞瘤分期晚、局部易复发及发生淋巴结转移显著相关。
Cox模型显示P27“ip‘蛋白是肾母细胞瘤的一个独立的预后标志
物。所有病例均经手术切除，术后均进行化疗，化疗采用长春新
碱、环磷酞胺、放线菌素D等药物，疗程6个月一1年。其中2
例进行放疗，31例得到随访，13例失访，死亡3例。
结论肿瘤的形成及预后与细胞周期调控的失常有密切关
系，在细胞增殖过程中，细胞周期素(cyclin)和细胞周期蛋白依
赖性激酶(C DK)起着非常重要的作用。周期蛋白(cydin)和周
期蛋白依赖性激酶(c dks)是细胞周期的正向调节因子，细胞
山祖盯医早略J吃学
刃气d卜.学巾七今仑J忆2(X)2
周期蛋白依赖性激酶抑制剂(c dki)是细胞周期的负向调节因
子。CDK包括催化亚单位CDK和活性亚单位cyclin，二者组
成复合体。cyclinE一CDKZ和cyclinD一CnK4复合物在Gl期具
有催化活性，并限制细胞通过这个时期的速度。G;期CDK是
一个正性和负性调节的综合体，决定着细胞是否自主进入细胞
周期，其中一个因素是CDK蛋白水平，另一个是CDK抑制蛋
白的变化。P27kiv‘正是一种抑制蛋白。P27脚‘在两个水平上起
作用:①P27“，p，能够抑制人类eyelin A-CDKZ、cyelinE一CDKZ、
cyclinB一OKI和HI组蛋白酶活性。②p27“‘p，能够抑制eyclin
E一CDKZ、eyelin A-CDKZ、eyelin DZ一CDK4复合物在Thr一160
磷酸化的能力。目前认为P27kiP，可能最直接地影响G/S限制点
的调控，阻断细胞增殖和肿瘤形成。近几年来国外对P27印的
研究已做了大量工作，但国内对P27kiPI的研究以及与肿瘤的关
系方面的研究较少。目前认为它与非小细胞肺癌、乳腺癌、结
肠癌等多种肿瘤的发生、发展、预后等生物学行为均有密切关
系。PZ 7kiv，基因蛋白在各种分化不同的肿瘤组织中表达不同，
被认为是肿瘤独立的标志物。
P27饰‘低表达与肾母细胞瘤分期晚、局部易复发及发生淋
巴结转移显著相关。P27kiP，高表达则相反。我们认为P27kin，蛋
白鑫细胞瘤的一个独立的预后标志物。临床医一、可以参薯
P27饰，表达的高低来决定术后是否采用放疗或化疗，若P27饰‘
低表达，无论淋巴结有无转移，都应加大放疗或(和)化疗的
山飞叮医月呼，悦学
习甩d匕学劝之翻仑岁忆2‘刃2
辅助治疗，若P27kiv’高表达则考虑减少放疗或(和)化疗的力度，
以减少森药物及放射性物质对患，L的副作用。
Objective: To investigate the expression of P27 in nephroblastoma, and the relationship between its expression and prognosis of the patients as well as clinic pathological characteristic. Nephroblastoma is one of the most common malignancy solid tumor in children, rare in adult. Nephroblastoma may come from metanephrogenic blastema's undifferentiation. It may be hereditary or non-hereditary. The age of hereditary nephroblastoma is less. All the bilateral nephroblastoma and 15-20% of unilateral unilateral nephroblastoma is hereditary. The forming and prognosis of tumor is closely related to adjustment disorder of cell cycle. Cyclin and CDKs are positive adjustment factor of cell cycle, and CDKi is negative. P27kip1 is thermal stability protein whose molecular weight is 27KD. P27kip1 is discovered by Polyak in 1994. P27kip1 is major inhibitor of CDK2/cyclin E and CDK4/cyclin D. At present, P27kip1 may directly affect adjustment point of Gap/Synthesis, and resist cell proliferation and forming of tumor. Presently, most research about P27kip1 has been done abroad, but seldom in China. Now most scholar think that P27kip1 is related to non-small cell lung cancer,
breast carcinomas and coloreactal carcinomas. P27kip1 expresses differently in different tumor tissue. P27kip1 is considered an independent marker of tumor.
Methods:The expression of P27kipl in 44 cases of nephroblastoma was detected by immunohistochemical method. Anlysis the relationship between P27kip1 expression and prognosis of the patients as well as clinic pathological characteristic. Discuss the function of P27kip1 in forming and development of nephroblastoma. All patients were followed up. The univariate and multivariate prognostic analyses were performed by using Cox regression model.
Results: The high expressive rate of P27kip1 for nephroblastoma was 65.91%(29/44), the low expressive rate was 34.09%(15/44). Low P27 expression in nephroblastoma was significantly associated with late stage , local recurrence , and high incidence of lymph node metastasis, But high P27kip1 expression is contrary. All patients were operated and recepted chemotherapy. Vincristini Sulfas ,Cytoxan and Dactinomycin were used. The course of treatment was 6 months to 1 year. 2 cases received radiotherapy. 3 1 cases were followed up. 3 cases died.
Conclusion:. P27kip1 is an independent and valid prognostic marker of nephroblastoma .
临床上对于肿瘤的治疗常采用手术加化疗、放疗的综合治疗，何种病儿术后需要行何种辅助治疗、治疗剂量及时间的长短，主要是依据临床分期、病理类型以及淋巴结的状况。但是临床上有的患儿分期早、无淋巴结转移，但预后却不佳。因此，肾母细胞瘤的预后除与其发病早晚及其肿瘤大小有关外，主要与其肿瘤的生物学特性有关。为了判断恶性肿瘤的生物学特征，国内外学者目前都在致力于研究能够预测恶性肿瘤病人预
山妞盯民月呼，气学
毛凡创七学，勺之翻仑岁忆2以〕2
后的生物学指标，目的是更合理地应用综合治疗的方法，提高
病人的生存期。P27tip，是新近发现的一种抑癌基因，主要通过对
CDK的抑制作用，阻断细胞周期从G;到S期的转换，阻断细
胞增殖和肿瘤的形成。P27kin，基因蛋白在各种分化不同的肿瘤
组织中表达不同，被认为是肿瘤独立的标志物。
方法应用特异而敏感的免疫组织化学S一方法对44例肾
母细胞瘤的P27kinl蛋白的表达水平进行了检测，并分析了其与临
床病理学特征和预后的关系，从而探讨其在肾母细胞瘤发生、发
展中的作用，同时对本组病人进行随访，了解P27kivl蛋白与肾母
细胞瘤预后的关系。用Cox回归模型作单因素和多因素预后分
析。
结果P27饰，蛋白在肾、母细胞瘤中高表达率为
65 .91%(29/44)，低表达率为34.090/ofl5/44)，p27“p‘的低表达与
肾母细胞瘤分期晚、局部易复发及发生淋巴结转移显著相关。
Cox模型显示P27“ip‘蛋白是肾母细胞瘤的一个独立的预后标志
物。所有病例均经手术切除，术后均进行化疗，化疗采用长春新
碱、环磷酞胺、放线菌素D等药物，疗程6个月一1年。其中2
例进行放疗，31例得到随访，13例失访，死亡3例。
结论肿瘤的形成及预后与细胞周期调控的失常有密切关
系，在细胞增殖过程中，细胞周期素(cyclin)和细胞周期蛋白依
赖性激酶(C DK)起着非常重要的作用。周期蛋白(cydin)和周
期蛋白依赖性激酶(c dks)是细胞周期的正向调节因子，细胞
山祖盯医早略J吃学
刃气d卜.学巾七今仑J忆2(X)2
周期蛋白依赖性激酶抑制剂(c dki)是细胞周期的负向调节因
子。CDK包括催化亚单位CDK和活性亚单位cyclin，二者组
成复合体。cyclinE一CDKZ和cyclinD一CnK4复合物在Gl期具
有催化活性，并限制细胞通过这个时期的速度。G;期CDK是
一个正性和负性调节的综合体，决定着细胞是否自主进入细胞
周期，其中一个因素是CDK蛋白水平，另一个是CDK抑制蛋
白的变化。P27kiv‘正是一种抑制蛋白。P27脚‘在两个水平上起
作用:①P27“，p，能够抑制人类eyelin A-CDKZ、cyelinE一CDKZ、
cyclinB一OKI和HI组蛋白酶活性。②p27“‘p，能够抑制eyclin
E一CDKZ、eyelin A-CDKZ、eyelin DZ一CDK4复合物在Thr一160
磷酸化的能力。目前认为P27kiP，可能最直接地影响G/S限制点
的调控，阻断细胞增殖和肿瘤形成。近几年来国外对P27印的
研究已做了大量工作，但国内对P27kiPI的研究以及与肿瘤的关
系方面的研究较少。目前认为它与非小细胞肺癌、乳腺癌、结
肠癌等多种肿瘤的发生、发展、预后等生物学行为均有密切关
系。PZ 7kiv，基因蛋白在各种分化不同的肿瘤组织中表达不同，
被认为是肿瘤独立的标志物。
P27饰‘低表达与肾母细胞瘤分期晚、局部易复发及发生淋
巴结转移显著相关。P27kiP，高表达则相反。我们认为P27kin，蛋
白鑫细胞瘤的一个独立的预后标志物。临床医一、可以参薯
P27饰，表达的高低来决定术后是否采用放疗或化疗，若P27饰‘
低表达，无论淋巴结有无转移，都应加大放疗或(和)化疗的
山飞叮医月呼，悦学
习甩d匕学劝之翻仑岁忆2‘刃2
辅助治疗，若P27kiv’高表达则考虑减少放疗或(和)化疗的力度，
以减少森药物及放射性物质对患，L的副作用。
Objective: To investigate the expression of P27 in nephroblastoma, and the relationship between its expression and prognosis of the patients as well as clinic pathological characteristic. Nephroblastoma is one of the most common malignancy solid tumor in children, rare in adult. Nephroblastoma may come from metanephrogenic blastema's undifferentiation. It may be hereditary or non-hereditary. The age of hereditary nephroblastoma is less. All the bilateral nephroblastoma and 15-20% of unilateral unilateral nephroblastoma is hereditary. The forming and prognosis of tumor is closely related to adjustment disorder of cell cycle. Cyclin and CDKs are positive adjustment factor of cell cycle, and CDKi is negative. P27kip1 is thermal stability protein whose molecular weight is 27KD. P27kip1 is discovered by Polyak in 1994. P27kip1 is major inhibitor of CDK2/cyclin E and CDK4/cyclin D. At present, P27kip1 may directly affect adjustment point of Gap/Synthesis, and resist cell proliferation and forming of tumor. Presently, most research about P27kip1 has been done abroad, but seldom in China. Now most scholar think that P27kip1 is related to non-small cell lung cancer,
breast carcinomas and coloreactal carcinomas. P27kip1 expresses differently in different tumor tissue. P27kip1 is considered an independent marker of tumor.
Methods:The expression of P27kipl in 44 cases of nephroblastoma was detected by immunohistochemical method. Anlysis the relationship between P27kip1 expression and prognosis of the patients as well as clinic pathological characteristic. Discuss the function of P27kip1 in forming and development of nephroblastoma. All patients were followed up. The univariate and multivariate prognostic analyses were performed by using Cox regression model.
Results: The high expressive rate of P27kip1 for nephroblastoma was 65.91%(29/44), the low expressive rate was 34.09%(15/44). Low P27 expression in nephroblastoma was significantly associated with late stage , local recurrence , and high incidence of lymph node metastasis, But high P27kip1 expression is contrary. All patients were operated and recepted chemotherapy. Vincristini Sulfas ,Cytoxan and Dactinomycin were used. The course of treatment was 6 months to 1 year. 2 cases received radiotherapy. 3 1 cases were followed up. 3 cases died.
Conclusion:. P27kip1 is an independent and valid prognostic marker of nephroblastoma .
引文
[1] Polyak K,Lee Mong Hong,Erdjument Bromage H.et al.Cloning of P27,a cyclin-dependentt kinase inhibitor and a potential mediator of extracellular anttimitogenic signals [J] Cell. 1994;78(1):59-66
[2] Hideo Toyoshima, Tong Hunter.P27,a novel inhibitor of G_1 cyclin-CDK protein kinase activity, is related to P21 .Cell. 1994,78:67-74
[3] Pietenpol JA, Bohlander SK,Sato Y, et al.Assignment of the human P27~(kip1) gene to 12p13 and its aanalysis in leukemias [J] Cancer Res. 1995 ;55(6):1206-1210
[4] Esposito V Baldi A.De luca A.et al.Prognositic role of the cyclin-dependant kinase inhibitor P27 in non-small cell lung cancer[J].Cancer Res. 1997,57:3381-3385
[5] Tan P. Cady B.Wanner M.et al.The cell cycle inhibitor P27 is an independent prognosistic marker in small(T_(1a,b)invasive breast carcinomas [J].Cancer Res. 1997,57:1259-1263
[6] Loda M.Cukor B.Tam SW.et al.Increased proteasome-dependant
degradation of cyclin-dependant kinase inhibitor P27 in agreessive coloreactal carcinomas [J].Nat Med. 1997,3:231-234
[7] Singh SP.Lipman J.Goldman H.et al.Loss or altered subcellular localization of P27 in Barrett's associated adenocarcinoma [J].Caneer Res. 1998,58:1730-1735
[8] Yang RM. Naitoh J. Murphy M.et al.Low P27 expression predicts poor disease-free survival in patients with prostate cancer [J].J Urol＞1998,159:941-945
[9] Catzavelos C,Bhattacharya N,Ung YC,et al. Decreased levels of the cell-cycle inhibitor P27~(kip1) protein:prognostic implications in primary breast cancer [J] Nature Medieion 1997,3(2):227-230
[10] Peggy L Porter, Kathleen E Malone, Patrick J Heagerty, et al. Expression of cell-cycle regulators P27~(kip1) and cyclin E alone and in combination correlate with survival in young breast cancer patient. Nature Medicine, 1997,3:222-225
[11] Ciaparrone M,Yamamosto H, Yao Y, et al. Localization and expression of P27~(kip1) in multistage colorectal carcinogenesis [J].Cancer Res, 1998,58:114-122
[12] Yatabe Y,Masuda A, Koshikawa T, et al.P27~(kip1) in human lung cancers:differential changes in small cell and non-small cell carcinomas [J],Cancer Res. 1998,58:1042-1047
[13] Kudo Y,Takata T, Yasui W, et al.Reduced expression of
cyclindependent kinase inhibitor P27~(kip1) is an indicator of malignant behavior in oral squamous cell carcinoma [J].Cancer, 1998,83:2447-2455
[14] Ponce-Castaneda MV,Lee,et al.P27~(kip1):chromosomal mapping to 12p~(12)-12p~(13.1) and absence of mutation in human tumors [J].Cancer Res,1995,55:1211-1214
[15] Cheng J,Willingham T, Shuford M,et al.Tumor suppression and inhibition of aneuploid cell accumulation in human tutor cells by ectopic over expression of the cyclin-dependent kinase inhibitor P27~(kip1) [J].J Clin L Invest, 1996,97:1983-1988
[16] Lioyd RV,Jin L,Qian X,et al.Aberrant P27~(kip1) expression in endocrine and other tumors [J].Am J Pathol, 1997,150:401-407
[17] Lidhar K,Korbonits M, Jordan S,et al.Lowexpression of the cell cycle inhibitor P27~(kip1) in nomal corticotroph cells,corticotroph tumors and malignant pituitary tumors [J].J Clin Endocrinol Metab, 1999,84:3823-3830
[18] 曹红亮，张广德，夏文华等．P27蛋白在乳腺癌中的表达与预后的关系．[J]癌症，2000，19(3)：239-241
[19] 江洪，吕大同，易胜中等．P27蛋白在肺鳞状细胞癌中的表达及其意义．[J]癌症，2000，19(7)：699-701
[20] 郭艳琳，梁晓燕，李士瑛等．P27~(kip1)在星形细胞瘤中表达的意义．[J]山西医科大学学报，2001，32(2)：107-109
[21] P.A. Voute,C. Kalifa,A. Barret. Cancer in children .[NY]1998,259-273
[2] Hideo Toyoshima, Tong Hunter.P27,a novel inhibitor of G_1 cyclin-CDK protein kinase activity, is related to P21 .Cell. 1994,78:67-74
[3] Pietenpol JA, Bohlander SK,Sato Y, et al.Assignment of the human P27~(kip1) gene to 12p13 and its aanalysis in leukemias [J] Cancer Res. 1995 ;55(6):1206-1210
[4] Esposito V Baldi A.De luca A.et al.Prognositic role of the cyclin-dependant kinase inhibitor P27 in non-small cell lung cancer[J].Cancer Res. 1997,57:3381-3385
[5] Tan P. Cady B.Wanner M.et al.The cell cycle inhibitor P27 is an independent prognosistic marker in small(T_(1a,b)invasive breast carcinomas [J].Cancer Res. 1997,57:1259-1263
[6] Loda M.Cukor B.Tam SW.et al.Increased proteasome-dependant
degradation of cyclin-dependant kinase inhibitor P27 in agreessive coloreactal carcinomas [J].Nat Med. 1997,3:231-234
[7] Singh SP.Lipman J.Goldman H.et al.Loss or altered subcellular localization of P27 in Barrett's associated adenocarcinoma [J].Caneer Res. 1998,58:1730-1735
[8] Yang RM. Naitoh J. Murphy M.et al.Low P27 expression predicts poor disease-free survival in patients with prostate cancer [J].J Urol＞1998,159:941-945
[9] Catzavelos C,Bhattacharya N,Ung YC,et al. Decreased levels of the cell-cycle inhibitor P27~(kip1) protein:prognostic implications in primary breast cancer [J] Nature Medieion 1997,3(2):227-230
[10] Peggy L Porter, Kathleen E Malone, Patrick J Heagerty, et al. Expression of cell-cycle regulators P27~(kip1) and cyclin E alone and in combination correlate with survival in young breast cancer patient. Nature Medicine, 1997,3:222-225
[11] Ciaparrone M,Yamamosto H, Yao Y, et al. Localization and expression of P27~(kip1) in multistage colorectal carcinogenesis [J].Cancer Res, 1998,58:114-122
[12] Yatabe Y,Masuda A, Koshikawa T, et al.P27~(kip1) in human lung cancers:differential changes in small cell and non-small cell carcinomas [J],Cancer Res. 1998,58:1042-1047
[13] Kudo Y,Takata T, Yasui W, et al.Reduced expression of
cyclindependent kinase inhibitor P27~(kip1) is an indicator of malignant behavior in oral squamous cell carcinoma [J].Cancer, 1998,83:2447-2455
[14] Ponce-Castaneda MV,Lee,et al.P27~(kip1):chromosomal mapping to 12p~(12)-12p~(13.1) and absence of mutation in human tumors [J].Cancer Res,1995,55:1211-1214
[15] Cheng J,Willingham T, Shuford M,et al.Tumor suppression and inhibition of aneuploid cell accumulation in human tutor cells by ectopic over expression of the cyclin-dependent kinase inhibitor P27~(kip1) [J].J Clin L Invest, 1996,97:1983-1988
[16] Lioyd RV,Jin L,Qian X,et al.Aberrant P27~(kip1) expression in endocrine and other tumors [J].Am J Pathol, 1997,150:401-407
[17] Lidhar K,Korbonits M, Jordan S,et al.Lowexpression of the cell cycle inhibitor P27~(kip1) in nomal corticotroph cells,corticotroph tumors and malignant pituitary tumors [J].J Clin Endocrinol Metab, 1999,84:3823-3830
[18] 曹红亮，张广德，夏文华等．P27蛋白在乳腺癌中的表达与预后的关系．[J]癌症，2000，19(3)：239-241
[19] 江洪，吕大同，易胜中等．P27蛋白在肺鳞状细胞癌中的表达及其意义．[J]癌症，2000，19(7)：699-701
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