β-catenin，CyclinD1，Smad4在胰腺癌中的表达及其意义
摘要
胰腺癌是消化道恶性肿瘤之一，其恶性程度高，发展迅速，确诊时往往已属晚期，手术切除率低，预后差。尽管针对胰腺癌做了大量研究，但其发生机制仍未阐明。癌基因的激活，抑癌基因的失活和细胞周期的紊乱都可能与胰腺癌的发生有关。近来细胞内相互交错的信号转导网络成为研究热点，最近研究表明，Wnt和TGF-β信号转导通路有协同作用，共同促进肿瘤的发生。β-连环蛋白(β-catenin，β-cat)是Wnt信号通路中的重要调控因子，具有双重功能：既能与E-cadherin形成β-cat／E-cad复合物，介导细胞间黏附，维持上皮细胞的极性和完整性；同时又参与Wnt信号转导，Wnt信号异常激活可导致其在胞质聚集并进入细胞核调节下游靶基因，引起细胞增殖分化异常。已证实cyclinD1是β-cat的下游靶基因。CyclinD1是作用于G1期的细胞周期蛋白，可推进细胞由G1期进入S期，促进细胞增殖。Smad4为胰腺特异抑癌基因，是TGF-β转导通路中的必须调控子，Smad4的突变导致TGF-β通路的阻断，细胞发生癌变。本课题应用免疫组化技术检测正常胰腺、良性胰腺疾病及胰腺癌中β-cat、CyclinD1、和Smad4的表达情况，探讨胰腺癌的可能发生机制及其临床意义。
材料与方法
1．收集郑州大学第一、二附属医院1994—2002年间胰腺存档蜡块，癌旁经病理证实正常胰腺组织14例，良性胰腺疾病10例，原发胰腺导管腺癌37例。每例均有详细的临床资料。每个蜡块以4μm厚度连续切片5—6张，分别进行H-E和免疫组化染色。
郑州大学2004年硕士论文
日一catenin、
cyelinnl、smad4在胰腺癌中的表达及其意义
采用免疫组化链霉亲和素一生物素复合物(Strept户份idin Biotin eomplex，s妞e)
方法检测p一cat、CydinDI和Smad4在正常胰腺、良性胰腺疾病和胰腺癌中的
表达情况。
应用sPSS10.O统计软件，采用Fisher’s精确概率法和Spearman相关分析进行统
计，取Q=0.05为检验水准。
结果
1.p一eat主要定位于正常胰腺的细胞膜上，呈棕黄色颗粒，在胰腺癌中p一cat呈异
常表达，细胞膜表达减少，细胞质或细胞核呈棕黄色。37例胰腺癌中异常表达
为67.57%(25/37)，显著高于正常胰腺(0%，0/14)(尸<0.05)，但与胰腺良性
疾病(40%，4/10)无显著差异(尸>.05)。在胰腺癌中，p一eat在m/W期的异常表
达有17例(85%)，显著高于I/11期(47.06%，8/17)(P<0.05)。有淋巴结转移
组异常表达率为85%(17/20)，与无淋巴结转移组(47.06%，8/17)相比，差异
有显著性(尸<0.05)。p一cat在高、中低分化中差异无显著性(尸>.05)
2.CydinDI表达主要表达于细胞核内呈棕黄色颗粒。在胰腺癌中有26例表达，在
胰腺良性疾病中有3例表达，而正常胰腺无1例表达。在胰腺癌中的表达率显
著高于正常胰腺和良胜疾病(尸<0.05)。CychnDI的表达情况与胰腺癌的病理分
级、TNM分期、有无淋巴结转移均无关(尸>0.05)。
3.Smad4主要表达在细胞质和(或)细胞核中，呈弥漫性棕黄色。在37例胰腺癌
中表达率为51.35%(19/37)，显著低于正常胰腺(92.85%，13/14)和良性胰腺
疾病(90%，9/10)(尸<0.05)。smad4蛋白表达与胰腺癌的病理学分级、临床分期、
有无淋巴结转移均无统计学意义(尸>0.05)。
4.p一cat与CydinDI在胰腺癌中共阳性有21例，共阴性7例，二者表达有明显相
关(P<0.05)，日一cat与Smad4的表达也有相关性(P<0.05)，日一eat阳性者有17
例Smad4也呈阳性，日一eat阴性者smad4阳性有2例。Smad4与Cyelinol共阳
性表达有16例，二者无明显相关(尸>0.05)。
结论
1.日一cat在胰腺癌中的异常表达率显著高于正常胰腺，与分化程度无关，与临床分
郑州大学2004年硕士论文
旦一catenin、
eyelinDI、smad4在胰腺癌中的表达及其意义
期、淋巴结转移密切相关，提示p一cat在胰腺癌发生和进展中可能有重要作用，
促进癌细胞转移和浸润。
2.cyclinDI在胰腺癌中呈高表达，但与病理分级、临床分期和淋巴结转移无关，
3.Smad4的阳性表达在正常胰腺、良性胰腺疾病及胰腺癌中呈下降趋势，在胰腺
癌中的表达与临床病理参数无统计学意义，说明Smad4缺失在胰腺癌的形成过
程中有重要作用，Smad4的失活可导致TGF一p信号通路中断，细胞生长失去抑
制。
4.日
一eat与Cyclinnz在胰腺癌中的表达有相关性，CyelinDI是p一eat的靶基因，
一cat通过激活CyclinDI持续转录促进肿瘤细胞增殖。
5.在胰腺癌中卜cat和Smad4的表达密切相关，Wnt与TGF一p信号通路有交互作
用，p一cat和Smad4协同作用可能促进胰腺癌的发生。
Pancreatic carcinoma is one of the gastrointestinal malignancies. The prognosis is poor because of its rapid progress, low rate resecting and most cases are discovered at the late stage. Although many researchers studied pancreatic cancer a lot,the mechanism of tumorigenesis is not very clear yet. It has been demonstrated that the activation of oncogene, the inactivation of tumor suppress gene and the aberrance of the cell cycle regulation ,all these may lead to pancreatic cancer. Recently, the researchers had focused on the signaling pathways' crosstalk. Several studies have shown that cooperation between transforming growth factor (TGF-8) and Wnt signaling pathway play a role in tumorigenesis. 6-catenin is required for cell-cell adhesion. 6-catenin mediates cell adhesion through interactions with E-cadherin, and at the same time, it is a regulator of the Wnt pathway. Wnt signaling allows 8-cat to accumulate in the cytoplasm and subsequently translocate to the nucleus and at where 8-cat activates the target
genes, CyclinD1. It pushes cell cycle from G1 phase to S phase increasing cell proliferation. As a tumor suppress gene of pancreas, Smad4 is a necessary regulator in TGF-6 pathway . The mutation of Smad4 leads to the disruption of TGF-6 pathway so that promotes the development of the cancer. In order to investigate the possible mechanism of pancreatic carcinogenesis and provide something helpful for diagnosis and therapy, an immunohistichemical technique was used to detect the expression of 8-catenin, CyclinDl, Smad4 in normal pancreatic tissues, benign diseases and cancer of pancreas. Material and methods:
1. 14 normal pancreatic tissues confirmed pathologically which were adjacent to the tumor, 10 benign pancreatic disease and 37 primary pancreatic ductal adenocarcinoma tissues were collected. Each case has detailed information.
2. SABC immunohistochemical technique was used to detect the expression of B-catenin, CyclinDl, Smad4 in these three kinds of tissues.
3. SPSS10.0 statistical software was used to analyze the date. Using Fisher's exact probabilities analyzed the correlation between G-catenin, CyclinDl, Smad4 and clincopathological features of tumors. Spearman rank correlation was used to analyze the relationship among three protein .A difference was considered significant if P value was less than 0.05.
Results
1. In normal pancreatic tissues the staining of B-catenin was located on the cell membrance , but in the pancreatic cancer the membrance staining decreased and mainly located in the cytoplasm or nucleus. The abnormal expression was 67.57 %( 25/37) in pancreatic cancer, only 40 %( 4/10) cases were detected abnormal staining in benign disease; none of the staining in normal pancreas was abnormal. There were significant differences among them (P<0.05). In pancreatic cancer, the abnormal expression rate of I / II stages (47.06%) was lower than that of III/IV stages (85% )(P<0.05). The abnormal expression of the B-catenin in cancer tissues with lymph node metastasis (85%,17/23) was significantly higher than the ones with no metastasis (47.06%,8/17) (P<0.05).But it had no relationship with pathological differentiation grade(P>0.05)
2. Positive staining of CyclinDl was mainly located in the nucleus. 26 cases of pancreatic cancer and 3 cases of benign disease were detected positive staining; there was no positive expression in normal pancreas. There were significant differences between cancer and benign, normal tissues (P<0.05). No significant differences were found between the expression of CyclinDl and the differentiation, clinical stage and lymph node metastasis (P>0.05).
3. The expression of Smad4 was observed in the cytoplasm and nucleus. The expression
rate (51.35%, 19/37) of pancreatic cancer was lower than that of the normal pancreas (92.85. %, 13/14) and benign disease (90%, 9/10) (P<0.05). Smad4 expression had no relationship with the clinical parameters of pancreatic cancer. (P>0.05).
4. The expression of 6-catenin and CyclinDl were both positive in 21 ca
材料与方法
1．收集郑州大学第一、二附属医院1994—2002年间胰腺存档蜡块，癌旁经病理证实正常胰腺组织14例，良性胰腺疾病10例，原发胰腺导管腺癌37例。每例均有详细的临床资料。每个蜡块以4μm厚度连续切片5—6张，分别进行H-E和免疫组化染色。
郑州大学2004年硕士论文
日一catenin、
cyelinnl、smad4在胰腺癌中的表达及其意义
采用免疫组化链霉亲和素一生物素复合物(Strept户份idin Biotin eomplex，s妞e)
方法检测p一cat、CydinDI和Smad4在正常胰腺、良性胰腺疾病和胰腺癌中的
表达情况。
应用sPSS10.O统计软件，采用Fisher’s精确概率法和Spearman相关分析进行统
计，取Q=0.05为检验水准。
结果
1.p一eat主要定位于正常胰腺的细胞膜上，呈棕黄色颗粒，在胰腺癌中p一cat呈异
常表达，细胞膜表达减少，细胞质或细胞核呈棕黄色。37例胰腺癌中异常表达
为67.57%(25/37)，显著高于正常胰腺(0%，0/14)(尸<0.05)，但与胰腺良性
疾病(40%，4/10)无显著差异(尸>.05)。在胰腺癌中，p一eat在m/W期的异常表
达有17例(85%)，显著高于I/11期(47.06%，8/17)(P<0.05)。有淋巴结转移
组异常表达率为85%(17/20)，与无淋巴结转移组(47.06%，8/17)相比，差异
有显著性(尸<0.05)。p一cat在高、中低分化中差异无显著性(尸>.05)
2.CydinDI表达主要表达于细胞核内呈棕黄色颗粒。在胰腺癌中有26例表达，在
胰腺良性疾病中有3例表达，而正常胰腺无1例表达。在胰腺癌中的表达率显
著高于正常胰腺和良胜疾病(尸<0.05)。CychnDI的表达情况与胰腺癌的病理分
级、TNM分期、有无淋巴结转移均无关(尸>0.05)。
3.Smad4主要表达在细胞质和(或)细胞核中，呈弥漫性棕黄色。在37例胰腺癌
中表达率为51.35%(19/37)，显著低于正常胰腺(92.85%，13/14)和良性胰腺
疾病(90%，9/10)(尸<0.05)。smad4蛋白表达与胰腺癌的病理学分级、临床分期、
有无淋巴结转移均无统计学意义(尸>0.05)。
4.p一cat与CydinDI在胰腺癌中共阳性有21例，共阴性7例，二者表达有明显相
关(P<0.05)，日一cat与Smad4的表达也有相关性(P<0.05)，日一eat阳性者有17
例Smad4也呈阳性，日一eat阴性者smad4阳性有2例。Smad4与Cyelinol共阳
性表达有16例，二者无明显相关(尸>0.05)。
结论
1.日一cat在胰腺癌中的异常表达率显著高于正常胰腺，与分化程度无关，与临床分
郑州大学2004年硕士论文
旦一catenin、
eyelinDI、smad4在胰腺癌中的表达及其意义
期、淋巴结转移密切相关，提示p一cat在胰腺癌发生和进展中可能有重要作用，
促进癌细胞转移和浸润。
2.cyclinDI在胰腺癌中呈高表达，但与病理分级、临床分期和淋巴结转移无关，
3.Smad4的阳性表达在正常胰腺、良性胰腺疾病及胰腺癌中呈下降趋势，在胰腺
癌中的表达与临床病理参数无统计学意义，说明Smad4缺失在胰腺癌的形成过
程中有重要作用，Smad4的失活可导致TGF一p信号通路中断，细胞生长失去抑
制。
4.日
一eat与Cyclinnz在胰腺癌中的表达有相关性，CyelinDI是p一eat的靶基因，
一cat通过激活CyclinDI持续转录促进肿瘤细胞增殖。
5.在胰腺癌中卜cat和Smad4的表达密切相关，Wnt与TGF一p信号通路有交互作
用，p一cat和Smad4协同作用可能促进胰腺癌的发生。
Pancreatic carcinoma is one of the gastrointestinal malignancies. The prognosis is poor because of its rapid progress, low rate resecting and most cases are discovered at the late stage. Although many researchers studied pancreatic cancer a lot,the mechanism of tumorigenesis is not very clear yet. It has been demonstrated that the activation of oncogene, the inactivation of tumor suppress gene and the aberrance of the cell cycle regulation ,all these may lead to pancreatic cancer. Recently, the researchers had focused on the signaling pathways' crosstalk. Several studies have shown that cooperation between transforming growth factor (TGF-8) and Wnt signaling pathway play a role in tumorigenesis. 6-catenin is required for cell-cell adhesion. 6-catenin mediates cell adhesion through interactions with E-cadherin, and at the same time, it is a regulator of the Wnt pathway. Wnt signaling allows 8-cat to accumulate in the cytoplasm and subsequently translocate to the nucleus and at where 8-cat activates the target
genes, CyclinD1. It pushes cell cycle from G1 phase to S phase increasing cell proliferation. As a tumor suppress gene of pancreas, Smad4 is a necessary regulator in TGF-6 pathway . The mutation of Smad4 leads to the disruption of TGF-6 pathway so that promotes the development of the cancer. In order to investigate the possible mechanism of pancreatic carcinogenesis and provide something helpful for diagnosis and therapy, an immunohistichemical technique was used to detect the expression of 8-catenin, CyclinDl, Smad4 in normal pancreatic tissues, benign diseases and cancer of pancreas. Material and methods:
1. 14 normal pancreatic tissues confirmed pathologically which were adjacent to the tumor, 10 benign pancreatic disease and 37 primary pancreatic ductal adenocarcinoma tissues were collected. Each case has detailed information.
2. SABC immunohistochemical technique was used to detect the expression of B-catenin, CyclinDl, Smad4 in these three kinds of tissues.
3. SPSS10.0 statistical software was used to analyze the date. Using Fisher's exact probabilities analyzed the correlation between G-catenin, CyclinDl, Smad4 and clincopathological features of tumors. Spearman rank correlation was used to analyze the relationship among three protein .A difference was considered significant if P value was less than 0.05.
Results
1. In normal pancreatic tissues the staining of B-catenin was located on the cell membrance , but in the pancreatic cancer the membrance staining decreased and mainly located in the cytoplasm or nucleus. The abnormal expression was 67.57 %( 25/37) in pancreatic cancer, only 40 %( 4/10) cases were detected abnormal staining in benign disease; none of the staining in normal pancreas was abnormal. There were significant differences among them (P<0.05). In pancreatic cancer, the abnormal expression rate of I / II stages (47.06%) was lower than that of III/IV stages (85% )(P<0.05). The abnormal expression of the B-catenin in cancer tissues with lymph node metastasis (85%,17/23) was significantly higher than the ones with no metastasis (47.06%,8/17) (P<0.05).But it had no relationship with pathological differentiation grade(P>0.05)
2. Positive staining of CyclinDl was mainly located in the nucleus. 26 cases of pancreatic cancer and 3 cases of benign disease were detected positive staining; there was no positive expression in normal pancreas. There were significant differences between cancer and benign, normal tissues (P<0.05). No significant differences were found between the expression of CyclinDl and the differentiation, clinical stage and lymph node metastasis (P>0.05).
3. The expression of Smad4 was observed in the cytoplasm and nucleus. The expression
rate (51.35%, 19/37) of pancreatic cancer was lower than that of the normal pancreas (92.85. %, 13/14) and benign disease (90%, 9/10) (P<0.05). Smad4 expression had no relationship with the clinical parameters of pancreatic cancer. (P>0.05).
4. The expression of 6-catenin and CyclinDl were both positive in 21 ca
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36．谷丽君，陈杰，刘彤华，等．石蜡包埋人胰腺癌组织中Smad4蛋白和转化生长因子β及其Ⅱ型受体．中华病理学杂志，2001，30(6)：439—442．
37. Luttges J, Galehdari H, Brocker V, et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol, 2001,158(10): 1677-1683
38．吴春燕，郭晓钟．DPC4基因与胰腺癌关系的研究进展．国外医学消化系疾病分
册，2004，24(1)：26-28
39. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, et al. DPC4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol, 2000, 157(4): 755-761
40．杨竹林，李永国，王群伟，等．胰腺良恶性疾病组织中Smad4mRNA，PTENmRNA，p73mRNA表达及意义．中华肝胆外科杂志，2003，9(3)：169—171．
41. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of dpc4 in pancreatic intraepithelial neoplasia: evidence that dpc4 inactivation occurs in neoplastic progression. Cancer Res, 2000, 60(5): 2002-2006.
42. Shtutman M, Zhurinsky J, Simcha I, et al. The CyclinD1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA, 1999, 96(5): 5522-5527
43. Qiao Q, Ramadani M, Gansauge S, et al. Reduced membranous and ectopic cytoplasmic expression of beta catenin correlate with CyclinD1 overexpression and poor prognosis in pancreatic cancer. Int J Cancer. 2001, 95(3):194-197
44．李玉军，纪祥瑞．β连环蛋白、细胞周期蛋白D1和c-myc表达与胰腺癌发生及生物学行为的关系．中华病理学杂志，2003，32(3)：238-241．
45. Nishita M, Hashimoto MK, Ogata S, et al. Interaction between wnt and TGF-β signaling pathways during formation of spemann's organizer. Nature 2000, 403(17): 781-785
46. Labble EA, Letamendia A, Attisanol L. Association of smads with lymphoid enhancer banding factor 1/T cell-specific factors mediates cooperative signaling by the transforming growth factor beta and wnt pathways. Proc Natl Acad Sci USA 2000, 97(18): 8358-8363
47. Tian Y, Phillips A, Interaction between the Tranforming growth factor-β type Ⅰ receptor/Smad pathway and β-catenin during transforming growth factor β mediated adherens junctoin dissembly. Am J Pathol, 2002,160(5): 1619-1627.
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50. Villanueva A, Garcia C, Paules AB, et al. Disruption of the antiproliferative TGF-β-signaling pathways in human pancreatic cancer cells. Oncogene, 1998, 17(8): 1969-1978.
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34. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at chromosome 18q21.1. Science, 1996, 271:350-353.
35．谷丽君，陈杰，崔全才，等．DPC4基因在胰腺癌中的改变．中华肿瘤杂志，2001，23(4)：293-295
36．谷丽君，陈杰，刘彤华，等．石蜡包埋人胰腺癌组织中Smad4蛋白和转化生长因子β及其Ⅱ型受体．中华病理学杂志，2001，30(6)：439—442．
37. Luttges J, Galehdari H, Brocker V, et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol, 2001,158(10): 1677-1683
38．吴春燕，郭晓钟．DPC4基因与胰腺癌关系的研究进展．国外医学消化系疾病分
册，2004，24(1)：26-28
39. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, et al. DPC4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol, 2000, 157(4): 755-761
40．杨竹林，李永国，王群伟，等．胰腺良恶性疾病组织中Smad4mRNA，PTENmRNA，p73mRNA表达及意义．中华肝胆外科杂志，2003，9(3)：169—171．
41. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of dpc4 in pancreatic intraepithelial neoplasia: evidence that dpc4 inactivation occurs in neoplastic progression. Cancer Res, 2000, 60(5): 2002-2006.
42. Shtutman M, Zhurinsky J, Simcha I, et al. The CyclinD1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA, 1999, 96(5): 5522-5527
43. Qiao Q, Ramadani M, Gansauge S, et al. Reduced membranous and ectopic cytoplasmic expression of beta catenin correlate with CyclinD1 overexpression and poor prognosis in pancreatic cancer. Int J Cancer. 2001, 95(3):194-197
44．李玉军，纪祥瑞．β连环蛋白、细胞周期蛋白D1和c-myc表达与胰腺癌发生及生物学行为的关系．中华病理学杂志，2003，32(3)：238-241．
45. Nishita M, Hashimoto MK, Ogata S, et al. Interaction between wnt and TGF-β signaling pathways during formation of spemann's organizer. Nature 2000, 403(17): 781-785
46. Labble EA, Letamendia A, Attisanol L. Association of smads with lymphoid enhancer banding factor 1/T cell-specific factors mediates cooperative signaling by the transforming growth factor beta and wnt pathways. Proc Natl Acad Sci USA 2000, 97(18): 8358-8363
47. Tian Y, Phillips A, Interaction between the Tranforming growth factor-β type Ⅰ receptor/Smad pathway and β-catenin during transforming growth factor β mediated adherens junctoin dissembly. Am J Pathol, 2002,160(5): 1619-1627.
48. Letamendia A, Labbe E, Attisano L. Transcriptional regulation by smads. Crosstalk
between the TGF-β and wnt panthways. Jour Bone Sury, 2001: 83-A, S1-S31
49. Cullingworth J, Hooper ML, Harrisano DJ, et al. Carcinogen-induced pancreatic lesions in the mouse: effect of smad4 and APC genotypes. Oncogene, 2002,21(4): 4696-4701
50. Villanueva A, Garcia C, Paules AB, et al. Disruption of the antiproliferative TGF-β-signaling pathways in human pancreatic cancer cells. Oncogene, 1998, 17(8): 1969-1978.