b-catenin 的表达与早期胃癌多发性的关系
王轶淳, 孙明军, 中国医科大学附属第一医院内镜中心 辽宁省沈阳市 110001
傅炜昕,中国医科大学实验技术中心 辽宁省沈阳市 110001
傅宝玉,中国医科大学附属第一医院消化内科 辽宁省沈阳市 110001
通讯作者:王轶淳, 110001, 辽宁省沈阳市和平区南京北街155号, 中国医科大学附属第一医院内镜中心. susanwyichun@yahoo.com
电话: 024-23256666-6108 传真: 024-22703576
收稿日期: 2004-09-29 接受日期: 2004-10-11
摘要
目的:探讨b-catenin在早期胃癌中的表达与早期胃癌的多发性和单发性的关系.
方法:用免疫组织化学方法检测59例早期胃癌患者胃癌组织中b-catenin的表达情况.
结果:早期胃癌中存在b-catenin的异常表达，多发组的阳性率为60.00%，单发组的阳性率为13.79%，均高于对照组.多发组的阳性细胞百分率为(58.25±10.54)%，单发组为(29.91±5.14)%，两组比较差异有显著性(P<0.05).
结论:在早期胃癌中存在b-catenin的异常表达，与早期胃癌的多发性有关，b-catenin阳性的早期胃癌患者出现多发性胃癌的危险性高于b-catenin阴性者.
王轶淳, 孙明军, 傅炜昕, 傅宝玉. b-catenin的表达与早期胃癌多发性的关系. 世界华人消化杂志 2005;13(9):1150-1153
:多发组; B:单发组.
3 讨论b-catenin是一种多功能蛋白质，具有细胞黏附和信号传导功能[1，6-7].细胞内绝大多数的b-catenin与E-cadherin相结合，通过a-catenin与肌动蛋白细胞骨架相连，参与细胞间的黏附和细胞运动.当E-cadherin-catenin复合物中的任一结构发生变化时，都会影响细胞间连接.同时细胞中b-catenin的过度沉积可以促使细胞过度增生[8-9].b-catenin的生成与降解处于一种动态平衡状态，细胞中的糖原合成酶激酶-3b(GSK-3b)可以使b-catenin的N端丝氨酸残基和苏氨酸残基磷酸化，通过蛋白分解系统降解b-catenin，使细胞中的b-catenin稳定在一个较低的水平.当Wnt蛋白表达高时，与细胞膜上的受体结合，通过对adenomatous polyposis coli(APC)、GSK-3b等因素的抑制作用，使细胞内单聚体的b-catenin增多，与Tcf或者Lef结合，进入细胞核，而Tcf/Lef是DNA结合蛋白，进入细胞核内后，作为转录因子与相应的DNA结合，促进靶基因(如C-myc、cyclinD1、MMP-7等)[10-13]的持续转录，从而完成Wnt信号的传导.另一方面，APC蛋白与b-catenin结合，可以促进GSK-3b对b-catenin的磷酸化[14-15].而b-catenin基因本身的异常，如b-catenin的外显子3的N端在调节b-catenin的机制中，是一个非常重要的序列，如果该序列缺失或者突变，则出现b-catenin的降解障碍，导致b-catenin的蓄积.因此，APC的缺陷、b-catenin基因本身的突变以及Wnt途径中其他的变化，均可以导致b-catenin的蓄积.胃癌的发生发展是一个多因素多步骤的过程，涉及多种癌基因、抑癌基因、端粒及端粒酶、细胞黏附因子等[16-21].有研究[22]表明，b-catenin的异常表达与预后不良有相关性.胃癌组织中b-catenin在细胞膜表达的减弱与分化不良及存活时间短有关系[23].本研究表明，在早期胃癌中存在b-catenin的异常表达.与正常胃组织相比，在胃癌细胞膜的表达缺失.考虑该蛋白质表达的减弱或缺失，可能导致a-catenin不能与cadherin相连接，影响细胞间的正常连接，从而使肿瘤细胞的黏附能力下降，获得转移、侵袭的能力.
b-catenin的异常表达在肿瘤发展中的效应可能不同.Nhieu et al的研究[24]发现，肝癌中b-catenin明显蓄积于细胞核，与b-catenin基因的突变有相关性.突变的b-catenin在细胞核的蓄积可能增加肿瘤复发的危险性，预后不好.对不同分期卵巢癌中b-catenin的表达与组织学分型以及疾病转归的关系的研究[25]发现，细胞核表达b-catenin是预后良好的标志，仅有细胞膜表达的，预后不好.有研究指出，Wnt信号传导通路与G蛋白通路等其他通路之间有交互作用[26]，可以形成复杂的网络，提示b-catenin的异常表达在肿瘤发展过程中有多重效应[27-29].本研究结果表明，正常胃组织中无b-catenin在细胞核的阳性表达，而胃癌组织的细胞核中b-catenin呈阳性，表达明显增强，提示存在b-catenin的蓄积.多发组b-catenin的阳性细胞所占的比率明显高于单发组，两组比较差异有显著性，提示b-catenin的异常表达与早期胃癌的多发性有关，b-catenin阳性的早期胃癌患者，出现多发性胃癌的危险性高于b-catenin阴性者，为加强对细胞核b-catenin表达异常的早期胃癌患者进行严格的定期随访提供了依据.另外，b-catenin是Wnt通路中的关键环节，其与上游及下游因子之间的关系非常复杂[30-33].本次实验中多发组有4例的两次胃癌切除标本b-catenin的表达不同，一次为阳性，另一次为阴性，考虑可能是两次肿瘤的发生途径不同.实验结果还显示，多发组中有4 例、单发组中有1例存在b-catenin在细胞质中的表达，而细胞核中呈阴性反应，考虑在这些胃癌的发生过程中，不是通过b-catenin的蓄积进而进入细胞核引起癌基因的激活，而是存在其他的致癌途径.
我们未对是否存在b-catenin基因异常进行检测，b-catenin的蓄积是其基因本身的异常还是Wnt途径中其他因素异常所致，目前尚不清楚，有待进一步的研究.
4 参考文献1 Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST, Yoo NJ, Lee JY. Frequent somatic
mutation of the b-catenin gene in intestinal-type gastric cancer. Cancer Res 1999;59:4257-4260
2 Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of b-catenin-Tcf signaling in
colon cancer by mutations in b-catenin or APC. Science 1997;275:1787-1790
3 Voeller HJ, Truica CI, Gelmann EP. b-catenin mutations in human prostate cancer. Cancer Res 1998;58:2520-2523
4 Chan E, Gat U, McNiff JM, Fuchs E. A common human skin tumor is caused by activating mutations in b-catenin.
Nat Genet 1999;21:410-413
5 Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y. Activation
of the b-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.
Cancer Res 1998;58:2524-2527
6 Gumbiner BM. Signal transduction by b-catenin. Curr Opin Cell Biol 1995;7:634-640
7 Cui J, Zhou X, Liu Y, Tang Z, Romeih M. Wnt signaling in hepatocellular carcinoma:analysis of mutation and expression
of beta-catenin, T-cell facter-4 and glycogen synthase kinease 3-beta genes. J Gastroenterol Hepatol 2003;18:280-287
8 Cui J, Zhou XD, Liu YK, Tang ZY, Zile MH. Abnormal beta-catenin gene expression with invasiveness of primary
hepatocellular carcinoma in China. World J Gastroenterol 2001;7:542-546
9 Jiang Y, Zhou XD, Liu YK, Wu X, Huang XW. Association of hTcf-4 gene expression and mutation with clinicopathological
characteristics of hepatocellular carcinoma. World J Gastroenterol 2002;8:804-807
10 He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of
c-MYC as a target of the APC pathway. Science 1998;281:1509-1512
11 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Nature 1999;398:422-426
12 Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T. Beta-catenin regulates the expression of the matrix
metalloproteinase-7 in human colorectal cancer. Am J Pathol 1999;155:1033-1038
13 Monga SP, Monga HK, Tan X, Mule K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic
liver culture: role in proliferation, apoptosis, and lineage specification. Gastroenterology 2003;124:202-216
14 Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and
degradation of b-catenin. J Biol Chem 1997;272:24735-24738
15 Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin
complexes. Mol Cell Biol 1996;16:2128-2134
16 Li YL, He XM, Zheng HC, Wu DY, Yang XF, Xin Y, Fu BY. Expression of PTEN encoding product in malignant lesions of
gastric mucosa and its significance. Shijie Huaren Xiaohua Zazhi 2003;11:1294-1296
17 Fang DC, Luo YH, Yang SM, Li XA, Ling XL, Fang L. Mutation analysis of APC gene in gastric cancer with
microsatellite instabilly. World J Gastroenterol 2002;8:787-791
18 Song ZJ, Gong P, Wu YE. Relationship between the expression of iNOS, VEGF, tumor angiogenesis and gastric cancer.
World JGastroenterol 2002;8:591-595
19 Su JM, Gui L, Zhou YP, Zha XL. Expression of focal adhesion kinase and alpha5 and beta1 integrins in carcinomas and
its clinical significance. World J Gastroenterol 2002;8:613-618
20 Liu DH, Zhang XY, Fan DM, Huang YX, Zhang JS, Huang WQ, Zhang YQ, Huang QS, Ma WY, Chai YB, Jin M. Expression
of vascular endothelial growth factor and its role in oncogenesis of human gastric carcinoma.
World JGastroenterol 2001;7:500-505
21 Fang DC, Yang SM, Zhou XD, Wang DX, Luo YH. Telomere erosion is independent of microsatellite instability but
related to loss of heterozygosity in gastric cancer. World J Gastroenterol 2001;7:522-536
22 Jawhari A, Jordan S, Poole S, Browne P, Pignatelli M, Farthing MJ. Abnormal immunoreactivity of the
E-cadherin-catenin complex in gastric carcinoma:relationship with patient survival. Gastroenterology 1997;112:46-54
23 Ramesh S, Nash J, McCulloch PG. Reduction in membranous expression of b-catenin and increased cytoplasmic
E-cadherin expression predict poor survival in gastric cancer. Br J Cancer 1999;81:1392-1397
24 Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated b-catenin in
hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol 1999;155:703-710
25 Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suarez A, Armas A. beta-catenin expression pattern in stage I and
II ovarian carcinomas : relationship with beta-catenin gene mutations, clinicopathological features, and clinical outcome.
Am J Pathol 1999;155:527-536
26 Gleason JE, Korswagen HC, Eisenmann DM. Activation of Wnt signaling bypasses the requirement for RTK/Ras
signaling during C. elegans vulval induction. Genes Dev 2002;16:1281-1290
27 Tsukashita S, Kushima R, Bamba M, Nakamura E, Mukaisho K, Sugihara H, Hattori T. Beta-catenin expression in
intramucosal neoplastic lesions of the stomach. Comparative analysis of adenoma/dysplasia, adenocarcinoma and
signet-ring cell carcinoma. Oncology 2003;64:251-258
28 Li YJ, Ji XR. Relationship between expression of E-cadherin-catenin complex and clinicopathologic characteristics of
pancreatic cancer. World J Gastroenterol 2003;9:368-372
29 Qiang YW, Endo Y, Rubin JS, Rudiloff S. Wnt signaling in B-cell neoplasia. Oncogene 2003;22:1536-1545
30 Ebert MP, Yu J, Hoffmann J, Rocco A, Rocken C, Kahmann S, Muller O, Korc M, Sung JJ, Malfertheiner P. Loss of
beta-catenin expression in metastatic gastric cancer. J Clin Oncol 2003;21:1708-1714
31 Lowy AM, Fenoglio-Preiser C, Kim OJ, Kordich J, Gomez A, Knight J, James L, Groden J. Dysregulation of beta-catenin
expression correlates with tumor differentiation in pancreatic duct adenocarcinoma. Ann Surg Oncol 2003;10:284-290
32 Miyoshi K, Hennighausen L. Beta-catenin:a transforming actor on many stages. Breast Cancer Res 2003;5:63-68
33 Su XK, Zhao XM, Li JQ, Cui XJ, Xie XH, Yang HY, Xu FB, Shi M. Role of b-catenin and cyclin D1 expression in
intrahepatic dissemination of liver cancer. Shijie Huaren Xiaohua Zazhi 2003;11:1362-1364
编辑 张海宁, 百拇医药( 王轶淳,孙明军, 傅炜昕,傅宝玉)
傅炜昕,中国医科大学实验技术中心 辽宁省沈阳市 110001
傅宝玉,中国医科大学附属第一医院消化内科 辽宁省沈阳市 110001
通讯作者:王轶淳, 110001, 辽宁省沈阳市和平区南京北街155号, 中国医科大学附属第一医院内镜中心. susanwyichun@yahoo.com
电话: 024-23256666-6108 传真: 024-22703576
收稿日期: 2004-09-29 接受日期: 2004-10-11
摘要
目的:探讨b-catenin在早期胃癌中的表达与早期胃癌的多发性和单发性的关系.
方法:用免疫组织化学方法检测59例早期胃癌患者胃癌组织中b-catenin的表达情况.
结果:早期胃癌中存在b-catenin的异常表达，多发组的阳性率为60.00%，单发组的阳性率为13.79%，均高于对照组.多发组的阳性细胞百分率为(58.25±10.54)%，单发组为(29.91±5.14)%，两组比较差异有显著性(P<0.05).
结论:在早期胃癌中存在b-catenin的异常表达，与早期胃癌的多发性有关，b-catenin阳性的早期胃癌患者出现多发性胃癌的危险性高于b-catenin阴性者.
王轶淳, 孙明军, 傅炜昕, 傅宝玉. b-catenin的表达与早期胃癌多发性的关系. 世界华人消化杂志 2005;13(9):1150-1153
:多发组; B:单发组.
3 讨论b-catenin是一种多功能蛋白质，具有细胞黏附和信号传导功能[1，6-7].细胞内绝大多数的b-catenin与E-cadherin相结合，通过a-catenin与肌动蛋白细胞骨架相连，参与细胞间的黏附和细胞运动.当E-cadherin-catenin复合物中的任一结构发生变化时，都会影响细胞间连接.同时细胞中b-catenin的过度沉积可以促使细胞过度增生[8-9].b-catenin的生成与降解处于一种动态平衡状态，细胞中的糖原合成酶激酶-3b(GSK-3b)可以使b-catenin的N端丝氨酸残基和苏氨酸残基磷酸化，通过蛋白分解系统降解b-catenin，使细胞中的b-catenin稳定在一个较低的水平.当Wnt蛋白表达高时，与细胞膜上的受体结合，通过对adenomatous polyposis coli(APC)、GSK-3b等因素的抑制作用，使细胞内单聚体的b-catenin增多，与Tcf或者Lef结合，进入细胞核，而Tcf/Lef是DNA结合蛋白，进入细胞核内后，作为转录因子与相应的DNA结合，促进靶基因(如C-myc、cyclinD1、MMP-7等)[10-13]的持续转录，从而完成Wnt信号的传导.另一方面，APC蛋白与b-catenin结合，可以促进GSK-3b对b-catenin的磷酸化[14-15].而b-catenin基因本身的异常，如b-catenin的外显子3的N端在调节b-catenin的机制中，是一个非常重要的序列，如果该序列缺失或者突变，则出现b-catenin的降解障碍，导致b-catenin的蓄积.因此，APC的缺陷、b-catenin基因本身的突变以及Wnt途径中其他的变化，均可以导致b-catenin的蓄积.胃癌的发生发展是一个多因素多步骤的过程，涉及多种癌基因、抑癌基因、端粒及端粒酶、细胞黏附因子等[16-21].有研究[22]表明，b-catenin的异常表达与预后不良有相关性.胃癌组织中b-catenin在细胞膜表达的减弱与分化不良及存活时间短有关系[23].本研究表明，在早期胃癌中存在b-catenin的异常表达.与正常胃组织相比，在胃癌细胞膜的表达缺失.考虑该蛋白质表达的减弱或缺失，可能导致a-catenin不能与cadherin相连接，影响细胞间的正常连接，从而使肿瘤细胞的黏附能力下降，获得转移、侵袭的能力.
b-catenin的异常表达在肿瘤发展中的效应可能不同.Nhieu et al的研究[24]发现，肝癌中b-catenin明显蓄积于细胞核，与b-catenin基因的突变有相关性.突变的b-catenin在细胞核的蓄积可能增加肿瘤复发的危险性，预后不好.对不同分期卵巢癌中b-catenin的表达与组织学分型以及疾病转归的关系的研究[25]发现，细胞核表达b-catenin是预后良好的标志，仅有细胞膜表达的，预后不好.有研究指出，Wnt信号传导通路与G蛋白通路等其他通路之间有交互作用[26]，可以形成复杂的网络，提示b-catenin的异常表达在肿瘤发展过程中有多重效应[27-29].本研究结果表明，正常胃组织中无b-catenin在细胞核的阳性表达，而胃癌组织的细胞核中b-catenin呈阳性，表达明显增强，提示存在b-catenin的蓄积.多发组b-catenin的阳性细胞所占的比率明显高于单发组，两组比较差异有显著性，提示b-catenin的异常表达与早期胃癌的多发性有关，b-catenin阳性的早期胃癌患者，出现多发性胃癌的危险性高于b-catenin阴性者，为加强对细胞核b-catenin表达异常的早期胃癌患者进行严格的定期随访提供了依据.另外，b-catenin是Wnt通路中的关键环节，其与上游及下游因子之间的关系非常复杂[30-33].本次实验中多发组有4例的两次胃癌切除标本b-catenin的表达不同，一次为阳性，另一次为阴性，考虑可能是两次肿瘤的发生途径不同.实验结果还显示，多发组中有4 例、单发组中有1例存在b-catenin在细胞质中的表达，而细胞核中呈阴性反应，考虑在这些胃癌的发生过程中，不是通过b-catenin的蓄积进而进入细胞核引起癌基因的激活，而是存在其他的致癌途径.
我们未对是否存在b-catenin基因异常进行检测，b-catenin的蓄积是其基因本身的异常还是Wnt途径中其他因素异常所致，目前尚不清楚，有待进一步的研究.
4 参考文献1 Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST, Yoo NJ, Lee JY. Frequent somatic
mutation of the b-catenin gene in intestinal-type gastric cancer. Cancer Res 1999;59:4257-4260
2 Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of b-catenin-Tcf signaling in
colon cancer by mutations in b-catenin or APC. Science 1997;275:1787-1790
3 Voeller HJ, Truica CI, Gelmann EP. b-catenin mutations in human prostate cancer. Cancer Res 1998;58:2520-2523
4 Chan E, Gat U, McNiff JM, Fuchs E. A common human skin tumor is caused by activating mutations in b-catenin.
Nat Genet 1999;21:410-413
5 Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y. Activation
of the b-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.
Cancer Res 1998;58:2524-2527
6 Gumbiner BM. Signal transduction by b-catenin. Curr Opin Cell Biol 1995;7:634-640
7 Cui J, Zhou X, Liu Y, Tang Z, Romeih M. Wnt signaling in hepatocellular carcinoma:analysis of mutation and expression
of beta-catenin, T-cell facter-4 and glycogen synthase kinease 3-beta genes. J Gastroenterol Hepatol 2003;18:280-287
8 Cui J, Zhou XD, Liu YK, Tang ZY, Zile MH. Abnormal beta-catenin gene expression with invasiveness of primary
hepatocellular carcinoma in China. World J Gastroenterol 2001;7:542-546
9 Jiang Y, Zhou XD, Liu YK, Wu X, Huang XW. Association of hTcf-4 gene expression and mutation with clinicopathological
characteristics of hepatocellular carcinoma. World J Gastroenterol 2002;8:804-807
10 He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of
c-MYC as a target of the APC pathway. Science 1998;281:1509-1512
11 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Nature 1999;398:422-426
12 Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T. Beta-catenin regulates the expression of the matrix
metalloproteinase-7 in human colorectal cancer. Am J Pathol 1999;155:1033-1038
13 Monga SP, Monga HK, Tan X, Mule K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic
liver culture: role in proliferation, apoptosis, and lineage specification. Gastroenterology 2003;124:202-216
14 Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and
degradation of b-catenin. J Biol Chem 1997;272:24735-24738
15 Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin
complexes. Mol Cell Biol 1996;16:2128-2134
16 Li YL, He XM, Zheng HC, Wu DY, Yang XF, Xin Y, Fu BY. Expression of PTEN encoding product in malignant lesions of
gastric mucosa and its significance. Shijie Huaren Xiaohua Zazhi 2003;11:1294-1296
17 Fang DC, Luo YH, Yang SM, Li XA, Ling XL, Fang L. Mutation analysis of APC gene in gastric cancer with
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编辑 张海宁, 百拇医药( 王轶淳,孙明军, 傅炜昕,傅宝玉)
