β-连环素和上皮钙黏附素免疫组化检测在大肠癌中的研究
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摘要
目的：研究β-连环素(β-catenin，β-cat)和上皮钙黏附素(E-cadherin，E-cad)在大肠癌发生、发展中的作用和在预测肿瘤的转移潜能、评估预后及指导临床处理中有重要意义。方法：应用免疫组织化学染色方法ABC法检测20例正常人大肠黏膜、40例大肠腺瘤、20例腺瘤癌变及58例大肠癌组织的β-cat、E-cad的表达情况。大肠癌58例(结肠癌27例、直肠癌31例)，其中高分化腺癌15例，中分化腺癌24例，低分化腺癌19例；有淋巴结转移者33例，无淋巴结转移者25例；按Duke分期A期10例，B期12例，C期16例，D期20例；大肠腺瘤40例，大肠腺瘤癌变20例，20例正常人大肠黏膜取自经纤维结肠镜活检并经病理学诊断为非大肠肿瘤，且无大肠癌家族史就诊的患者作为正常对照。并对判别结果行统计学分析(x~2检验)。结果：正常大肠黏膜β-cat、E-cad呈胞膜阳性表达。大肠腺瘤、腺瘤癌变和大肠癌组织β-cat表达特征发生改变，胞膜表达缺失，呈胞质和／或胞核异位表达，腺瘤癌变β-cat异位表达率90％，显著高于大肠腺瘤(65％，P＜0.001)和大肠癌(65.5％，P＜0.05)；β-cat异位表达与大肠癌的组织分化程度、淋巴结转移、Duke分期等因素有密切关系。大肠癌β-cat、E-cad胞膜表达缺失率分别为77.6％、70.7％，显著高于大肠腺瘤(35％、30％)和腺瘤癌变(40％、35％)(P＜0.001)，且与大肠癌淋巴结转移和Duke分期有关。结论：β-cat异位表达可能参与了大肠癌发生、发展过程，是大肠癌发生的早期事件。β-cat、E-cad胞膜表达缺失可能与大肠癌的侵袭和转移有关。
Objective To investigate the role of β -catenin and E-cadherin in the carcinogenesis and progression of colorectal carcinoma.Methods Expression of β -catenin and E-cadherin was examined immunohistochemically in 20 cases of normal colonic mucosa,40 cases of colorectal adenoma , 20 cases of colorectal adenoma carcinogenesis and 58 cases of colorectal carcinoma.Results In normal colonic mucosa, β -catenin and E-cadherin were detected in the cell membranes of epithelial cells, p-catenin expression was characterized by alterations in colorectal adenoma,adenoma canceration,and colorectal cancerous tissues;membranous expression fell into deletion,a cytoplasmic and/or nuclear ectopic expression occurred instead;thep-catenin ectopic expression rate of adenoma ( 65 % , P<0.01) and colorectal carcinoma(65.5%, P<0.05) ; P-catenin's ectopic expression was related with the tissue differentiation degree of colorectal carcinoma,lymph node metastasis,and Dukes'staging.Deletion rates of membranous expression of p-catenin and
E-cadherin in colorectal carcinoma were 77.6% and 70.7% respectively remarkably greater than those in colorectal adenoma(35.0%,30.0%) and in adenoma canceration(40.0%,35.0%)( P < 0.01) ,this also relating to colorectal carcinoma's lymph node metastasis and Dukes' staging.Conclusion The cytoplasmic and nuclearp-catenin expression(ectopic expression) might play a pivotal role in the carcinogenesis and progression of colorectal carcinoma . The delation of membranous p-catenin and E-cadherin expression might be related to the invasion and metastasis of colorectal carcinoma.
Objective To investigate the role of β -catenin and E-cadherin in the carcinogenesis and progression of colorectal carcinoma.Methods Expression of β -catenin and E-cadherin was examined immunohistochemically in 20 cases of normal colonic mucosa,40 cases of colorectal adenoma , 20 cases of colorectal adenoma carcinogenesis and 58 cases of colorectal carcinoma.Results In normal colonic mucosa, β -catenin and E-cadherin were detected in the cell membranes of epithelial cells, p-catenin expression was characterized by alterations in colorectal adenoma,adenoma canceration,and colorectal cancerous tissues;membranous expression fell into deletion,a cytoplasmic and/or nuclear ectopic expression occurred instead;thep-catenin ectopic expression rate of adenoma ( 65 % , P<0.01) and colorectal carcinoma(65.5%, P<0.05) ; P-catenin's ectopic expression was related with the tissue differentiation degree of colorectal carcinoma,lymph node metastasis,and Dukes'staging.Deletion rates of membranous expression of p-catenin and
E-cadherin in colorectal carcinoma were 77.6% and 70.7% respectively remarkably greater than those in colorectal adenoma(35.0%,30.0%) and in adenoma canceration(40.0%,35.0%)( P < 0.01) ,this also relating to colorectal carcinoma's lymph node metastasis and Dukes' staging.Conclusion The cytoplasmic and nuclearp-catenin expression(ectopic expression) might play a pivotal role in the carcinogenesis and progression of colorectal carcinoma . The delation of membranous p-catenin and E-cadherin expression might be related to the invasion and metastasis of colorectal carcinoma.
引文
[1] Maruyama K,Ochiai A,Akimoto S,et al. Cyoplasmic beta-catenin accumulation as a predictor of hematogenous metastamis in human coldrectal. Cancer[J]. Oncology,2000,59(4):302-309.
[2] 仲翔，张文军．细胞黏合分子受体研究进展和抗癌应用前景．科学通报，1998，43：2577
[3] 纪小龙，施作霖，主编．诊断免疫组织化学．北京：军事医学科学出版社，1997．20
[4] Overduin M, Harvey TS,Bagby S,et al. Solution structure of the frequent nuclear beta-catenin accumulation and associated mutations in endometrioid-type endometfial and ovarian carcinomas with squamous differention[J]. J Pathol,2001,194(1):59-67.
[5] Shih IM, Yu J,He TC,et al. The β-catenin binding domain of adenomatous polyposis coil is sufficient for tumor suppression[J]. Cancer Res,2000,60(6):1671-1676.
[6] Wong CM, Fan ST, Ng IO. Beta-Catenin mutation and overexpression in hepatocellular carcinoma:clinicopathologic and promostic significance[J]. Cancer,2001,92(1):136-145.
[7] Shum CT, Wu Ms,Lin MT, et aI. Immunohistoehemical evaluation of cadherin and catenin expression in earlygastric carcinomas:correlation with clinicopathologic characterstics and Helicobacter pylori infection[J]. Ontology,2001,60(4):339-345.
[8] Brabletz,T, Henmann K,Jung A, et al. Expression of nuclear betacatenin and cmyc is conelated adenomas[J]. AM J Pathol, 2000,156(3):865-870.
[9] Ozawa M,Kemler R. Molecular organization of the uvomomlincatenin complex. Jcell Biol, 1992,116:989.
[10] Shibamoto S. Tyrosine phosphorylation of β-catenin and plakojlobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells. Cell Adhes commun,1994,1;295-305.
[11] Butz S,Kemler R. Ditinct cadherin-cdtenin complexes in Ca2+ dependent Cel-cell adhesion. FEB S Lett, 1994,355:195.
[12] Nathke Si, Hinck L,Swedlow JR, et al. Defining interac-tions and distributions of cadherin and catenin complexes in polarized cells. JCell Biol;1994,125:1341.
[13] Mori PJ. Beta-catenin signaling and cancer. Bioessays,1999,21(12): 1021.
[14] Noren NK,Liu BP, Burridge K,et al. P120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol,2000. 150:568.
[15] Caca K,Kolligs FT, Ji X,et al. β-and γ-catenin mutations,but not E-cadherin inactivation,underlie T-cell lactor/lymphoid enhancer factoy transcriptional deregulation in gastric and pancreatic cancer. Cell Gell Growth Differ,1999,10:369.
[16] Jawhari A, Jordan S, Poole S,et al. Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma:Relationship with patient survival. Gastroenterology, 1997,112:46-54.
[17] Hiraguri S,Godfrey T, Nakamyra H,et al. Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res,1998,58:1972-1977.
[18] Kawanishi J,Kato J,Sasaki K,et al. Dysfunction of E-cadherin Due to mutation ofβ-catenin in a scirrhous gastric cancer cell line. Nippon Rinsho, 1995,53:1590-1594.
[19] Peifer M. β-catenin as oncogene the smoking gun. Science, 1997,275:1752.
[20] Kobayashi K,Sagae s,Nishioka Y, et al. Mutation of theβ-catenin gene
in endometrial carcinomas. Jpn J Cancer Res,1999,90:55.
[21]. Koch A,Denkhaus D,Albrecht S,et al. Childbood hepato-mas frequently a mutated degradation targeting box of the β-catenin gene. Cancer Res, 1999,59:269.
[22] Bankfalvi A,Terpe Hj,Breukelmann D,et al. Lmmunophenot-Ypicand prognostic analysis of e-cadherin andβ-catenin expression during breast carcinogenesis and tumour progression:a comparative study with CD44. Histopathology, 1999,34:2517
[23] 韩安家，熊敏，李智，等．上皮钙依赖黏附素相关分子在乳腺浸润性小叶癌和导管癌中的表达意义．中华病理学杂志，2001，30：27-29
[24] 方伟岗．肿瘤转移的分子生物学．见：张道蘅，主编．医学分子生物学．北京：北京医科大学出版社，1999．869-880．
[25] Kanai Y, Ushijima S,Hui AM,et al. The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J Cancer, 1997,71:355-359.
[26] Ozawa M,Baribault H,Kemmer R. The cytoplassmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J, 1989,8; 1711-1717.
[27] Christofori G, Semb H. The role of the cell-adhesion mole cule E-cadherin as a tumor suppressor gene. Trends Biochem Sci,1999,24(2):7376.
[28]. M. Beta-eatanin asoncogene:the smoking gun. Science,1997, 275(5307):17521-17753.
[29]. Hinck L,Nathke IS,Papkoff J,et al. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol, 1994,125:1327-1340.
[2] 仲翔，张文军．细胞黏合分子受体研究进展和抗癌应用前景．科学通报，1998，43：2577
[3] 纪小龙，施作霖，主编．诊断免疫组织化学．北京：军事医学科学出版社，1997．20
[4] Overduin M, Harvey TS,Bagby S,et al. Solution structure of the frequent nuclear beta-catenin accumulation and associated mutations in endometrioid-type endometfial and ovarian carcinomas with squamous differention[J]. J Pathol,2001,194(1):59-67.
[5] Shih IM, Yu J,He TC,et al. The β-catenin binding domain of adenomatous polyposis coil is sufficient for tumor suppression[J]. Cancer Res,2000,60(6):1671-1676.
[6] Wong CM, Fan ST, Ng IO. Beta-Catenin mutation and overexpression in hepatocellular carcinoma:clinicopathologic and promostic significance[J]. Cancer,2001,92(1):136-145.
[7] Shum CT, Wu Ms,Lin MT, et aI. Immunohistoehemical evaluation of cadherin and catenin expression in earlygastric carcinomas:correlation with clinicopathologic characterstics and Helicobacter pylori infection[J]. Ontology,2001,60(4):339-345.
[8] Brabletz,T, Henmann K,Jung A, et al. Expression of nuclear betacatenin and cmyc is conelated adenomas[J]. AM J Pathol, 2000,156(3):865-870.
[9] Ozawa M,Kemler R. Molecular organization of the uvomomlincatenin complex. Jcell Biol, 1992,116:989.
[10] Shibamoto S. Tyrosine phosphorylation of β-catenin and plakojlobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells. Cell Adhes commun,1994,1;295-305.
[11] Butz S,Kemler R. Ditinct cadherin-cdtenin complexes in Ca2+ dependent Cel-cell adhesion. FEB S Lett, 1994,355:195.
[12] Nathke Si, Hinck L,Swedlow JR, et al. Defining interac-tions and distributions of cadherin and catenin complexes in polarized cells. JCell Biol;1994,125:1341.
[13] Mori PJ. Beta-catenin signaling and cancer. Bioessays,1999,21(12): 1021.
[14] Noren NK,Liu BP, Burridge K,et al. P120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol,2000. 150:568.
[15] Caca K,Kolligs FT, Ji X,et al. β-and γ-catenin mutations,but not E-cadherin inactivation,underlie T-cell lactor/lymphoid enhancer factoy transcriptional deregulation in gastric and pancreatic cancer. Cell Gell Growth Differ,1999,10:369.
[16] Jawhari A, Jordan S, Poole S,et al. Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma:Relationship with patient survival. Gastroenterology, 1997,112:46-54.
[17] Hiraguri S,Godfrey T, Nakamyra H,et al. Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res,1998,58:1972-1977.
[18] Kawanishi J,Kato J,Sasaki K,et al. Dysfunction of E-cadherin Due to mutation ofβ-catenin in a scirrhous gastric cancer cell line. Nippon Rinsho, 1995,53:1590-1594.
[19] Peifer M. β-catenin as oncogene the smoking gun. Science, 1997,275:1752.
[20] Kobayashi K,Sagae s,Nishioka Y, et al. Mutation of theβ-catenin gene
in endometrial carcinomas. Jpn J Cancer Res,1999,90:55.
[21]. Koch A,Denkhaus D,Albrecht S,et al. Childbood hepato-mas frequently a mutated degradation targeting box of the β-catenin gene. Cancer Res, 1999,59:269.
[22] Bankfalvi A,Terpe Hj,Breukelmann D,et al. Lmmunophenot-Ypicand prognostic analysis of e-cadherin andβ-catenin expression during breast carcinogenesis and tumour progression:a comparative study with CD44. Histopathology, 1999,34:2517
[23] 韩安家，熊敏，李智，等．上皮钙依赖黏附素相关分子在乳腺浸润性小叶癌和导管癌中的表达意义．中华病理学杂志，2001，30：27-29
[24] 方伟岗．肿瘤转移的分子生物学．见：张道蘅，主编．医学分子生物学．北京：北京医科大学出版社，1999．869-880．
[25] Kanai Y, Ushijima S,Hui AM,et al. The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J Cancer, 1997,71:355-359.
[26] Ozawa M,Baribault H,Kemmer R. The cytoplassmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J, 1989,8; 1711-1717.
[27] Christofori G, Semb H. The role of the cell-adhesion mole cule E-cadherin as a tumor suppressor gene. Trends Biochem Sci,1999,24(2):7376.
[28]. M. Beta-eatanin asoncogene:the smoking gun. Science,1997, 275(5307):17521-17753.
[29]. Hinck L,Nathke IS,Papkoff J,et al. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol, 1994,125:1327-1340.