上皮钙黏附素、β-连环素、黏着斑激酶在大肠癌的表达及临床意义
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摘要
大肠癌包括结肠癌和直肠癌，是常见的恶性肿瘤。近20年来，我国该病发病率上升趋势十分明显。大肠癌的发生、发展及转移是一个多因素、多阶段的复杂过程，涉及到癌基因的激活、抑癌基因的失活、细胞黏附的改变及蛋白酶活性改变等多个环节。
上皮钙黏附素(E-cadherin，E-cad．)是一种跨膜糖蛋白分子，通过钙依赖的同种亲和性细胞-细胞间的黏附参与建立和维持细胞间的连接，在E-cadherin介导的细胞-细胞间黏附中，E-cadherin起着细胞黏附的拉链作用。β-连环素(β-catenin，β-cat．)在胞膜与E-cad．结合成复合体，该复合体通过α-catenin与细胞骨架的肌动蛋白微丝网连接。E-cad．-cat复合体介导同型细胞-细胞黏附，已知在胚胎发育、上皮细胞表型形成和维持中发挥重要作用。任何破坏细胞内该复合体的因素也将使细胞黏附功能丧失。许多临床和实验研究发现E-cad．的黏附功能在人类大多数上皮细胞癌中常常丢失，包括大肠癌、乳腺癌、前列腺癌等。大肠腺瘤中β-cat．可异位表达于胞浆和／或胞核，并与核内TCF／LEF家族成员结合启动一些基因转录，参与大肠癌发生。
黏着斑激酶(focal adhesion kinase，FAK)是Schaller等发现的能被scr内源性蛋白酪氨酸激酶激活的主要底物，属于非受体蛋白酪氨酸激酶，具有调节细胞发育、生长、存活和凋亡，调节细胞与ECM(细胞外基质)黏附的功能。FAK通过与焦点黏附物结合，在整和素介导的细胞与ECM黏附中发挥重要作用。FAK活性与其酪氨酸磷酸化水平密切相关。结肠癌中FAK酪氨酸磷酸化水平升高，活性增强。本研究旨在探讨E-cad．、β-cat．、FAK在不同大肠黏膜的表达以及它们的表达与大肠癌各种临床病理因素之间的关系，为大肠癌的早期诊断、治疗及预后判断提供理论依据。
郑州大学2004年硕士毕业论文
上皮钙薪附素、p一连环素、勃着斑激酶在大肠癌的表达及临床意义
材料和方法:(1)49例癌组织标本来源于2 003年1月一2003年10月河南省
人民医院、河南省肿瘤医院普外科手术切除的标本和郑州大学一附院1999年3
月一1999年7月普外科手术切除的标本。12例正常大肠豁膜、28例大肠腺瘤(均
为轻中度不典型增生)来自2003年河南省人民医院内镜室镜下切除的标本，所有
病例均经手术和病理证实。2003年标本经4%多聚甲醛(含有0.1%DEPC)液固定，
1999标本经10%中性福尔马林固定，常规脱水后石蜡包埋。(2)采用免疫组化SP
(链霉卵白素一过氧化物酶法)法检测E一cad.、p一cat.、FAK在不同大肠勃膜的
表达情况。(3)统计工具采用SPSS10.O版软件。样本率比较采用x，检验和四格
表精确概率法，相关分析采用Spearman相关分析，对实验分组资料以a=0 .05
作为检验水准。
结果:1.E一cad.在正常大肠豁膜上皮细胞和大肠腺瘤细胞呈胞膜阳性表达，
仅有少数细胞膜表达缺失。大肠癌E一cad.膜表达明显缺失，缺失率为57.1%，与
前两组比较差异有显著性(只0.01)。p一cat.在正常大肠豁膜上皮细胞和大肠
腺瘤细胞呈胞膜阳性表达，仅有少数膜表达缺失。大肠癌p一cat.膜表达明显缺
失，缺失率为67.3%，与前两组比较差异有显著性(只0.01)。大肠腺瘤、腺癌
p一cat.呈胞浆和/或胞核异位表达，大肠腺瘤p一cat.异位表达率35.7%，高于
正常勃膜组(只0.05)。大肠癌p一cat.异位表达率61.2%，显著高于大肠腺瘤
组(只0.05)。队K在多数正常大肠勃膜上皮细胞呈胞浆阴性表达，少数呈胞浆
弱阳性表达。大肠腺瘤FAK胞浆阳性表达率39.3%，与正常大肠豁膜组比较差异
无显著性(乃0.05)。大肠癌FAK胞浆阳性表达率65.3%，与前两组比较差异有
显著性(只0.01)。
2.E一cad.膜表达缺失率在大肠癌结肠组为50.0%，直肠组为62.IW0，两组相
比差异无显著性(乃0.05)。在不同浸润深度的大肠癌标本中，E一cad.膜表达缺
失率在未超过深肌层组为46.2%，在超过深肌层组为61.1%，两组相比差异无显
著性(乃0.05)。E一cad.膜表达缺失率在大肠癌高、中、低不同分化组分别为
68.4%、62.5%、35.7%，三组相比差异无显著性(乃0.05)。E一cad.膜表达缺失
率在大肠癌有淋巴结转移组为84.20k，在无淋巴结转移组为40.0%，两组相比差
异有显著性(只0.01)。在大肠癌不同DukeS分期的标本中，E一cad.膜表达缺失
率在AB期组为40.0%，CD期组为84.2%，两组相比差异有显著性(只0.01)。
郑州大学2004年硕士毕业论文
上皮钙勃附素、日一连环素、勃着斑激酶在大肠癌的表达及临床意义
3.p一cat.异位表达率在大肠癌结肠组为60.0%，直肠组为62.1%，两组相比
差异无显著性(乃0.05)。在不同浸润深度的大肠癌标本中，p一cat.异位表达
率在未超过深肌层组为30.8%，在超过深肌层组为72.2%，两组相比差异有显著
性(只0.05)。D一cat.异位表达率在高、中、低不同分化组分别为57.9%、75.0%、
50.0%，三组相比差异无显著性(乃0.05)。p一cat.异位表达率在有淋巴结转移
组为89.5%，在无淋巴结转移组为42.3%，两组相比差异有显著性(只0.01)。
在大肠癌不同Dukes分期的标本中，B一cat.异位表达率在AB期组为42.3%，C
D期组为89.5%，两组相比差异有显著性(只0.01)。
4.p一cat.膜表达缺失率在大肠癌结肠组为70.5%，直肠?
Colorectal cancer is a kind of common and malignant tumor. The incidence of this disease has been increasing significantly in recent 20 years in China. The tumorigenesis and metastasis of colorectal cancer is a complicated process with many steps concerning the activation of oncogenes, inactivation of anti-oncogenes, the changing of adhesion among cells and the changing of activation of enzymes etc.
E-cadherin (E-cad.) is a kind of crossing-membrace glucoprotein molecule, which, dependenting on calcium, establishes and holds homotypic cell adhesion and it is a kind of sliding fastener among homotypic cells. β-catenin( B -cat.) linked to E-cad.on cell membrace comes into being a kind of complex, which links to the actin in the cell framework through a-catenin.It is known that the homotypic cell adhesion, depending on the E-cad./ β-cat complex, plays an important role in the forming and maintaining of epithelial style.The factors which destroy this complex will breakdown the homotypic cell adhesion .Many clinic studies and experiments show that function of E-cad. always drops in most of cancers including colorectal cancer,breast cancer,prostate cancer etc. The cytoplasmic and /or nuclear expression of β-catenin may appear in the colorectal adenoma. β-cat. can link to the members of TCF/LEF family and stamp the transcription of some genes,which contributes to the tumorigenesis of colorectum.
FAK(focal adhesion kinase) discovered by Schaller is a major substance which can be activated by src-ingeneration protein-tyrosine kinase and it is a non-receptor
protein-tyrosion kinase.It can regulate the developing, keeping alive, apoptosis of cells and adhesion between cells and ECM.It plays a role in the integrin-mediated signal transduction pathway through linking to the Focal Adhesion Foci.The activation of FAK is closely associated with its phosphptyrosine content and increases with its enhanced level of phosphotyrosine in colorectal cancer.The aim of this study is ,through evaluating the expression of E-cad., β-cat. and FAK in different colorectal mucosa and the relationship between their expression and clinicopathologocal factors,to provide theoretical basis for early diagnosis,therapy and prognosis of colorectal cancer.
Materials and Methods:(1)49 surgically resected colorectal cancer samples,12 normal colorectal mucosa samples and 28 endoscopic resected colorectal adenoma samples with mild to moderate displasia were all confirmed pathologically. The samples in 2003 were fixed in 4% Polyoxymethylene/ 0.1M PBS (0.1%DEPC), and the rest were fixed in 10% neutral formalin. All the samples were embedded in paraffin. (2)SP immunohistochemistry technique was used to detect the expression of E-cad., β-cat. and FAK in the different colorectal mucosa.(3) The data was analysed by software SPSS 10.0. x2-test and spearman correlation were used to compare difference between groups, a =0.05 was considered as statistically significant value.
Results: (1) The membranous expression of E-cad. appeared in most of nomal colorectal mucosa and colorectal adenoma.The reduced membranous expression of E-cad.appeared in a majority of colorectal cancer.The reduced membranous expression rate of E-cad. was 57.1% in colorectal cancer,which was significantly higher than the last two groups(P<0.01). The reduced membranous expression rate of 3 -cat. was 67.3% in colorectal cancer, which was significantly higher than the last two groups(P<0.01).The cytoplasmic and/or nuclear expression of β-catenin was found in the colorectal adenoma and cancer.The rate of the cytoplasmic and /or nuclear expression of β-catenin was 61.2% in coloretal cancer,which was significantly higher than that in colorectal adenoma(35.7%, P<0.05). Moreover, the rate of cytoplasmic and /or nuclear expression of β-catenin in colorectal adenoma
was significantly higher than that in normal colorectal epithelium. FAK was expressed in cytoplasm.The rate of FAK expression was 65.3% in colorectal cancer, which was significantly higher than that in the colorectal adenoma
上皮钙黏附素(E-cadherin，E-cad．)是一种跨膜糖蛋白分子，通过钙依赖的同种亲和性细胞-细胞间的黏附参与建立和维持细胞间的连接，在E-cadherin介导的细胞-细胞间黏附中，E-cadherin起着细胞黏附的拉链作用。β-连环素(β-catenin，β-cat．)在胞膜与E-cad．结合成复合体，该复合体通过α-catenin与细胞骨架的肌动蛋白微丝网连接。E-cad．-cat复合体介导同型细胞-细胞黏附，已知在胚胎发育、上皮细胞表型形成和维持中发挥重要作用。任何破坏细胞内该复合体的因素也将使细胞黏附功能丧失。许多临床和实验研究发现E-cad．的黏附功能在人类大多数上皮细胞癌中常常丢失，包括大肠癌、乳腺癌、前列腺癌等。大肠腺瘤中β-cat．可异位表达于胞浆和／或胞核，并与核内TCF／LEF家族成员结合启动一些基因转录，参与大肠癌发生。
黏着斑激酶(focal adhesion kinase，FAK)是Schaller等发现的能被scr内源性蛋白酪氨酸激酶激活的主要底物，属于非受体蛋白酪氨酸激酶，具有调节细胞发育、生长、存活和凋亡，调节细胞与ECM(细胞外基质)黏附的功能。FAK通过与焦点黏附物结合，在整和素介导的细胞与ECM黏附中发挥重要作用。FAK活性与其酪氨酸磷酸化水平密切相关。结肠癌中FAK酪氨酸磷酸化水平升高，活性增强。本研究旨在探讨E-cad．、β-cat．、FAK在不同大肠黏膜的表达以及它们的表达与大肠癌各种临床病理因素之间的关系，为大肠癌的早期诊断、治疗及预后判断提供理论依据。
郑州大学2004年硕士毕业论文
上皮钙薪附素、p一连环素、勃着斑激酶在大肠癌的表达及临床意义
材料和方法:(1)49例癌组织标本来源于2 003年1月一2003年10月河南省
人民医院、河南省肿瘤医院普外科手术切除的标本和郑州大学一附院1999年3
月一1999年7月普外科手术切除的标本。12例正常大肠豁膜、28例大肠腺瘤(均
为轻中度不典型增生)来自2003年河南省人民医院内镜室镜下切除的标本，所有
病例均经手术和病理证实。2003年标本经4%多聚甲醛(含有0.1%DEPC)液固定，
1999标本经10%中性福尔马林固定，常规脱水后石蜡包埋。(2)采用免疫组化SP
(链霉卵白素一过氧化物酶法)法检测E一cad.、p一cat.、FAK在不同大肠勃膜的
表达情况。(3)统计工具采用SPSS10.O版软件。样本率比较采用x，检验和四格
表精确概率法，相关分析采用Spearman相关分析，对实验分组资料以a=0 .05
作为检验水准。
结果:1.E一cad.在正常大肠豁膜上皮细胞和大肠腺瘤细胞呈胞膜阳性表达，
仅有少数细胞膜表达缺失。大肠癌E一cad.膜表达明显缺失，缺失率为57.1%，与
前两组比较差异有显著性(只0.01)。p一cat.在正常大肠豁膜上皮细胞和大肠
腺瘤细胞呈胞膜阳性表达，仅有少数膜表达缺失。大肠癌p一cat.膜表达明显缺
失，缺失率为67.3%，与前两组比较差异有显著性(只0.01)。大肠腺瘤、腺癌
p一cat.呈胞浆和/或胞核异位表达，大肠腺瘤p一cat.异位表达率35.7%，高于
正常勃膜组(只0.05)。大肠癌p一cat.异位表达率61.2%，显著高于大肠腺瘤
组(只0.05)。队K在多数正常大肠勃膜上皮细胞呈胞浆阴性表达，少数呈胞浆
弱阳性表达。大肠腺瘤FAK胞浆阳性表达率39.3%，与正常大肠豁膜组比较差异
无显著性(乃0.05)。大肠癌FAK胞浆阳性表达率65.3%，与前两组比较差异有
显著性(只0.01)。
2.E一cad.膜表达缺失率在大肠癌结肠组为50.0%，直肠组为62.IW0，两组相
比差异无显著性(乃0.05)。在不同浸润深度的大肠癌标本中，E一cad.膜表达缺
失率在未超过深肌层组为46.2%，在超过深肌层组为61.1%，两组相比差异无显
著性(乃0.05)。E一cad.膜表达缺失率在大肠癌高、中、低不同分化组分别为
68.4%、62.5%、35.7%，三组相比差异无显著性(乃0.05)。E一cad.膜表达缺失
率在大肠癌有淋巴结转移组为84.20k，在无淋巴结转移组为40.0%，两组相比差
异有显著性(只0.01)。在大肠癌不同DukeS分期的标本中，E一cad.膜表达缺失
率在AB期组为40.0%，CD期组为84.2%，两组相比差异有显著性(只0.01)。
郑州大学2004年硕士毕业论文
上皮钙勃附素、日一连环素、勃着斑激酶在大肠癌的表达及临床意义
3.p一cat.异位表达率在大肠癌结肠组为60.0%，直肠组为62.1%，两组相比
差异无显著性(乃0.05)。在不同浸润深度的大肠癌标本中，p一cat.异位表达
率在未超过深肌层组为30.8%，在超过深肌层组为72.2%，两组相比差异有显著
性(只0.05)。D一cat.异位表达率在高、中、低不同分化组分别为57.9%、75.0%、
50.0%，三组相比差异无显著性(乃0.05)。p一cat.异位表达率在有淋巴结转移
组为89.5%，在无淋巴结转移组为42.3%，两组相比差异有显著性(只0.01)。
在大肠癌不同Dukes分期的标本中，B一cat.异位表达率在AB期组为42.3%，C
D期组为89.5%，两组相比差异有显著性(只0.01)。
4.p一cat.膜表达缺失率在大肠癌结肠组为70.5%，直肠?
Colorectal cancer is a kind of common and malignant tumor. The incidence of this disease has been increasing significantly in recent 20 years in China. The tumorigenesis and metastasis of colorectal cancer is a complicated process with many steps concerning the activation of oncogenes, inactivation of anti-oncogenes, the changing of adhesion among cells and the changing of activation of enzymes etc.
E-cadherin (E-cad.) is a kind of crossing-membrace glucoprotein molecule, which, dependenting on calcium, establishes and holds homotypic cell adhesion and it is a kind of sliding fastener among homotypic cells. β-catenin( B -cat.) linked to E-cad.on cell membrace comes into being a kind of complex, which links to the actin in the cell framework through a-catenin.It is known that the homotypic cell adhesion, depending on the E-cad./ β-cat complex, plays an important role in the forming and maintaining of epithelial style.The factors which destroy this complex will breakdown the homotypic cell adhesion .Many clinic studies and experiments show that function of E-cad. always drops in most of cancers including colorectal cancer,breast cancer,prostate cancer etc. The cytoplasmic and /or nuclear expression of β-catenin may appear in the colorectal adenoma. β-cat. can link to the members of TCF/LEF family and stamp the transcription of some genes,which contributes to the tumorigenesis of colorectum.
FAK(focal adhesion kinase) discovered by Schaller is a major substance which can be activated by src-ingeneration protein-tyrosine kinase and it is a non-receptor
protein-tyrosion kinase.It can regulate the developing, keeping alive, apoptosis of cells and adhesion between cells and ECM.It plays a role in the integrin-mediated signal transduction pathway through linking to the Focal Adhesion Foci.The activation of FAK is closely associated with its phosphptyrosine content and increases with its enhanced level of phosphotyrosine in colorectal cancer.The aim of this study is ,through evaluating the expression of E-cad., β-cat. and FAK in different colorectal mucosa and the relationship between their expression and clinicopathologocal factors,to provide theoretical basis for early diagnosis,therapy and prognosis of colorectal cancer.
Materials and Methods:(1)49 surgically resected colorectal cancer samples,12 normal colorectal mucosa samples and 28 endoscopic resected colorectal adenoma samples with mild to moderate displasia were all confirmed pathologically. The samples in 2003 were fixed in 4% Polyoxymethylene/ 0.1M PBS (0.1%DEPC), and the rest were fixed in 10% neutral formalin. All the samples were embedded in paraffin. (2)SP immunohistochemistry technique was used to detect the expression of E-cad., β-cat. and FAK in the different colorectal mucosa.(3) The data was analysed by software SPSS 10.0. x2-test and spearman correlation were used to compare difference between groups, a =0.05 was considered as statistically significant value.
Results: (1) The membranous expression of E-cad. appeared in most of nomal colorectal mucosa and colorectal adenoma.The reduced membranous expression of E-cad.appeared in a majority of colorectal cancer.The reduced membranous expression rate of E-cad. was 57.1% in colorectal cancer,which was significantly higher than the last two groups(P<0.01). The reduced membranous expression rate of 3 -cat. was 67.3% in colorectal cancer, which was significantly higher than the last two groups(P<0.01).The cytoplasmic and/or nuclear expression of β-catenin was found in the colorectal adenoma and cancer.The rate of the cytoplasmic and /or nuclear expression of β-catenin was 61.2% in coloretal cancer,which was significantly higher than that in colorectal adenoma(35.7%, P<0.05). Moreover, the rate of cytoplasmic and /or nuclear expression of β-catenin in colorectal adenoma
was significantly higher than that in normal colorectal epithelium. FAK was expressed in cytoplasm.The rate of FAK expression was 65.3% in colorectal cancer, which was significantly higher than that in the colorectal adenoma
引文
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8 Yomizo A, Mai M, Bostwick DG,et al. Mutation and expression analysis of the p73 gene in prostate cancer. Prostate, 1999, 39(2):94-100.
9 Kawasal Y, Senda T, Ishidate T, et al.Asef, a link between the tumor suppressor APC and G-protein signaling. Science,2000, 289 (5428) : 1197.
10 Hristofori G, Semb H. The role of the cell-adherin molecule E-cadherin as a tumor-suppressor gene.Trends Bio-chem Sci, 999,24(2):73-76.
11 李文俊，吴人亮．β-连环素与肿瘤发生、浸润和转移．国外医学分子生物学2001，23(2)：82-86．
12 Gunther K, Brabletz T, Kraus C, et al.Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer.Dis Colon
Rectum, 1998,41(10):1256-1261.
13 Dorudi S, Hanby AM, Poulsom R, et al.Level of expression of E-cadherinmRNA in colorectal cancer correlates with clinical outcome.Br J cancer, 1995, 71(3):614-616.
14 Perl AK, Wilgenbus P, Dahl U, et al.A Causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 1998, 392(6617): 190-193.
15 张明金，许洪卫，王元和等．大肠癌钙上皮黏附素的表达及临床意义．临床肿瘤学杂志，2001，6(2)：112-116．
16 向德兵，吴晓华，李增鹏等．大肠癌β-连环素和钙上皮黏附素的表达及意义．月中瘤防治杂志，2002，9(1)：39-42．
17 Brabletz T, Jung A, Reu S, et al.Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 2001, 98(18):10356-10361.
18 Masur K, Lang K, Niggemann B, et al.High PKC alpha and low E-cadherin expression contribute to high migratory activity of colon carcinoma cell. Mol Biol Cell, 2002, 12(7): 1973-1982.
19 Van der wurff AA, Vermeulen SJ, An der linder EP, et al. Patterns of alphaand beta-catenin and E-cadherin expression in colorectal adenomas and carcinomas.J Pathol, 1997, 182(3):325-30.
20 EL-Bahrawy MA, Talbot TC. The expression of E-cadherin and Catenins in colorectal tumors from familial adnomatous polysis patients.J Pathol, 2002, 198(1):69-76.
21 Polard M, Debruyne P, Bras-Gocacves R, et al.Single alteration of P53 or E-cad. genes can alter the surgical resection benefit in an experimental modal of colon cancer.Dis Colon Pectum,2001,44(8): 1106-1112.
22 Gofuku J, hiozaki H, Tsujinaka T, et al.Expression of E-cadherin and alpha-catenin in patients with colorectal carcinoma. Correlation with cancer invasion and metastasis.Am J Clin Pathol,1999,111 (1) : 29-37.
23 Ilyas M,Novelli M,Wilkinson K,et al. Tumour recurrence is associated with
Jass grouping but not with differences in E-cadherin expression in moderately differentiated Dukes' B colorectal cancers.J Clin Pathol, 1997,50(3):218-222.
24 刘为国．上皮钙黏附素系统在肿瘤中意义及调控机制．国外医学病理生理和临床医学分册，1999，19(3)：24-26．
25 Kanazawa T, Watanable T, Kazama S, et al. Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer, 2002,102(3):225-229.
26 Muller N, Reinacher-schick A, Baldus S, et al.Smad4 induces the tumor suppressor E-cad. and P-Cad. in colon carcinoma cell. Oncogene, 2002, 21(39): 6049-6058.
27 Palmer HG, Gonzalez-Sancho JM.VitaminD3 promots the differentiation of colon carcinoma cells by the induction of E-cad. and the inhibition of β -cat. signaling. J Cell Biol, 2001, 154(2):369-387.
28 Tan C, Costello P, Sanghera J, et al.Inhibition of integrin linked kinase suppresses β-cat.-LEF/TCF-dependent transcription and expression of the E-cad. repressor, snail, in APC-/- human colon carcinoma cells.Oncogene, 2001,20(1): 133-140.
29 Hirose Y, Kuno T, Yamada Y, et al.Azoxymethane-induced beta-cateninaccumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis. Carcinogenesis, 24 (1): 107-111.
30 Valizadeh A, Karayiannakis AJ, el-Hariry I, et al. Expression of E-cadherinassociated moleculesl (α- β- and γ-catenins and p120) in colorectal polyps. Am J Pathol, 1997,150 (6) : 1977-1984.
31 Hao x, Tomlinson L, Liys M, et al. Reciprocity between membranous and nuclear expression of β -catenin in colorectal tumors. Virchows Arch, 1997, 431(3):167-172.
32 Maruyama K, Ochiai A, Akimoto S,et al.Cytoplasmic beta-catenin accumulation as a predictor of hematogenous metastasis in human colorectal
cancer.Oncology,2000,59(4):302-309.
33 Brabletz T, Herrmann K, Dung A, et al.Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas.Am J Pathol,2000,156(3):865-870.
34 Shimizu Y, Shimi N, Shimizu S, et al. The relationship between the histopathological atypia expression β-catenin in colonic neoplasms resected by endoscopy; comparison with that of P53 protein.Nippon Shokakibyo Gakkai Zasshi, 1999,96(10): 1050-1056.
35 Ching JM, Chon YH, hen TC,et al.Nuclear β-catenin expression is closely related to ulcerative growth of colorectal carcinoma .Br J Cancer, 2002, 86(7):1124-1129.
36 Kapitejin E, Liefers GJ, Los LC, et al.Mechanisms of oncogenesis in colon versus rectal cancer.J Pathol,2001,195(2): 171-178.
37 Mikami T, Mitomi H, Hara A, et al. Decreased expression of CD44 , α -catenin, and deleted colon carcinoma and altered expression of β -catenin in ulcerative colitis-associated dysplasia and carcinoma,as compared with sporadic colon neoplasms.Cancer, 2000,89(4):733-740.
38 Ongolkov AV, Yamashita K, Mai M,et al. β -catenin and MMP-7 cosegregate in late-stage clinical colon cancer. Gastroenterolog, 2002, 122(1):60-71.
39 Yost C,Torres M,Miller JR,et al.The axis-inducing activity,stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.Genes Dev,1996, 10(11): 1443-1454.
40 Munn B,Gelos M,Siedow A,et al.Target gene of β -cat.-TCF/LEF singaling in human colorectal carcinomas.Proc Natl ad Sci USA, 1999, 96(15): 1603-1608.
41 Andrea B, Massimo P. Genetics-cellular basis. British Medical Bulletin, 2002, 64(10):45-58.
42 Sparks AB,Morin PJ,Vogelstein B,et al.Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer.Cancer Res 1998,
58(6): 1130-4.
43 Dale TC. Signal transduction by the Wnt family of ligands.Biochem J. 1998, 329(2):209-223.
44 Liu C,Kato Y,Zhang Z,et al. Beta-Trcp couples beta-catenin phosphorylationdegradation and regulates Xenopus axis formation.Proc Natl Acad Sci U S A. 1999,96(11):6273-6278.
45 Peifer M, Polakis. Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus.Science, 2000, 287(5458):1606-1609.
46 Mann B,Gelos M,Siedow A,et al.Target genes of beta-catenin-Tcell-factor /lymphoid-enhancre-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A, 1999,96(4):1603-1608.
47 Takahashi M,Fujita M, Furukawa Y, et al.Isalation of a novel human geng,APCDD1,as a direct target of the β -cat./TCG-4 complex with probable involvement in colorectal carcinogesis.Cancer Res, 2002, 62(20):5651-5656.
48 Conacci-Sorrell ME,Ben-Yedidia T,shtutman M,et al.Nr-CAM is a target of the β -cat./LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis.Genes Dev, 2002, 16(16): 2058-2072.
49 Miwa N,Furuse M,Tsukita M,et al.Involvement of claudin-1 in the β -cat./TCF signaling pathway and its frequent upregulation in human colorectal cancers.Oncol Res, 2000, 2(11-12):469-476.
50 Pierce M, Wang C, Stump M, Kamb A. Overexpression of the beta-catenin binding domain of cadherin selectively kills colorectal cancer cells. Int J Cancer, 2003,107(2): 229-237.
51 Mulholland DJ, Read JT, Rennie PS, et,al. Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis.Oncogene, 2003,22(36):5602-5613.
52 倪俊，陈玉林．粘着斑激酶．生理科学进展，1999，30(4)：367-369．
53 Zachary I.Focal adhesion kinase.Int Biochem Cell Bio, 1997, 29(7):929-934.
54 Wither BE,Hanks SK,Fry DW,et al.Correlations between the expression phosphotyrosine content and enzymatic activity of focal adhesion kinase,PP125FAK,in tumor and nontransformed cell.Cancer Biochem Biophys, 1996,15(3): 127-139.
55 Cance WG, Harris JE.Immunohistochemical analysis of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes.Clin Cancer Res, 2000, 6(6): 2417-2423.
56 Xu LH, Yang XH, Cynthia A, et al.The focal adhesion kinase suppresses transformation-associated,anchorage-independent apoptosis in human breast cancer cells.J.Biol.Chem,2000,275(39):30579-30604.
57 Su JM, Gui L.Expression of FAK and alpha5 and betal integrins in carcinomas and its clinical significance. World J Gastroenterol, 2002,8(4): 613-618.
58 官国先，寿楠海．粘着斑激酶的表达与直肠癌侵袭、转移的相关性研究．山东医药，2001，41(12)：7-8．
59 Ayaki M, Komastu K, Mukai M,et al.Reduced expression of FAK in liver metastases compared with matched primary human colorectal adenocarcinonas.Clin Cancer Res,2001,7(10):3106-3112.
60 Weiner TM, Lin ET, Craven KJ,et al.Expression of focal adhesion kinase and invasive cancer.The Lancet, 1993,342(10): 1024-1028.
61 Theocharis SE, Kouraklis GP, Kakisis JD, et al. Focal adhesion kinase expression is not a prognostic predictor in colon adenocarcinoma patients. Eur J Surg Oncol, 2003, 29(7):571-574.
62 Lark AL, Livasy CA, Calvo B, et al. Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. Clin Cancer Res, 2003, 9 (1):215-222.
63 Irby RB, Yeatman TJ. Scr-induced deregulation of E-cadherin in colon cancer
cells requires integrin signaling.Nat Cell Biol, 2002,4(8): 632-638.
64 Irby RB, Yeatman TJ.Increased scr activity disrupts cadherin/catenin-mediated homotypic adherin in human colon cancer and transformed rodent cells. Cancer Res, 2002, 62(9):2669-2674.
65 Weyant MJ, Carothers AM,Bertagnolli ME,et al.Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.Clin Cancer Res,2000, 6(3):949-956.
66 Weyant MJ, Carothers AM,Dannenberg AJ,et al.(+)-catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse.Cancer Res,2001,61 (1): 118-125.
2 Berx G, Staes K, VanHengel J, et al. Cloning and characterization of the humaninvasio suppressor gene E-cadherin (CDH1). Genomics, 1995, 26(2): 281-289.
3 Shapirol L, Fannon AM, Kwong PD, et al. Structural basis of cell-cell adhesion by cadherins. Nature, 1995, 374(6520):327-337.
4 Krans C, liehr T, HuLsken J, et al. Localization of the human beta-catenin gene (CTNNB 1) to 3p21: a region implicated in tumor development.Genomics, 1994, 23(1): 272-274.
5 Mcpherson JD, Morton RA, Eming CM, et al. Assignment of the human alpha-catenin gene (CTNNA 1) to chromosome 5q21-q22. Genomics, 1994, 19 (1): 188-190.
6 Voeller HJ, Truica CI, Gelmann EP. Beta-catenin mutations in humanprostate cancer.CanceRes, 1998, 58(12):2520-2523.
7 Miyoshi y, Iwao K, Nagasawa Y, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.Cancer Res, 1998, 58(12):2524-2527.
8 Yomizo A, Mai M, Bostwick DG,et al. Mutation and expression analysis of the p73 gene in prostate cancer. Prostate, 1999, 39(2):94-100.
9 Kawasal Y, Senda T, Ishidate T, et al.Asef, a link between the tumor suppressor APC and G-protein signaling. Science,2000, 289 (5428) : 1197.
10 Hristofori G, Semb H. The role of the cell-adherin molecule E-cadherin as a tumor-suppressor gene.Trends Bio-chem Sci, 999,24(2):73-76.
11 李文俊，吴人亮．β-连环素与肿瘤发生、浸润和转移．国外医学分子生物学2001，23(2)：82-86．
12 Gunther K, Brabletz T, Kraus C, et al.Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer.Dis Colon
Rectum, 1998,41(10):1256-1261.
13 Dorudi S, Hanby AM, Poulsom R, et al.Level of expression of E-cadherinmRNA in colorectal cancer correlates with clinical outcome.Br J cancer, 1995, 71(3):614-616.
14 Perl AK, Wilgenbus P, Dahl U, et al.A Causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 1998, 392(6617): 190-193.
15 张明金，许洪卫，王元和等．大肠癌钙上皮黏附素的表达及临床意义．临床肿瘤学杂志，2001，6(2)：112-116．
16 向德兵，吴晓华，李增鹏等．大肠癌β-连环素和钙上皮黏附素的表达及意义．月中瘤防治杂志，2002，9(1)：39-42．
17 Brabletz T, Jung A, Reu S, et al.Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 2001, 98(18):10356-10361.
18 Masur K, Lang K, Niggemann B, et al.High PKC alpha and low E-cadherin expression contribute to high migratory activity of colon carcinoma cell. Mol Biol Cell, 2002, 12(7): 1973-1982.
19 Van der wurff AA, Vermeulen SJ, An der linder EP, et al. Patterns of alphaand beta-catenin and E-cadherin expression in colorectal adenomas and carcinomas.J Pathol, 1997, 182(3):325-30.
20 EL-Bahrawy MA, Talbot TC. The expression of E-cadherin and Catenins in colorectal tumors from familial adnomatous polysis patients.J Pathol, 2002, 198(1):69-76.
21 Polard M, Debruyne P, Bras-Gocacves R, et al.Single alteration of P53 or E-cad. genes can alter the surgical resection benefit in an experimental modal of colon cancer.Dis Colon Pectum,2001,44(8): 1106-1112.
22 Gofuku J, hiozaki H, Tsujinaka T, et al.Expression of E-cadherin and alpha-catenin in patients with colorectal carcinoma. Correlation with cancer invasion and metastasis.Am J Clin Pathol,1999,111 (1) : 29-37.
23 Ilyas M,Novelli M,Wilkinson K,et al. Tumour recurrence is associated with
Jass grouping but not with differences in E-cadherin expression in moderately differentiated Dukes' B colorectal cancers.J Clin Pathol, 1997,50(3):218-222.
24 刘为国．上皮钙黏附素系统在肿瘤中意义及调控机制．国外医学病理生理和临床医学分册，1999，19(3)：24-26．
25 Kanazawa T, Watanable T, Kazama S, et al. Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer, 2002,102(3):225-229.
26 Muller N, Reinacher-schick A, Baldus S, et al.Smad4 induces the tumor suppressor E-cad. and P-Cad. in colon carcinoma cell. Oncogene, 2002, 21(39): 6049-6058.
27 Palmer HG, Gonzalez-Sancho JM.VitaminD3 promots the differentiation of colon carcinoma cells by the induction of E-cad. and the inhibition of β -cat. signaling. J Cell Biol, 2001, 154(2):369-387.
28 Tan C, Costello P, Sanghera J, et al.Inhibition of integrin linked kinase suppresses β-cat.-LEF/TCF-dependent transcription and expression of the E-cad. repressor, snail, in APC-/- human colon carcinoma cells.Oncogene, 2001,20(1): 133-140.
29 Hirose Y, Kuno T, Yamada Y, et al.Azoxymethane-induced beta-cateninaccumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis. Carcinogenesis, 24 (1): 107-111.
30 Valizadeh A, Karayiannakis AJ, el-Hariry I, et al. Expression of E-cadherinassociated moleculesl (α- β- and γ-catenins and p120) in colorectal polyps. Am J Pathol, 1997,150 (6) : 1977-1984.
31 Hao x, Tomlinson L, Liys M, et al. Reciprocity between membranous and nuclear expression of β -catenin in colorectal tumors. Virchows Arch, 1997, 431(3):167-172.
32 Maruyama K, Ochiai A, Akimoto S,et al.Cytoplasmic beta-catenin accumulation as a predictor of hematogenous metastasis in human colorectal
cancer.Oncology,2000,59(4):302-309.
33 Brabletz T, Herrmann K, Dung A, et al.Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas.Am J Pathol,2000,156(3):865-870.
34 Shimizu Y, Shimi N, Shimizu S, et al. The relationship between the histopathological atypia expression β-catenin in colonic neoplasms resected by endoscopy; comparison with that of P53 protein.Nippon Shokakibyo Gakkai Zasshi, 1999,96(10): 1050-1056.
35 Ching JM, Chon YH, hen TC,et al.Nuclear β-catenin expression is closely related to ulcerative growth of colorectal carcinoma .Br J Cancer, 2002, 86(7):1124-1129.
36 Kapitejin E, Liefers GJ, Los LC, et al.Mechanisms of oncogenesis in colon versus rectal cancer.J Pathol,2001,195(2): 171-178.
37 Mikami T, Mitomi H, Hara A, et al. Decreased expression of CD44 , α -catenin, and deleted colon carcinoma and altered expression of β -catenin in ulcerative colitis-associated dysplasia and carcinoma,as compared with sporadic colon neoplasms.Cancer, 2000,89(4):733-740.
38 Ongolkov AV, Yamashita K, Mai M,et al. β -catenin and MMP-7 cosegregate in late-stage clinical colon cancer. Gastroenterolog, 2002, 122(1):60-71.
39 Yost C,Torres M,Miller JR,et al.The axis-inducing activity,stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.Genes Dev,1996, 10(11): 1443-1454.
40 Munn B,Gelos M,Siedow A,et al.Target gene of β -cat.-TCF/LEF singaling in human colorectal carcinomas.Proc Natl ad Sci USA, 1999, 96(15): 1603-1608.
41 Andrea B, Massimo P. Genetics-cellular basis. British Medical Bulletin, 2002, 64(10):45-58.
42 Sparks AB,Morin PJ,Vogelstein B,et al.Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer.Cancer Res 1998,
58(6): 1130-4.
43 Dale TC. Signal transduction by the Wnt family of ligands.Biochem J. 1998, 329(2):209-223.
44 Liu C,Kato Y,Zhang Z,et al. Beta-Trcp couples beta-catenin phosphorylationdegradation and regulates Xenopus axis formation.Proc Natl Acad Sci U S A. 1999,96(11):6273-6278.
45 Peifer M, Polakis. Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus.Science, 2000, 287(5458):1606-1609.
46 Mann B,Gelos M,Siedow A,et al.Target genes of beta-catenin-Tcell-factor /lymphoid-enhancre-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A, 1999,96(4):1603-1608.
47 Takahashi M,Fujita M, Furukawa Y, et al.Isalation of a novel human geng,APCDD1,as a direct target of the β -cat./TCG-4 complex with probable involvement in colorectal carcinogesis.Cancer Res, 2002, 62(20):5651-5656.
48 Conacci-Sorrell ME,Ben-Yedidia T,shtutman M,et al.Nr-CAM is a target of the β -cat./LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis.Genes Dev, 2002, 16(16): 2058-2072.
49 Miwa N,Furuse M,Tsukita M,et al.Involvement of claudin-1 in the β -cat./TCF signaling pathway and its frequent upregulation in human colorectal cancers.Oncol Res, 2000, 2(11-12):469-476.
50 Pierce M, Wang C, Stump M, Kamb A. Overexpression of the beta-catenin binding domain of cadherin selectively kills colorectal cancer cells. Int J Cancer, 2003,107(2): 229-237.
51 Mulholland DJ, Read JT, Rennie PS, et,al. Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis.Oncogene, 2003,22(36):5602-5613.
52 倪俊，陈玉林．粘着斑激酶．生理科学进展，1999，30(4)：367-369．
53 Zachary I.Focal adhesion kinase.Int Biochem Cell Bio, 1997, 29(7):929-934.
54 Wither BE,Hanks SK,Fry DW,et al.Correlations between the expression phosphotyrosine content and enzymatic activity of focal adhesion kinase,PP125FAK,in tumor and nontransformed cell.Cancer Biochem Biophys, 1996,15(3): 127-139.
55 Cance WG, Harris JE.Immunohistochemical analysis of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes.Clin Cancer Res, 2000, 6(6): 2417-2423.
56 Xu LH, Yang XH, Cynthia A, et al.The focal adhesion kinase suppresses transformation-associated,anchorage-independent apoptosis in human breast cancer cells.J.Biol.Chem,2000,275(39):30579-30604.
57 Su JM, Gui L.Expression of FAK and alpha5 and betal integrins in carcinomas and its clinical significance. World J Gastroenterol, 2002,8(4): 613-618.
58 官国先，寿楠海．粘着斑激酶的表达与直肠癌侵袭、转移的相关性研究．山东医药，2001，41(12)：7-8．
59 Ayaki M, Komastu K, Mukai M,et al.Reduced expression of FAK in liver metastases compared with matched primary human colorectal adenocarcinonas.Clin Cancer Res,2001,7(10):3106-3112.
60 Weiner TM, Lin ET, Craven KJ,et al.Expression of focal adhesion kinase and invasive cancer.The Lancet, 1993,342(10): 1024-1028.
61 Theocharis SE, Kouraklis GP, Kakisis JD, et al. Focal adhesion kinase expression is not a prognostic predictor in colon adenocarcinoma patients. Eur J Surg Oncol, 2003, 29(7):571-574.
62 Lark AL, Livasy CA, Calvo B, et al. Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. Clin Cancer Res, 2003, 9 (1):215-222.
63 Irby RB, Yeatman TJ. Scr-induced deregulation of E-cadherin in colon cancer
cells requires integrin signaling.Nat Cell Biol, 2002,4(8): 632-638.
64 Irby RB, Yeatman TJ.Increased scr activity disrupts cadherin/catenin-mediated homotypic adherin in human colon cancer and transformed rodent cells. Cancer Res, 2002, 62(9):2669-2674.
65 Weyant MJ, Carothers AM,Bertagnolli ME,et al.Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.Clin Cancer Res,2000, 6(3):949-956.
66 Weyant MJ, Carothers AM,Dannenberg AJ,et al.(+)-catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse.Cancer Res,2001,61 (1): 118-125.