胃癌中Wnt-5a、β-catenin和E-cadherin的表达及临床意义
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摘要
目的:检测Wnt-5a mRNA在胃癌及正常胃组织中的表达以及Wnt-5a、β-catenin和E-cadherin蛋白在胃癌、癌旁组织和正常胃组织中的表达,研究Wnt-5a与胃癌发生发展及各临床病理因素间的关系,结合β-catenin、E-cadherin蛋白在胃癌中的表达并分析三者的相关关系,进一步探讨正常胃组织向胃癌转变的分子生物学机制,探讨胃癌中Wnt-5a的早期诊断和预后价值,为临床治疗和药物开发提供新的作用靶点。
方法:采用实时定量RT-PCR技术,对10例手术切除的新鲜胃癌和正常切缘组织(距肿瘤边缘5cm以上)进行Wnt-5a mRNA的检测;采用免疫组化SP法对84例胃癌、相应癌旁组织及其中20例正常胃组织中Wnt-5a、β-catenin和E-cadherin蛋白的表达进行检测。采用配对t检验、卡方检验及Spearman等级相关等方法进行统计学分析。
结果:
1.Wnt-5a mRNA在胃癌及正常组织中表达的相对含量分别为:5.919±1.869、1.281±0.744,两者间差异具有统计学意义(t=-2.374,P＜0.05),其中80%(8/10例)胃癌组织Wnt-5a mRNA显示上调。
2.Wnt-5a蛋白在正常胃组织中均为阴性表达,在胃癌和癌旁组织中的阳性表达率分别为40.54%(34/84例)、14.29%(12/84例);其中100%(5/5例)肠上皮化生和62.5%(5/8例)不典型增生的癌旁组织Wnt-5a阳性表达;与正常组比较,Wnt-5a在胃癌组中显著高表达,差异有统计学意义(P＜0.01),但在癌旁组中的表达差异无统计学意义(P＞0.05);Wnt-5a在胃粘液腺癌中下调表达,与管状腺癌、乳头状腺癌、印戒细胞癌比较,差异具有统计学意义(P＜0.05),但四种组织学分型之间的组间比较差异不显著(P＞0.05);Wnt-5a在TNMⅢ、Ⅳ期病例组的表达显著高于Ⅰ、Ⅱ期(P＜0.001),在淋巴结转移组的表达显著高于无淋巴管转移组(P＜0.01),在低分化组与高中分化组的表达差异无统计学意义(P＞0.05)。
3.β-catenin在正常胃组织100%出现细胞膜的正常表达;在胃癌及癌旁组织中则出现胞质下降表达以及胞质和/或胞核的异常表达,其阳性率分别为70.23%(59/84例)、38.1%(32/84例),其中胃癌组β-catenin的核阳性率为19.0%(16/84例);与正常组比较,β-catenin在胃癌和癌旁组中的异常表达均有统计学意义(P＜0.01);统计分析显示β-catenin的异常表达与TNM分期和淋巴结转移相关(P＜0.05),与肿瘤分化程度无明显相关(P＞0.05)。
4.E-cadherin在正常胃组织膜表达阳性率为100%,在胃癌及癌旁组织膜下降/缺失表达率分别为57.14%(48/84例)、15.48%(13/84例);与正常组比较,E-cadherin在胃癌组的下调表达差异显著(P＜0.05),在癌旁组的下调无统计学意义(P＞0.05);E-cadherin在胃癌中的下调表达相关于TNM分期、淋巴结转移及肿瘤的分化程度(P＜0.05)。
5.Wnt-5a在胃癌组织中的阳性表达与β-catenin的异常表达呈负相关关系(r=-0.367,P=0.001),与E-cadherin的膜下降/缺失表达之间呈正相关关系(r=0.262,P=0.016)。
结论:
1.Wnt-5a mRNA及蛋白在胃癌中均上调表达,Wnt-5a在胃癌中可能发挥癌基因样作用,且Wnt-5a基因的异常活化可能部分参与了胃癌发生的始动过程;其高表达是胃癌发生及演进过程中的频发事件,并与胃癌的临床分期及淋巴结转移相关,该蛋白极可能成为判断胃癌预后不良的指标。
2.β-catenin在胃癌胞浆和/或胞核中异常高表达,可能参与了胃癌的发生发展过程;β-catenin的异常表达与胃癌的临床分期及淋巴结转移相关。
3.E-cadherin在胃癌中显示有意义的下降表达,参与了胃癌的侵袭转移;其异常表达相关于肿瘤的TNM分期、分化程度及淋巴结转移。
4.Wnt-5a在胃癌中的高表达与β-catenin在胃癌中的异常表达呈负相关关系,提示Wnt-5a与β-catenin在胃癌发生的不同时相表达,二者可能经由不同的信号通路在胃癌发生中发挥作用。
5.Wnt-5a在胃癌中的高表达与E-cadherin下调表达间存在正相关关系,前者除涉及胃癌的发生发展外还可能协同E-cadherin在胃癌的浸润转移中发挥作用。
Objective To detect the expression of Wnt-5a mRNA in gastric carcinoma and the corresponding peri-tumor tissue,and the expression of Wnt-5a,β-catenin and E-cadherin protein were also examined in gastric carcinoma(GC),peri-tumor tissue and normal stomach tissue.Approach the relationship between expression of Wnt-5a with the occurrence of GC and clinicopathologic characters,and discuss the correlation with the expression of Wnt-5a,β-catenin and E-cadherin in order to explore the mechanism of molecular biology for the occurrence and development of GC.We therefore wanted to investigate the role of Wnt-5a expression in tumor,with focus on diagnosis and prognosis in GC,Wnt-5a is not only a good prognostic indicator of gastric cancer but also a candidate for a molecular target of therapy for gastric cancer.
Methods Real time RT-PCR was performed in ten fresh gastric carcinoma sample and the corresponding normal tissue to detect mRNA expression of Wnt-5a gene. Eighty-four gastric carcinoma cases and the corresponding peri-tumor tissues and twenty normal stomach mucosa were examined Wnt-5a,β-catenin and E-cadherin by SP immunohistochemical method.The results was treated by matched-pairs T test, chi-square test and Spearman Correlation analysis.
Results
1.Real time RT-PCR analysis showed that Wnt-5a mRNA was overexpressed in GC, and the level of Wnt-5a mRNA in tumor and normal region were5.919±1.869,1.281±0.744 respectively,with a significant difference(P<0.05).Wnt-5a mRNA was up-regulation in 80%(8/10 cases) GC.
2.Wnt-5a protein was negative in all normal gastric tissue,the positive expression rate of Wnt-5a protein in peri-tumor tissue and GC was 14.29%(12/84cases),40.54% (34/84cases) respectively.Wnt-5a protein was positive in 5 cases which develop intestinal metaplasia and 5/8 cases which develop atypical hyperplasia of all the peri-tumor tissue.Compare with the normal tissue,expression of Wnt-5a has a significant highly positive rate in gastric carcinoma(P<0.05),but no significance in peri-tumor tissue(P>0.05);negative expression of Wnt-5a in mucinous adenocarcinoma has a significant difference compare with that in tubular adenocarcinoma,papillary adenocarcinoma and signet-ring cell carcinoma,but no significant difference with histology type in group comparison(P>0.05).Abnormal expression of Wnt-5a was significantly associated with advanced TNM stages (P<0.001),and lymph node metastasis(P<0.01),but no relation with tumor grades(P>0.05).
3.The membranous expression rate ofβ-catenin in normal gastric mucosa was 100%. it was observed in cytoplasm and/or cellular nucleus in GC and peri-tumor tissue, and the positive rate were respectively:70.23%(59/84),38.10%(29/84),of the total carcinoma casesβ-catenin cellular nucleus expression was observed in 19.05%(16 cases).Abnormal expression ofβ-catenin has statistical significance (P<0.01) in tumor and peri- tumor tissue compare with normal tissue,and the abnormal expression ofβ-catenin was associated with advanced tumor stages (P<0.05) and lymph node metastasis(P<0.05),but no correlation with tumor grades(P>0.05).
4.The membranous expression rate of E-cadherin in normal mucosa was 100%,The low/loss membranous expression rate of E-cadherin in peri-tumor tissue and gastric carcinoma were 57.14%(48/84) and 84.5%(13/84) respectively.Compare with normal tissue,down-regulation of E-cadherin has a significant highly positive rate in gastric carcinoma(P<0.05),but no significance in peri-tumor tissue(P>0.05); Reduced expression of E-cadherin was significantly associated with advanced tumor stages,lymph node metastasis and the tumor grades(P<0.05,respectively).
5.The expression of Wnt-5a was correlated withβ-catenin(r=-0.367,P<0.01) and E-cadherin(r=0.262,P<0.05) in GC.
Conclusions:
1.Wnt-5a mRNA and protein were up-regulation in GC.Wnt-5a may play a tumor stimulator function,and Wnt-5a gene may have been activated in early period of tumorigenesis.The high expression of Wnt-5a may be a frequent event in the occurrence and development of GC,and was associated with advanced tumor stages and lymph node metastasis.Wnt-5a protein may become an useful prognosis indicator of GC.
2.β-catenin was detected in cytoplasm and/or cellular nucleus in gastric carcinoma and peri-tumor tissue,which indicate thatβ-catenin may participate in the occurrence of gastric caicinoma.Expression ofβ-catenin was associated with advanced tumor stages and lymph node metastasis.
3.Reduced membranous expression of E-cadherin was a significant event in GC and associated with advanced tumor stages,lymph node metastasis and the tumor grades.
4.The expression of Wnt-5a was negative correlated withβ-catenin in GC, suggesting that the expression of Wnt-5a andβ-catenin is mutually exclusive.The two molecules may suppress the expression of each other,and may play important role in the occurrence of GC via different signal pathway.
5.The expression of Wnt-5a was positively correlated with E-cadherin in GC.Wnt-5a may besides play direct function in the occurrence and progression of GC and also may be in coordination with the expression of E-cadherin to enhance the invasion and metastasis of GC.
方法:采用实时定量RT-PCR技术,对10例手术切除的新鲜胃癌和正常切缘组织(距肿瘤边缘5cm以上)进行Wnt-5a mRNA的检测;采用免疫组化SP法对84例胃癌、相应癌旁组织及其中20例正常胃组织中Wnt-5a、β-catenin和E-cadherin蛋白的表达进行检测。采用配对t检验、卡方检验及Spearman等级相关等方法进行统计学分析。
结果:
1.Wnt-5a mRNA在胃癌及正常组织中表达的相对含量分别为:5.919±1.869、1.281±0.744,两者间差异具有统计学意义(t=-2.374,P＜0.05),其中80%(8/10例)胃癌组织Wnt-5a mRNA显示上调。
2.Wnt-5a蛋白在正常胃组织中均为阴性表达,在胃癌和癌旁组织中的阳性表达率分别为40.54%(34/84例)、14.29%(12/84例);其中100%(5/5例)肠上皮化生和62.5%(5/8例)不典型增生的癌旁组织Wnt-5a阳性表达;与正常组比较,Wnt-5a在胃癌组中显著高表达,差异有统计学意义(P＜0.01),但在癌旁组中的表达差异无统计学意义(P＞0.05);Wnt-5a在胃粘液腺癌中下调表达,与管状腺癌、乳头状腺癌、印戒细胞癌比较,差异具有统计学意义(P＜0.05),但四种组织学分型之间的组间比较差异不显著(P＞0.05);Wnt-5a在TNMⅢ、Ⅳ期病例组的表达显著高于Ⅰ、Ⅱ期(P＜0.001),在淋巴结转移组的表达显著高于无淋巴管转移组(P＜0.01),在低分化组与高中分化组的表达差异无统计学意义(P＞0.05)。
3.β-catenin在正常胃组织100%出现细胞膜的正常表达;在胃癌及癌旁组织中则出现胞质下降表达以及胞质和/或胞核的异常表达,其阳性率分别为70.23%(59/84例)、38.1%(32/84例),其中胃癌组β-catenin的核阳性率为19.0%(16/84例);与正常组比较,β-catenin在胃癌和癌旁组中的异常表达均有统计学意义(P＜0.01);统计分析显示β-catenin的异常表达与TNM分期和淋巴结转移相关(P＜0.05),与肿瘤分化程度无明显相关(P＞0.05)。
4.E-cadherin在正常胃组织膜表达阳性率为100%,在胃癌及癌旁组织膜下降/缺失表达率分别为57.14%(48/84例)、15.48%(13/84例);与正常组比较,E-cadherin在胃癌组的下调表达差异显著(P＜0.05),在癌旁组的下调无统计学意义(P＞0.05);E-cadherin在胃癌中的下调表达相关于TNM分期、淋巴结转移及肿瘤的分化程度(P＜0.05)。
5.Wnt-5a在胃癌组织中的阳性表达与β-catenin的异常表达呈负相关关系(r=-0.367,P=0.001),与E-cadherin的膜下降/缺失表达之间呈正相关关系(r=0.262,P=0.016)。
结论:
1.Wnt-5a mRNA及蛋白在胃癌中均上调表达,Wnt-5a在胃癌中可能发挥癌基因样作用,且Wnt-5a基因的异常活化可能部分参与了胃癌发生的始动过程;其高表达是胃癌发生及演进过程中的频发事件,并与胃癌的临床分期及淋巴结转移相关,该蛋白极可能成为判断胃癌预后不良的指标。
2.β-catenin在胃癌胞浆和/或胞核中异常高表达,可能参与了胃癌的发生发展过程;β-catenin的异常表达与胃癌的临床分期及淋巴结转移相关。
3.E-cadherin在胃癌中显示有意义的下降表达,参与了胃癌的侵袭转移;其异常表达相关于肿瘤的TNM分期、分化程度及淋巴结转移。
4.Wnt-5a在胃癌中的高表达与β-catenin在胃癌中的异常表达呈负相关关系,提示Wnt-5a与β-catenin在胃癌发生的不同时相表达,二者可能经由不同的信号通路在胃癌发生中发挥作用。
5.Wnt-5a在胃癌中的高表达与E-cadherin下调表达间存在正相关关系,前者除涉及胃癌的发生发展外还可能协同E-cadherin在胃癌的浸润转移中发挥作用。
Objective To detect the expression of Wnt-5a mRNA in gastric carcinoma and the corresponding peri-tumor tissue,and the expression of Wnt-5a,β-catenin and E-cadherin protein were also examined in gastric carcinoma(GC),peri-tumor tissue and normal stomach tissue.Approach the relationship between expression of Wnt-5a with the occurrence of GC and clinicopathologic characters,and discuss the correlation with the expression of Wnt-5a,β-catenin and E-cadherin in order to explore the mechanism of molecular biology for the occurrence and development of GC.We therefore wanted to investigate the role of Wnt-5a expression in tumor,with focus on diagnosis and prognosis in GC,Wnt-5a is not only a good prognostic indicator of gastric cancer but also a candidate for a molecular target of therapy for gastric cancer.
Methods Real time RT-PCR was performed in ten fresh gastric carcinoma sample and the corresponding normal tissue to detect mRNA expression of Wnt-5a gene. Eighty-four gastric carcinoma cases and the corresponding peri-tumor tissues and twenty normal stomach mucosa were examined Wnt-5a,β-catenin and E-cadherin by SP immunohistochemical method.The results was treated by matched-pairs T test, chi-square test and Spearman Correlation analysis.
Results
1.Real time RT-PCR analysis showed that Wnt-5a mRNA was overexpressed in GC, and the level of Wnt-5a mRNA in tumor and normal region were5.919±1.869,1.281±0.744 respectively,with a significant difference(P<0.05).Wnt-5a mRNA was up-regulation in 80%(8/10 cases) GC.
2.Wnt-5a protein was negative in all normal gastric tissue,the positive expression rate of Wnt-5a protein in peri-tumor tissue and GC was 14.29%(12/84cases),40.54% (34/84cases) respectively.Wnt-5a protein was positive in 5 cases which develop intestinal metaplasia and 5/8 cases which develop atypical hyperplasia of all the peri-tumor tissue.Compare with the normal tissue,expression of Wnt-5a has a significant highly positive rate in gastric carcinoma(P<0.05),but no significance in peri-tumor tissue(P>0.05);negative expression of Wnt-5a in mucinous adenocarcinoma has a significant difference compare with that in tubular adenocarcinoma,papillary adenocarcinoma and signet-ring cell carcinoma,but no significant difference with histology type in group comparison(P>0.05).Abnormal expression of Wnt-5a was significantly associated with advanced TNM stages (P<0.001),and lymph node metastasis(P<0.01),but no relation with tumor grades(P>0.05).
3.The membranous expression rate ofβ-catenin in normal gastric mucosa was 100%. it was observed in cytoplasm and/or cellular nucleus in GC and peri-tumor tissue, and the positive rate were respectively:70.23%(59/84),38.10%(29/84),of the total carcinoma casesβ-catenin cellular nucleus expression was observed in 19.05%(16 cases).Abnormal expression ofβ-catenin has statistical significance (P<0.01) in tumor and peri- tumor tissue compare with normal tissue,and the abnormal expression ofβ-catenin was associated with advanced tumor stages (P<0.05) and lymph node metastasis(P<0.05),but no correlation with tumor grades(P>0.05).
4.The membranous expression rate of E-cadherin in normal mucosa was 100%,The low/loss membranous expression rate of E-cadherin in peri-tumor tissue and gastric carcinoma were 57.14%(48/84) and 84.5%(13/84) respectively.Compare with normal tissue,down-regulation of E-cadherin has a significant highly positive rate in gastric carcinoma(P<0.05),but no significance in peri-tumor tissue(P>0.05); Reduced expression of E-cadherin was significantly associated with advanced tumor stages,lymph node metastasis and the tumor grades(P<0.05,respectively).
5.The expression of Wnt-5a was correlated withβ-catenin(r=-0.367,P<0.01) and E-cadherin(r=0.262,P<0.05) in GC.
Conclusions:
1.Wnt-5a mRNA and protein were up-regulation in GC.Wnt-5a may play a tumor stimulator function,and Wnt-5a gene may have been activated in early period of tumorigenesis.The high expression of Wnt-5a may be a frequent event in the occurrence and development of GC,and was associated with advanced tumor stages and lymph node metastasis.Wnt-5a protein may become an useful prognosis indicator of GC.
2.β-catenin was detected in cytoplasm and/or cellular nucleus in gastric carcinoma and peri-tumor tissue,which indicate thatβ-catenin may participate in the occurrence of gastric caicinoma.Expression ofβ-catenin was associated with advanced tumor stages and lymph node metastasis.
3.Reduced membranous expression of E-cadherin was a significant event in GC and associated with advanced tumor stages,lymph node metastasis and the tumor grades.
4.The expression of Wnt-5a was negative correlated withβ-catenin in GC, suggesting that the expression of Wnt-5a andβ-catenin is mutually exclusive.The two molecules may suppress the expression of each other,and may play important role in the occurrence of GC via different signal pathway.
5.The expression of Wnt-5a was positively correlated with E-cadherin in GC.Wnt-5a may besides play direct function in the occurrence and progression of GC and also may be in coordination with the expression of E-cadherin to enhance the invasion and metastasis of GC.
引文
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[32] Wharton KA J r. Runnin with the Dvl: p roteins that associate with Dsh /Dvl and their significance to Wnt signal transduction [J]. Dev Biol, 2003, 253 (1):1-17.
[33] Cheng-long Huang, Dage Liu, Jun Nakano, et al. Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor—An Expression in Non-Small-Cell Lung Cancer[J]. 2005, 23(34) :8765-8773.
[34] Yonemura Y, Endou Y, Tabachi K, et al. Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2-40[J]. Hum Pathol,2006,37(9): 1193-1199.
[35] Manabu Kurayoshi, Naohide Oue, Hideki Yamamoto, et al. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion[J]. Cancer Research, 2006, 66(21): 10439-10448 .
[36]回允中 主译 外科病理学[M].北京大学医学出版社,北京,2006:666.
[37]Saitoh T,Mine T,Katoh M.Frequent up-regulation of WNT-5A mRNA in primary gastric cancer[J].Int J Mol Med,2002,9(5):515-519.
[38]刘晓红,周航波,马恒辉,等.肝细胞肝癌中Wnt-5a、β-catenin和E-cadherin蛋白的表达及临床意义[J].临床与实验病理学杂志.2007,23(4):400-403.
[39]Jung,Jung Kee Chung,Young A Kim,et al.E-Bvirus,β-catenin and E-cadherin in Gastric Carcinomas[J].Korean Med Sci,2007,22:855-61.
[40]Mikels AJ,Nusse R.Purified Wnt-5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context[J].PloS Biol,2006,4(4):e115.
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[3] Katoh M. WNT/PCP signaling pathway and human cancer (review) [J]. Oncol Rep, 2005,14(6): 1583-88.
[4] Cheng XX, Wang ZC, Chen XY, et al. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumor dissemination [J]. Cancer Lett, 2005,223(2): 339-47.
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[13] 张开基,李万成. GSK-3 β:一个在信号转导中的关键酶[J].国际呼吸杂志,2007, 27(2): 130-132.
[14] Zheng HP, Zhou W, Xu LH, et al. Correlation between gene polymorphisms of Wnt signalling pathway related components and risk of gastric carcinoma: a case-control study [J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2006,23(6): 647-651.
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[37]Saitoh T,Mine T,Katoh M.Frequent up-regulation of WNT-5A mRNA in primary gastric cancer[J].Int J Mol Med,2002,9(5):515-519.
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[1] David M, Eisenmann. Wnt signaling[J]. WormBook, 2005,25:1-17
[2] Katoh M, Katoh M. Comparative genomics on Wnt8a and Wnt8b genes[J]. Int J Oncol, 2005,26(4): 1129-1133.
[3] Katoh M. WNT/PCP signaling pathway and human cancer (review) [J]. Oncol Rep, 2005,14(6): 1583-88.
[4] Cheng XX, Wang ZC, Chen XY, et al. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumor dissemination [J]. Cancer Lett, 2005,223(2): 339-47.
[5] Katoh M, Katoh M. Conserved POU/OCT- and GATA-binding sites in 5'-flanking promoter region of mammalian WNT8B orthologs[J].Int J Oncol, 2007, 30 (5):1273-77.
[6] Saitoh T, Kirikoshi H, Mine T, et al. Proto-oncogene WNT10B is up-regulated by tumor necrosis factor alpha in human gastric cancer cell line MKN45 [J].Int J Oncol, 2001,19(6): 1187-1192.
[7] Ogasawara N, Tsukamoto T, Mizoshita T, et al. Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer [J]. Histopathology, 2006 ,49(6):612-621.
[8] Tatematsu M, Tsukamoto T, Inada K. Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia [J]. Cancer Sci, 2003,94:135-141.
[9] Rodriguez-Sanjuan JC, Fontalba A, Mayorga M, et al. A novel mutation in the E-cadherin gene in the first family with hereditary diffuse gastric cancer reported in Spain [J].Eur J Surg Oncol, 2006, 32(10):1110-1113.
[10] Henderson BR. Nuclear cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover [J]. Nat Cell Biol, 2001,2: 653-660.
[11] Rosin-Arbesfeld R, Cliffe A, Brabletz T, etal. Nuclear export of the APC tumor suppressor controls beta-catenin function in transcription [J]. EMBO J ,2004, 22:1101-1113
[12] Grace A, Butler D, Gallagher M, etal. APC gene expression in gastric carcinoma:an immunohistochemical study [J]. Appl Immunohis chem. Mol Morphol, 2002,10(3):221-224.
[13] 张开基,李万成. GSK-3 β:一个在信号转导中的关键酶[J].国际呼吸杂志,2007, 27(2): 130-132.
[14] Zheng HP, Zhou W, Xu LH, et al. Correlation between gene polymorphisms of Wnt signalling pathway related components and risk of gastric carcinoma: a case-control study [J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2006,23(6): 647-651.
[15] Manabu Kurayoshil, Naohide Oue, Hideki Yamamoto , et al .Expression of Wnt-5a Is Correlated with Aggressiveness of Gastric Cancer by Stimulating Cell Migration and Invasion [J]. Cancer Res, 2006,66(21): 10439-48.
[16] Lu Z, Hunter T.Wnt-Independent beta-catenin transactivation in tumor development [J]. Cell Cycle, 2004,3(5):571-573.
[17] Mikhail V, Semenov, SnapShot etal. Noncanonical Wnt Signaling Pathways [J].Cell, 2007,131(7): 1378.
[18] Kurayoshi M, Oue N, Yamamoto H, et al. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion [J]. Cancer Res, 2006 , 66(21): 10439-48.
[19] Nojima M, Suzuki H, Toyota M,, et al. Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer[J].Oncogene, 2007 ,26(32):4699-4713.
[20] Cheng YY, Yu J, Wong YP, et al. Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer [J]. Br J Cancer, 2007, 97(7):895-901.
[21] Zhao CH, Bu XM, Zhang N. Hypermethylation and aberrant expression of Wnt antagonist secreted frizzled-related protein 1 in gastric cancer[J]. World J Gastroenterol,2007,13(15):2214-2217.
[22] Taniguchi H, Yamamoto H, Hirata T, et al. Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers.cancers[J].Oncogene, 2005,24(53):7946-7952.
[23]Kawano Y,KyptaR.Secreted antagonists of the Wnt signaling pathway[J].Cell Sci,2003,116(13),2627- 2634.
[24]汪华,邓长生,余峰.糖原合成酶激酶-3β与胃癌细胞增殖关系的研究[J].数理医药学杂志,2006,19(5):509-510.
[25]郑亚民,李非,董承等.胃癌组织Axin蛋白的表达与侵袭转移的相关性[J].世界华人消化杂志,2006,14(8):763-766.
[26]Kuhl M,SheldahlL C,Park M,et al.The Wnt/Ca2+ pathway:a New vertebrate Wnt signaling pathway takes shape[J].Trends Genet,2000,16(7):279-283.
[27]于颖彦,朱正纲,严超等.胃癌与Wnt/β-连环素信号通道活化的关系[J].中华实验外科杂志,2004,21(12):1557.
[28]Koppert LB,van der Velden AW,van de Wetering M,et al.Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression[J].Br J Cancer,2004,90(4):892-899.