Wnt/β-catenin信号通路拮抗因子Chibby在鼻咽癌组织中的表达及意义
摘要
背景与目的:鼻咽癌发病率居头颈部恶性肿瘤之首。近年来,大量研究表明,Wnt/β-catenin信号通路与鼻咽癌的发生、发展存在密切的关系。Wnt/β-catenin信号通路关键因子β-catenin与核转录因子TCF/LEF结合启动靶基因表达是该信号通路活化的关键步骤,而chibby是β-catenin抑制因子,通过对β-catenin的抑制阻止靶基因的表达,可能是一种潜在的肿瘤抑制因子。因此,本研究运用Real time PCR及免疫组织化学的方法检测鼻咽癌组织中chibby mRNA及蛋白的表达,探讨鼻咽癌组织中chibby mRNA及蛋白的表达水平及临床病理学意义。
材料与方法:(1)2010.4-2011.01在我院门诊初诊确诊的符合入组条件的鼻咽鳞癌患者45例,取其病变部位活检标本及对侧正常鼻咽粘膜筛检标本共90份。(2)提取总RNA,反转录为cDNA,采用Real time PCR检测所有标本chibby mRNA的表达水平。(3)采用免疫组织化学方法检测所有标本chibby蛋白的表达水平。(4)测量鼻咽癌组织chibby mRNA及蛋白降低的发生率,及其与各临床特征的相关性。
结果:(1)鼻咽癌组织chibby mRNA表达降低率为68.9%(31/45,95% CI 53%-82%)。Chibby mRNA在鼻咽癌组织中相对表达量低于正常鼻咽粘膜(0.0776±0.0059,0.0835±0.0056,P<0.05)。(2)鼻咽癌组织chibby蛋白表达降低率为73.3%(33/45,95% CI 58%-85%)。chibby蛋白在鼻咽癌组织中的阳性率低于正常鼻咽粘膜(42.2% 19/45,91.1% 41/45,P<0.05)。(3)chibby mRNA及蛋白表达水平与T分期及临床分期有相关(P<0.05),与性别、年龄、颈淋巴结转移无明显相关性(P>0.05)。
结论:(1)chibby mRNA及蛋白在鼻咽癌组织中表达均降低;(2)chibby的表达水平与肿瘤T分期及临床分期相关,T分期及临床分期越高,chibby表达越低;同时未能发现chibby的表达与性别、年龄、颈淋巴结转移及WHO病理分型相关。
Background and Objective:
Nasopharyngeal carcinoma (NPC) is one of the common head and neck cancers, which incidence rate is in the first head and neck cancer. In recent years, a large number of studies have shown that there is a close relationship between wnt/β-catenin signaling pathway and the development of NPC.β-catenin ,a critical factor of Wnt/β-catenin signaling pathway ,combined with nuclear transcription factor TCF / LEF , starts with the expression of target gene. This is the critical step of the activation of signaling pathway. chibby ,aβ-catenin inhibitor, prevent expression of target gene through inhibition ofβ-catenin .It may be a potential tumor suppressor. We analyse the Chibby expression and its function in NPC.
Material and Methods:
Forty-five cases of NPC were included in this study. Tumour and matched contralateral mucosa were sampled. Chibby expression levels were investigated by quantitative RT-PCR, and immunohistochemical methods revealed correct expression patterns of Chibby protein. The chibby expression levels and expression patterns of Chibby protein in different groups of different characters were analysed.
Result:
The rate of low expressions of Chibby mRNA is in tumour 68.9% (31/45 95% CI 53%-82%), the expressions in the tumour and matched contralateral mucosa were 0.0776±0.0059 and 0.0835±0.0056(P<0.05). The rate of low expressions of Chibby protein in tumour is 73.3% (33/45, 95% CI 58%-85%), the positive rate in the tumour and matched contralateral mucosa were 42.2%(19/45) and 91.1%(41/45), P<0.05. The early tumour staging and the clinical staging had the low chibby expression levels and expression patterns of Chibby protein.
Conclusion:
There is low expression of Chibby mRNA and protein in NPC, The chibby expression levels and expression patterns of Chibby protein associate with tumour staging and clinical staging.
材料与方法:(1)2010.4-2011.01在我院门诊初诊确诊的符合入组条件的鼻咽鳞癌患者45例,取其病变部位活检标本及对侧正常鼻咽粘膜筛检标本共90份。(2)提取总RNA,反转录为cDNA,采用Real time PCR检测所有标本chibby mRNA的表达水平。(3)采用免疫组织化学方法检测所有标本chibby蛋白的表达水平。(4)测量鼻咽癌组织chibby mRNA及蛋白降低的发生率,及其与各临床特征的相关性。
结果:(1)鼻咽癌组织chibby mRNA表达降低率为68.9%(31/45,95% CI 53%-82%)。Chibby mRNA在鼻咽癌组织中相对表达量低于正常鼻咽粘膜(0.0776±0.0059,0.0835±0.0056,P<0.05)。(2)鼻咽癌组织chibby蛋白表达降低率为73.3%(33/45,95% CI 58%-85%)。chibby蛋白在鼻咽癌组织中的阳性率低于正常鼻咽粘膜(42.2% 19/45,91.1% 41/45,P<0.05)。(3)chibby mRNA及蛋白表达水平与T分期及临床分期有相关(P<0.05),与性别、年龄、颈淋巴结转移无明显相关性(P>0.05)。
结论:(1)chibby mRNA及蛋白在鼻咽癌组织中表达均降低;(2)chibby的表达水平与肿瘤T分期及临床分期相关,T分期及临床分期越高,chibby表达越低;同时未能发现chibby的表达与性别、年龄、颈淋巴结转移及WHO病理分型相关。
Background and Objective:
Nasopharyngeal carcinoma (NPC) is one of the common head and neck cancers, which incidence rate is in the first head and neck cancer. In recent years, a large number of studies have shown that there is a close relationship between wnt/β-catenin signaling pathway and the development of NPC.β-catenin ,a critical factor of Wnt/β-catenin signaling pathway ,combined with nuclear transcription factor TCF / LEF , starts with the expression of target gene. This is the critical step of the activation of signaling pathway. chibby ,aβ-catenin inhibitor, prevent expression of target gene through inhibition ofβ-catenin .It may be a potential tumor suppressor. We analyse the Chibby expression and its function in NPC.
Material and Methods:
Forty-five cases of NPC were included in this study. Tumour and matched contralateral mucosa were sampled. Chibby expression levels were investigated by quantitative RT-PCR, and immunohistochemical methods revealed correct expression patterns of Chibby protein. The chibby expression levels and expression patterns of Chibby protein in different groups of different characters were analysed.
Result:
The rate of low expressions of Chibby mRNA is in tumour 68.9% (31/45 95% CI 53%-82%), the expressions in the tumour and matched contralateral mucosa were 0.0776±0.0059 and 0.0835±0.0056(P<0.05). The rate of low expressions of Chibby protein in tumour is 73.3% (33/45, 95% CI 58%-85%), the positive rate in the tumour and matched contralateral mucosa were 42.2%(19/45) and 91.1%(41/45), P<0.05. The early tumour staging and the clinical staging had the low chibby expression levels and expression patterns of Chibby protein.
Conclusion:
There is low expression of Chibby mRNA and protein in NPC, The chibby expression levels and expression patterns of Chibby protein associate with tumour staging and clinical staging.
引文
【1】孔维佳,周梁,王斌全等.耳鼻咽喉-头颈外科学[M].1版.北京:人民卫生出版社,2005:179-183.
【2】Sham JS, Choy D, Choi PH. Nasopharyngeal carcinoma: the significance of neck node involvement in relation to the pattern of distant failure[J]. Br J Radiol 1990,63: 108–113.
【3】余子豪,徐国镇等.肿瘤放射治疗学[M].4版.中国协和医科大学出版社,2008:443.
【4】Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer[J]. Nat. Rev. Cancer, 2008, 8:387–398.
【5】Takemaru K, Ohmitsu M, Li F. An oncogenic hub: betacatenin as a molecular target for cancer therapeutics[J]. Handb. Exp. Pharmacol, 2008,18: 261–284.
【6】Veeman MT, Axelrod JD, Moon RT. A second canon Functions and mechanisms of beta-catenin- independent Wnt signaling[J]. Dev Cell, 2003, 5(3): 367-377.
【7】Saneyoshi T, Kume S, Amasaki Y , et al.The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos[J]. Nature, 2002, 417(6886):295-299
【8】Li FQ,Singh AM,Mofunanya A,et a1.Chibby promotes adipocyte differentiation through inhibition of beta-catenin signaling[J]. Mol Cell Biol,2007,27(12):4345-4354.
【9】Macdonald B, Semenov M, and He X. SnapShot: Wnt/Beta-catenin signaling[J]. Cell, 2007,131:1204.
【10】Bienz M, Clevers H. Armadillo/beta-catenin signals in the nucleus-proof beyond a reasonable doubt?[J] Nat Cell Biol, 2003,5(3):179-182.
【11】Chen X, et al. Wnt signaling: the good and the bad [J].Acta Biochim Biophys Sin (shanghai), 2008, 40(7):577-594.
【12】Stadeli R, Hoffmans R, and Basler K. Transcription under the control of nuclear Arm/beta-catenin[J]. Curr. Biol, 2006, 16: 378-385.
【13】Zeng ZY, Zhou YH, Zhang WL, et al. Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway[J]. Hum Pathol, 2007,38(1):120-133.
【14】Shi W, Bastianutto C, Li A, et al. Multiple dysregulated pathways in nasopharyngealcarcinoma revealed by gene expression profiling[J]. Cancer, 2006, 119:2467-2475.
【15】Chen HC, Chen GH, Chen YH, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma[J]. British Journal of Cancer, 2009,100:1002-1011.
【16】Lin YC, You L, Xu Z, et al. Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines[J]. Biochem Biophys Res Commun, 2006, 34(12):635-640.
【17】Lin QQ, Li JT, Wang M. Role of Wnt/β-catenin Pathway in Differentiation of Nasopharyngeal Carcinoma[J]. Journal of Sun Yat-Sen University (MEDICAL SCIENCES), 2005,26(4):384-387.
【18】Shnayder Y, Kuriakose MA, Xue XN, et al. Adhesion Molecules as Prognostic Factors in Nasopharyngeal Carcinoma[J]. Laryngoscope, 2001 ,111:1842-1846.
【19】Stephen L Chan, Yan Cui, Andrew van Hasselt, et al. The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas[J]. Laboratory Investigation, 2007,(87): 644–650.
【20】K. Takemaru, S. Yamaguchi, Y.S. Lee, et al. Chibby, a nuclear beta-catenin associated antagonist of the Wnt/Wingless pathway [J]. Nature, 2003, 422: 905–909.
【21】Xing Y, Takemaru K, Liu J, et al. Crystal structure of a full-length beta-catenin[J]. Structure 2008;16:478-87.
【22】Feng-Qian Li , Adaobi Mofunanya , Kimberley Harris, et al. Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity [J].Cell Biol, 2008, 181(7): 1141-1154.
【23】Schuierer MM, Graf E, Takemaru K,et al. Reduced expression of betacatenin inhibitor Chibby in colon carcinoma cell lines[J]. World J Gastroenterol, 2006, 12:1529–35.
【24】Karakoula K, Suarez-Merino B, Ward S, et al. Real-time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12-q13. Genes Chromosomes Cancer,2008, 47: 1005–22.
【25】Matern J, Koomagi R, Volm M, et al. Biological characterization of subgroups of squamous cell lung carcinoma [J].Clin Cancer Res, 1999, 5(6):1459-1463.
【26】Birgit Z, Stefanie W, Norbert G, et al. A novel antagonist of the Wnt pathway, is not involved in Wilms tumor development[J].Cancer Letters,2005,220:115–120.
【27】Sophie G, David T, Astrid L, et al. Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer[J]. BMC Cancer,2004 ,4:31-37.
[1] Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell, 2004,5:423 - 428.
[2] Zeng ZY, Zhou YH, Zhang WL, et al. Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway. Hum Pathol, 2007,38(1):120-133.
[3] Shi W, Bastianutto C, Li A, et al. Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling. Cancer ,2006 ,119:2467-2475.
[4] Veeman MT, Axelrod JD, Moon RT. A second canon Functions and mechanisms of beta-catenin- independent Wnt signaling. Dev Cell, 2003, 5(3): 367-377.
[5] Saneyoshi T, Kume S, Amasaki Y , et al.The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature, 2002, 417(6886):295-299.
[6] Chien A J, et al. A Wnt survival guide: from flies to human disease. Invest Dermatol, 2009, 129: 1614-1627.
[7] Muller T, Choidas A, Reichmann E, Ullrich A.Phosphorylation an d free pool of beta-catenin are regulated by tyrosine kinases an d tyrosine phosphatases during epithelial cell migration. Bid Chem, 1999,274:10173-10183.
[8] Kikuchi A. Regulation of beta-catenin signaling in the Wnt pathway. Biochem Biophys Res Commun , 2000, 268: 243-248.
[9] Waltzer L, Bienz M. The control of beta-catenin and TCF during embryonic development and cancer. Cancer Metastasis Rev, 1999, 18:231-246.
[10] Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene, 2003, 302(1/2): 179-183.
[11] Blake SM, Eliopoulos AG, Dawson CW, Young LS. The transmembrane domains of the EBV-encoded latent membrane protein 1 (LMP1) variant CAO regulate enhanced signaling activity. Virology ,2001,282:278-287.
[12] Tsai CN, Tsai CL, Tse KP, et al. The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc Natl Acad Sci U S A, 2002,99:10084-10089.
[13] Lo AK, Huang DP, Lo KW, et al. Phenotypic alterations induced by the Hong Kong-prevalent
Epstein-Barr virus-encoded LMP1 variant (2117-LMP1) in nasopharyngeal epithelial cells[J]. International Journal of Cancer, 2004,109:919-925.
[14] Niemhom S, Kitazawa S, Kitazawa R, et al. Hypermethylation of epithelial-cadherin gene promoter is associated with Epstein-Barr virus in nasopharyngeal carcinoma. Cancer Detection and Prevention, 2008, 32:127-134
[15] Shair KH, Schnegg CI, Nancy RT. Epstein-Barr virus latent membrane protein 1 Effects on Junctional Plakoglobin and induction of Cadhrin Switch. Cancer Res, 2009,69(14):5734-5742.
[16] Webb N, Connolly G, Tellam J et al. Epstein-Barr Virus Associated Modulation of Wnt Pathway Is Not Dependent on Latent Membrane Protein-1. Plos One, 2008,(3):3254.
[17] Morrison JA. Klingelhutz AJ,et al. Epstein-Barr Virus Latent Membrane Protein 2A Activatesβ-Catenin Signaling in Epithelial Cells. Journal of Virology, 2003,77(22): 12276-12284.
[18] Nicole Heussinger,Maike Büvtner,et al.Expression of the Epstein-Barr virus(EBV)-encoded latentmembrane protein 2A (LMP 2A)in EBV-associated nasopharyngeal carcinoma.Journal of Pathology, 2004, 203(2):696-699.
[19] +Li Q, Neng Z, zhong XZ, et al. Effect of WNT5A Knockdown on Metastasis in Nasopharyngeal Cancer Cells. Journal of University of South China(Medical Edition),2009,37(6):677-680.
[20] Chen HC, Chen GH, Chen YH, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma. British Journal of Cancer, 2009,100:1002-1011.
[21] Zheng Z, Pan J, Chu B, Wong YC. Downregulation and abnormal expression of E-cadherin and beta-catenin in nasopharyngeal carcinoma: close association with advanced disease stage and lymph node metastasis. Hum Pathol, 1999,30(4):458-466.
[22] Li Z, Ren Y, Lin S, Liang Y, Liang H. Association of E-cadherin andβ-catenin with metastasis in nasopharyngeal carcinoma. Chin Med J (Engl) 2004,117(8):1232–1239.
[23] Li z, Lin SX,Liang YJ.Detection of gene promoter methylation and mRNA , proteinexpression levels of E-cadherin in nasopharyngeal carcinoma. Zhonghua Bing Li Xue Za Zhi, 2003, 32(1):25-3 0.
[24] Shnayder Y, Kuriakose MA, Xue XN, et al. Adhesion Molecules as Prognostic Factors in Nasopharyngeal Carcinoma. Laryngoscope, 2001 ,111:1842-1846.
[25] Lin QQ, Li JT, Wang M. Role of Wnt/β-catenin Pathway in Differentiation of Nasopharyngeal Carcinoma. Journal of Sun Yat-Sen University (MEDICAL SCIENCES), 2005,26(4):384-387.
[26] Li Z, Lin SX, Liang YJ. Influence of E-cadherin promoter methylation and mutation of beta-catenin on invasion and metastasis of nasopharyngeal carcinoma cells. Zhonghua Zhong Liu Za Zhi. 2003,25(3):238-42.
[27] Peng C, Liu HY, Zhou M, et al. BRD7 suppresses the growth of Nasopharyngeal Carcinoma cells (HNE1) through negatively regulatingβ-catenin and ERK Pathways. Mol Cell Biochem ,2007,303:141–149.
[28] Lin YC, You L, Xu Z, et al. Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines. Biochem Biophys Res Commun, 2006, 34(12):635-640.
[29] Stephen L Chan, Yan Cui, Andrew van Hasselt, et al. The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas. Laboratory Investigation ,2007,(87): 644–650.
[30] Li J, Fan Y, Chen J, et al. Microarray analysis of differentially expressed genes between nasopharyngeal carcinoma cell lines 5-8F and 6-10B. Cancer Genetics and Cytogenetics , 2010 ,196:23-30.
【2】Sham JS, Choy D, Choi PH. Nasopharyngeal carcinoma: the significance of neck node involvement in relation to the pattern of distant failure[J]. Br J Radiol 1990,63: 108–113.
【3】余子豪,徐国镇等.肿瘤放射治疗学[M].4版.中国协和医科大学出版社,2008:443.
【4】Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer[J]. Nat. Rev. Cancer, 2008, 8:387–398.
【5】Takemaru K, Ohmitsu M, Li F. An oncogenic hub: betacatenin as a molecular target for cancer therapeutics[J]. Handb. Exp. Pharmacol, 2008,18: 261–284.
【6】Veeman MT, Axelrod JD, Moon RT. A second canon Functions and mechanisms of beta-catenin- independent Wnt signaling[J]. Dev Cell, 2003, 5(3): 367-377.
【7】Saneyoshi T, Kume S, Amasaki Y , et al.The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos[J]. Nature, 2002, 417(6886):295-299
【8】Li FQ,Singh AM,Mofunanya A,et a1.Chibby promotes adipocyte differentiation through inhibition of beta-catenin signaling[J]. Mol Cell Biol,2007,27(12):4345-4354.
【9】Macdonald B, Semenov M, and He X. SnapShot: Wnt/Beta-catenin signaling[J]. Cell, 2007,131:1204.
【10】Bienz M, Clevers H. Armadillo/beta-catenin signals in the nucleus-proof beyond a reasonable doubt?[J] Nat Cell Biol, 2003,5(3):179-182.
【11】Chen X, et al. Wnt signaling: the good and the bad [J].Acta Biochim Biophys Sin (shanghai), 2008, 40(7):577-594.
【12】Stadeli R, Hoffmans R, and Basler K. Transcription under the control of nuclear Arm/beta-catenin[J]. Curr. Biol, 2006, 16: 378-385.
【13】Zeng ZY, Zhou YH, Zhang WL, et al. Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway[J]. Hum Pathol, 2007,38(1):120-133.
【14】Shi W, Bastianutto C, Li A, et al. Multiple dysregulated pathways in nasopharyngealcarcinoma revealed by gene expression profiling[J]. Cancer, 2006, 119:2467-2475.
【15】Chen HC, Chen GH, Chen YH, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma[J]. British Journal of Cancer, 2009,100:1002-1011.
【16】Lin YC, You L, Xu Z, et al. Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines[J]. Biochem Biophys Res Commun, 2006, 34(12):635-640.
【17】Lin QQ, Li JT, Wang M. Role of Wnt/β-catenin Pathway in Differentiation of Nasopharyngeal Carcinoma[J]. Journal of Sun Yat-Sen University (MEDICAL SCIENCES), 2005,26(4):384-387.
【18】Shnayder Y, Kuriakose MA, Xue XN, et al. Adhesion Molecules as Prognostic Factors in Nasopharyngeal Carcinoma[J]. Laryngoscope, 2001 ,111:1842-1846.
【19】Stephen L Chan, Yan Cui, Andrew van Hasselt, et al. The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas[J]. Laboratory Investigation, 2007,(87): 644–650.
【20】K. Takemaru, S. Yamaguchi, Y.S. Lee, et al. Chibby, a nuclear beta-catenin associated antagonist of the Wnt/Wingless pathway [J]. Nature, 2003, 422: 905–909.
【21】Xing Y, Takemaru K, Liu J, et al. Crystal structure of a full-length beta-catenin[J]. Structure 2008;16:478-87.
【22】Feng-Qian Li , Adaobi Mofunanya , Kimberley Harris, et al. Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity [J].Cell Biol, 2008, 181(7): 1141-1154.
【23】Schuierer MM, Graf E, Takemaru K,et al. Reduced expression of betacatenin inhibitor Chibby in colon carcinoma cell lines[J]. World J Gastroenterol, 2006, 12:1529–35.
【24】Karakoula K, Suarez-Merino B, Ward S, et al. Real-time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12-q13. Genes Chromosomes Cancer,2008, 47: 1005–22.
【25】Matern J, Koomagi R, Volm M, et al. Biological characterization of subgroups of squamous cell lung carcinoma [J].Clin Cancer Res, 1999, 5(6):1459-1463.
【26】Birgit Z, Stefanie W, Norbert G, et al. A novel antagonist of the Wnt pathway, is not involved in Wilms tumor development[J].Cancer Letters,2005,220:115–120.
【27】Sophie G, David T, Astrid L, et al. Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer[J]. BMC Cancer,2004 ,4:31-37.
[1] Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell, 2004,5:423 - 428.
[2] Zeng ZY, Zhou YH, Zhang WL, et al. Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway. Hum Pathol, 2007,38(1):120-133.
[3] Shi W, Bastianutto C, Li A, et al. Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling. Cancer ,2006 ,119:2467-2475.
[4] Veeman MT, Axelrod JD, Moon RT. A second canon Functions and mechanisms of beta-catenin- independent Wnt signaling. Dev Cell, 2003, 5(3): 367-377.
[5] Saneyoshi T, Kume S, Amasaki Y , et al.The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature, 2002, 417(6886):295-299.
[6] Chien A J, et al. A Wnt survival guide: from flies to human disease. Invest Dermatol, 2009, 129: 1614-1627.
[7] Muller T, Choidas A, Reichmann E, Ullrich A.Phosphorylation an d free pool of beta-catenin are regulated by tyrosine kinases an d tyrosine phosphatases during epithelial cell migration. Bid Chem, 1999,274:10173-10183.
[8] Kikuchi A. Regulation of beta-catenin signaling in the Wnt pathway. Biochem Biophys Res Commun , 2000, 268: 243-248.
[9] Waltzer L, Bienz M. The control of beta-catenin and TCF during embryonic development and cancer. Cancer Metastasis Rev, 1999, 18:231-246.
[10] Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene, 2003, 302(1/2): 179-183.
[11] Blake SM, Eliopoulos AG, Dawson CW, Young LS. The transmembrane domains of the EBV-encoded latent membrane protein 1 (LMP1) variant CAO regulate enhanced signaling activity. Virology ,2001,282:278-287.
[12] Tsai CN, Tsai CL, Tse KP, et al. The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc Natl Acad Sci U S A, 2002,99:10084-10089.
[13] Lo AK, Huang DP, Lo KW, et al. Phenotypic alterations induced by the Hong Kong-prevalent
Epstein-Barr virus-encoded LMP1 variant (2117-LMP1) in nasopharyngeal epithelial cells[J]. International Journal of Cancer, 2004,109:919-925.
[14] Niemhom S, Kitazawa S, Kitazawa R, et al. Hypermethylation of epithelial-cadherin gene promoter is associated with Epstein-Barr virus in nasopharyngeal carcinoma. Cancer Detection and Prevention, 2008, 32:127-134
[15] Shair KH, Schnegg CI, Nancy RT. Epstein-Barr virus latent membrane protein 1 Effects on Junctional Plakoglobin and induction of Cadhrin Switch. Cancer Res, 2009,69(14):5734-5742.
[16] Webb N, Connolly G, Tellam J et al. Epstein-Barr Virus Associated Modulation of Wnt Pathway Is Not Dependent on Latent Membrane Protein-1. Plos One, 2008,(3):3254.
[17] Morrison JA. Klingelhutz AJ,et al. Epstein-Barr Virus Latent Membrane Protein 2A Activatesβ-Catenin Signaling in Epithelial Cells. Journal of Virology, 2003,77(22): 12276-12284.
[18] Nicole Heussinger,Maike Büvtner,et al.Expression of the Epstein-Barr virus(EBV)-encoded latentmembrane protein 2A (LMP 2A)in EBV-associated nasopharyngeal carcinoma.Journal of Pathology, 2004, 203(2):696-699.
[19] +Li Q, Neng Z, zhong XZ, et al. Effect of WNT5A Knockdown on Metastasis in Nasopharyngeal Cancer Cells. Journal of University of South China(Medical Edition),2009,37(6):677-680.
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