TGFBR3基因在膀胱癌中的表达及其临床意义
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摘要
背景与目的:转化生长因子β(transforming growth factor beta,TGF-β)信号转导通路在肿瘤的发生、发展进程中发挥着重要作用,TGF-β受体的变异或缺失将导致其抑制肿瘤作用的丧失。已有研究显示膀胱癌中TGFBR1和TGFBR2的表达是下降的,而作为TGF-β信号通路中辅助受体的TGFBR3基因在膀胱癌组织中表达情况尚不清楚。本实验旨在探索膀胱尿路上皮癌中TGFBR3表达,同时观察TGFBR3异常表达与肿瘤病理分级、临床分期、淋巴结转移及患者性别等的相关性。
方法:32对膀胱尿路上皮癌及癌旁组织均来自外科手术标本。应用免疫组织化检测膀胱癌组织以及癌旁膀胱组织中TGFBR3蛋白的表达。同时采用实时荧光定量PCR(Real-time PCR)检测本组膀胱癌及癌旁组织中TGFBR3 mRNA的表达。分析TGFBR3的表达与病理分级、临床分期、淋巴结转移及患者性别等的关系。
结果:本组32对样本研究显示TGFBR3蛋白在膀胱癌组织中的表达阳性率为25.00%(8/32),显著低于癌旁组织78.13%(25/32),差异有统计学意义(P<0.05)。TGFBR3 mRNA在膀胱癌及癌旁组织中均有表达,在癌组织中平均相对表达量为2.25±0.65,显著低于癌旁组织6.42±1.53,差异有统计学意义(P<0.05)。在I、II、III级膀胱癌组织中TGFBR3 mRNA表达量分别为:4.15±1.69、1.96±0.68和0.90±0.65,表达量随肿瘤的病理分级的逐渐升高而减少,但组间比较差异无统计学意义(P>0.05);在非肌层浸润性膀胱癌(Tis-T1)中TGFBR3 mRNA表达量为1.94±0.76,肌层浸润性膀胱癌(T2-T4)为2.46±0.97,差异无统计学意义(P>0.05)。TGFBR3 mRNA表达量在有淋巴结转移的患者为6.05±2.55,而在无淋巴结转移的患者表达量明显降低为1.37±0.42,差异有统计学意义(P<0.05);男性患者癌组织中TGFBR3 mRNA表达量为2.25±0.72,女性患者为2.26±1.42,差异无统计学意义(P>0.05)。
结论:在蛋白和mRNA水平上检测,膀胱癌组织中TGFBR3的表达量显著低于癌旁膀胱组织,显示了该基因的表达缺失在膀胱癌的发生、发展中起一定的作用。癌组织中TGFBR3 mRNA的表达量随肿瘤恶性程度的逐渐升高而减少,可能在膀胱癌的形成初期该基因起抑癌作用;TGFBR3 mRNA的表达量随肿瘤临床分期的升高而增加,尤其是在淋巴结转移的患者中表达量显著高于无淋巴结转移者,提示在膀胱癌形成后,该基因起促癌作用。
Background and Objective: The transforming growth factor beta (TGF-β) signalling system plays an important role in the carcinogenesis of the bladder. Alterations in many components of the TGF-βsignaling pathway, such as mutation or deletion of receptors and other signaling components are frequent events in human cancers and lead to a loss of the tumor suppressor function of that pathway. As we known: the TGF-βreceptor I and II (TGFBR1, TGFBR2) are lost in bladder cancer at the protein level. However, the expression of TGF-βreceptor III (TGFBR3) remains unclear. In this study we investigate the expression of TGF-βreceptor III (TGFBR3) in urothelial carcinoma of the bladder (BUC); and analyze its relevance with grade, stage, and other clinical parameters in BUC.
Methods: Fresh tissues and adjacent normal bladder tissues were obtained from 32 patients with BUC. TGFBR3 expression was measured by immunohistochemistry and real-time PCR. And its potential clinical significance was analyzed.
Results: The TGFBR3 protein was expressed 25.00%(8/32)in BUC and 78.13%(25/32)in adjacent normal tissues(P<0.05). Lower expression of TGFBR3 mRNA was detected in BUC (2.25±0.65) than in adjacent normal tissues (6.42±1.53,P<0.05). Respectively, expression level of TGFBR3 mRNA in grade I, II, III was 4.15±1.69, 1.96±0.68 and 0.90±0.65; in stage Tis-Tl,T2-T4 was 1.94±0.76 and 2.46±0.97. TGFBR3 mRNA expression in patients with and without lymph nodes metastasis was 6.05±2.55 and 1.37±0.42. Expression of TGFBR3 mRNA in male and female group was 2.25±0.72 and 2.26±1.42. TGFBR3 mRNA level did not correlate with grade, stage and gender (P>0.05). Higher level of expression was associated with lymph nodes metastasis (P<0.05).
Conclusion: Our study showes that TGFBR3 is significantly down-regulated in BUC than in adjacent normal bladder tissues, and different levels of TGFBR3 mRNA in patients with and without lymph nodes metastasis are found. So TGFBR3 may play an important role in the pathogenesis and development of BUC.
方法:32对膀胱尿路上皮癌及癌旁组织均来自外科手术标本。应用免疫组织化检测膀胱癌组织以及癌旁膀胱组织中TGFBR3蛋白的表达。同时采用实时荧光定量PCR(Real-time PCR)检测本组膀胱癌及癌旁组织中TGFBR3 mRNA的表达。分析TGFBR3的表达与病理分级、临床分期、淋巴结转移及患者性别等的关系。
结果:本组32对样本研究显示TGFBR3蛋白在膀胱癌组织中的表达阳性率为25.00%(8/32),显著低于癌旁组织78.13%(25/32),差异有统计学意义(P<0.05)。TGFBR3 mRNA在膀胱癌及癌旁组织中均有表达,在癌组织中平均相对表达量为2.25±0.65,显著低于癌旁组织6.42±1.53,差异有统计学意义(P<0.05)。在I、II、III级膀胱癌组织中TGFBR3 mRNA表达量分别为:4.15±1.69、1.96±0.68和0.90±0.65,表达量随肿瘤的病理分级的逐渐升高而减少,但组间比较差异无统计学意义(P>0.05);在非肌层浸润性膀胱癌(Tis-T1)中TGFBR3 mRNA表达量为1.94±0.76,肌层浸润性膀胱癌(T2-T4)为2.46±0.97,差异无统计学意义(P>0.05)。TGFBR3 mRNA表达量在有淋巴结转移的患者为6.05±2.55,而在无淋巴结转移的患者表达量明显降低为1.37±0.42,差异有统计学意义(P<0.05);男性患者癌组织中TGFBR3 mRNA表达量为2.25±0.72,女性患者为2.26±1.42,差异无统计学意义(P>0.05)。
结论:在蛋白和mRNA水平上检测,膀胱癌组织中TGFBR3的表达量显著低于癌旁膀胱组织,显示了该基因的表达缺失在膀胱癌的发生、发展中起一定的作用。癌组织中TGFBR3 mRNA的表达量随肿瘤恶性程度的逐渐升高而减少,可能在膀胱癌的形成初期该基因起抑癌作用;TGFBR3 mRNA的表达量随肿瘤临床分期的升高而增加,尤其是在淋巴结转移的患者中表达量显著高于无淋巴结转移者,提示在膀胱癌形成后,该基因起促癌作用。
Background and Objective: The transforming growth factor beta (TGF-β) signalling system plays an important role in the carcinogenesis of the bladder. Alterations in many components of the TGF-βsignaling pathway, such as mutation or deletion of receptors and other signaling components are frequent events in human cancers and lead to a loss of the tumor suppressor function of that pathway. As we known: the TGF-βreceptor I and II (TGFBR1, TGFBR2) are lost in bladder cancer at the protein level. However, the expression of TGF-βreceptor III (TGFBR3) remains unclear. In this study we investigate the expression of TGF-βreceptor III (TGFBR3) in urothelial carcinoma of the bladder (BUC); and analyze its relevance with grade, stage, and other clinical parameters in BUC.
Methods: Fresh tissues and adjacent normal bladder tissues were obtained from 32 patients with BUC. TGFBR3 expression was measured by immunohistochemistry and real-time PCR. And its potential clinical significance was analyzed.
Results: The TGFBR3 protein was expressed 25.00%(8/32)in BUC and 78.13%(25/32)in adjacent normal tissues(P<0.05). Lower expression of TGFBR3 mRNA was detected in BUC (2.25±0.65) than in adjacent normal tissues (6.42±1.53,P<0.05). Respectively, expression level of TGFBR3 mRNA in grade I, II, III was 4.15±1.69, 1.96±0.68 and 0.90±0.65; in stage Tis-Tl,T2-T4 was 1.94±0.76 and 2.46±0.97. TGFBR3 mRNA expression in patients with and without lymph nodes metastasis was 6.05±2.55 and 1.37±0.42. Expression of TGFBR3 mRNA in male and female group was 2.25±0.72 and 2.26±1.42. TGFBR3 mRNA level did not correlate with grade, stage and gender (P>0.05). Higher level of expression was associated with lymph nodes metastasis (P<0.05).
Conclusion: Our study showes that TGFBR3 is significantly down-regulated in BUC than in adjacent normal bladder tissues, and different levels of TGFBR3 mRNA in patients with and without lymph nodes metastasis are found. So TGFBR3 may play an important role in the pathogenesis and development of BUC.
引文
[1] Parkin MD, Bray F, Ferlay J, et al. Global Cancer Statistics, 2002. CA Cancer J Clin. 2005, 55:74-108.
[2]虞颂庭,臧美孚,夏溟.尿路上皮肿瘤概论.见:吴阶平,主编.吴阶平泌尿外科学.济南:山东科学技术出版社, 2004, 919-942.
[3]李宁忱,谢立平.膀胱癌诊断治疗指南.见:那彦群,孙光,主编. 2009版中国泌尿外科疾病诊断治疗指南.北京:人民卫生出版社, 2009, 16-46.
[4] Wrana JL, Attisano L, Mieser R, et al. Mechanism of activation of the TGF-beta receptor. Nature. 1994, 370:341-347.
[5] Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998, 67:753-791.
[6] Derynck R, Feng XH. TGF-beta receptor signaling. Biochim Biophys Acta. 1997, 1333:105 -150.
[7] Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006, 25(3):435-457.
[8] Levy L, Hill CS. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2006, 17(1-2):41-58.
[9] Tokunaga H, Lee DH, Kim IY, et al. Decreased expression of Transforming Growth Factor b Receptor Type 1 is associated with poor prognosis in bladder transitional cell carcinoma patients. Clin Cancer Res. 1999, 5(9):2520–2525.
[10] Van Tiborg AA, De Vries A, Zwarthoff EC.The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. J Pathol, 2001, 194(1):76-80.
[11] Chen T, Jackson C, Costello B, et al. An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. Int J Cancer. 2004, 112(3):420-425.
[12] Srinivas Veerla, Ioannis Panagopoulos, Yuesheng Jin, et al. Promoter Analysis of Epigenetically Controlled Genes in Bladder Cancer. Genes Chromosomes and Cancer. 2008, 47(5):368-378.
[13] Li Y, Yang K, Mao Q, et al. Inhibition of TGF-b receptor 1 by siRNA suppresses in the T24 bladder cancer cells via modulation of integrins and matrix metalloproteinase. Int Urol Nephrol. 2010, 42(2):315-323.
[14] Brait M, Begum S, Carvalho AL, et al. Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer. Cancer Epidemiol Biomarkers Prev. 2008, 17(10):2786-2794.
[15] Dong M, How T, Kirkbride KC, et al. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 2007, 117(1):206-217.
[16] Finger EC, Turley RS, Dong M, et al. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 2008, 29(3):528-535.
[17] Cooper SJ, Zou H, Legrand SN, et al. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010, 29(20):2905-2915.
[18] Gordon KJ, Dong M, Chislock EM, et al. Loss of type III transforming growth factorβreceptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis. 2008, 29(2): 252–262.
[19] Gatza CE, Oh SY, Blobe GC. Roles for the type III TGF-βreceptor in human cancer. Cellular Signalling, 2010, 22(8):1163–1174.
[20] S Markowitz, A Roberts, Tumor suppressor activity of the TGF-βpathway in human cancers, Cytokine Growth Factor Rev. 1996, 7:93–102.
[21] R Derynck, RJ Akhurst, A Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001, 29:117–129.
[22] I Shin, AV Bakin, U Rodeck, A Brunet, CL Arteaga, Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell. 2001, 12:3328–3339.
[23] ME Engel, PK Datta, HL Moses. Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. J Cell Biochem. 1998, Suppl 31:111–122.
[24] Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. PNAS. 2003, 100:8621–8623.
[25] Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005, 23:2078–2093.
[26] Wang XF, Lin HY, Ng-Eaton E, et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991, 15(4):797-805.
[27] López-Casillas F, Cheifetz S, Doody J, et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991, 67(4):785-795.
[28] López-Casillas F, Payne HM, Andres JL, et al. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors:mapping of ligand binding and GAG attachment sites. J Cell Biol. 1994, 124(4):557-568.
[29] Brown CB, Boyer AS, Runyan RB, et al. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999, 283:2080–2082.
[30] Reeves R, Edberg DD, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol. 2001, 21:575-594.
[31] Nakajima A, Ito Y, Asano M, et al. Functional role of transforming growth factor-beta type III receptorduring palatal fusion.Dev Dyn. 2007, 236:791–801.
[32] Sun L, Chen C. Expression of transforming grouth factor beta type III receptor suppresses tumorigenicity of human breast cancer. MDA-MB-231 cells. J Biol Chem. 1997, 272:25367-25372.
[33] Copland JA, Luxon BA, Ajani L, et al. Genomic profiling identifies alteration in TGF-beta signaling through loss of TGF-beta receptor and progression. Oncogene. 2003, 22:6109-6118.
[34] Chen W, Kirkbride KC, How T, et al. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 2003, 301:1394-1397.
[35] You HJ, How T, Blobe GC. The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis. 2009, 30(8): 1281-1287.
[36] Wu JT, Kral JG. The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J Surg Res. 2005, 123(1): 158–169.
[37] Criswell TL, Dumont N, Barnett JV, et al. Knockdown of the transforming growth factor-beta type III receptor impairs motility and invasion of metastatic cancer cells. Cancer Res. 2008, 68(18): 7304-7312.
[38] Iolascon A, Giordani L, Borriello A, et al. Reduced expression of transforming growth factor-beta receptor type III in high stage neuroblastomas, Br J Cancer. 2000, 82(6):1171-1176.
[39] Bristow RE, Baldwin RL, Yamada SD, et al. Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma. Cancer. 1999, 85(3):658-668.
[40] Bilandzic M, Chu S, Farnworth PG, et al. Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Mol Endocrinol. 2009, 23:539–548.
[41] Florio P, Ciarmela P, Reis FM, et al. Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. Eur J Endocrinol. 2005, 152(2):277-284.
[42] Sharifi N, Hurt EM, Kawasaki BT, et al. TGFBR3 loss and consequences in prostate cancer. Prostate. 2007, 67(3):301-311.
[43] Kapp JA, Honjo K, Kapp LM, et a1. TCR transgenic CD8+T cells activated in the presence of TGFbeta express FoxP3 and mediate linked suppression of primary immune responses and cardiac allografi rejection. Int Immunol. 2006, 18(11): 1549-1562.
[1] Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. Version 2.0. IARC Cancer Base No.5, 2004.
[2] Blobe GC, Schiemarm WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000, 342: 1350-1358.
[3] Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998, 67: 753-791.
[4] Sporn MB, Pwberts AB, Wakefield LM, et al. Transforming growt h factor -β: Biological function and chemical structure. Science. 1986, 233(4763):532 -534.
[5] Yamaguchi Y. Function, molecular structure and gene expression regulation of transforming growth factor-beta (TGF-beta). Nippon Rinsho. 1992, 50(8):1932-1938.
[6] Taipale J, Saharinen J, Keski-Oja J. Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Adv Cancer Res. 1998, 75: 87-134.
[7] Wrana JL, Attisano L, Wieser R, et al. Mechanism of activation of the TGF-beta receptor. Nature. 1994, 370(6488):341-347.
[8] Del Re E, Babitt JL, Pirani A, et al. In the absence of typeⅢreceptor,the transforming growth factor(TGF)-beta typeⅡreceptor requires the type I receptor to bind TGF-beta 2. J Biol Chem. 2004, 279(21): 22765-22772.
[9] López-Casillas F, Payne HM, Andres JL, et al. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol. 1994, 124(4):557-568.
[10] Wang XF, Lin HY, Ng-Eaton E, et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991, 15;(4) :797-805.
[11] Hempel N, How T, Cooper SJ, et al. Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 2008, 29(5):905-912.
[12] López-Casillas F, Cheifetz S, Doody J, et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991, 67(4):785-795.
[13] S Cheifetz, B Like, J Massague. Cellular distribution of type I and type II receptors for transforming growth factor-β. J Biol Chem. 1986, 261:9972–9978.
[14] J Massague′, B Like. Cellular receptors for type b transforming growth factor. Ligand binding and affinity labeling in human and rodent cell lines. J Biol Chem. 1985, 260:263–2645.
[15] Fanger BO, Wakefield LM, Sporn MB. Structure and properties of the cellular receptor for transforming growth factor type b. Biochemistry. 1986, 25:3083–3091.
[16] Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem. 2000, 267(24):6954-6967.
[17] Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signaling. Nature. 2003, 425(6958): 577-584.
[18] Masuyama N, Hanafusa H, Kusakabe M, et al. Identification of two Smad4 proteins in Xenopus. Their common and distinct properties. J Biol Chem. 1999, 274 (17): 12163-12170.
[19] Markowitz SD, Roberts AB. Tumor suppressor activity of the TGF-βpathway in human cancers. Cytokine Growth Factor Rev. 1996, 7:93-102.
[20] R Derynck, RJ Akhurst, A Balmain. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001, 29:117–129.
[21] I Shin, AV Bakin, U Rodeck, et al. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell 2001, 12:3328-3339.
[22] ME Engel, PK Datta, HL Moses. Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation.J Cell Biochem. 1998, Suppl 31:111-122.
[23] Roberts AB. Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. PNAS. 2003, 100:8621–8623.
[24] Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005, 23:2078–2093.
[25] Segerson EC, Beet hart PK. Suppressor activity of bone marrow cells and localization of fluorescent-labeled bone marrow cells within ovine endomet rial tissue. J Anita Sci, 2000, 78(3):709-717.
[26] Derynck R, Feng XH. TGF-beta receptor signaling. Biochim Biophys Acta. 1997, 1333(1):105-150.
[27] Kang SH, Bang YJ, Im YH, et a1. Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer. Oncogene, 1999, 18:7280-7286.
[28] Kim IY, Ahn HJ, Zelner DJ, et al. Genetic change in transforming growth factor beta(TGF-beta)receptor type I gene correlates with insensitivity to TGF-beta l in human prostate cancer cells. Cancer Res. 1996, 56:44-48.
[29] Zhang HT,Fei QY, Chen F, et a1. Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer. Lung Cancer. 2003, 40: 281-287.
[30] Bian Y, Caldes T, Wijnen J, et a1. TGFBRl*6A may contribute to hereditary colorectal cancer. J Clin Oncol, 2005, 23(13):3074-3078.
[31] Chen T, Jackson CR, Link A, et a1. Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Clin Cancer Res. 2006, 12(2): 392-397.
[32] Knaus PI, Lindemann D, DeCoteau JF. A dominant inhibitory mutant of the type II transforming growth factorβreceptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol. 1996, 16(7):3480-3489.
[33] De M, Yan W, de Jonge RR, et a1. Functional characterization of transforming growth factorβtype II receptor mutants in human cancer. Cancer Res. 1998, 58(9):1986-1992.
[34] Yasumi K, Guo R J, Hanai H, et a1. Transforming growth factorβtype II receptor(TGF-βR II) mutation in gastric lymphoma without mutator phenotype. Pathol Int. 1998, 48(2):134-137.
[35] Lynch MA, Nakashima R, Song H, et a1. Mutational analysis of the transforming growth factorβreceptor type II gene in human ovarian carcinoma. Cancer Res. 1998, 58(19):4227-4232.
[36] Zhang HT, Chen XF, Wang MH, et al. Defective expression of transforming growth factorβreceptor type II (TGFBR2) is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res. 2004, 10(7):2359-2367.
[37] Nadine Hempel, Tam How, Mei Dong, et al. Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion. Cancer Res. 2007, 67(11): 5231- 5238.
[38] Finger EC, Turley RS, Dong M, et al. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 2008, 29(3):528-535.
[39] Dong M, How T, Kirkbride KC, et al. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 2007, 117(1):206-217.
[40] Cooper SJ, Zou H, Legrand SN, et al. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010, 29(20):2905-2915.
[41] Sharifi N, Hurt EM, Kawasaki BT, et al. TGFBR3 loss and consequences in prostate cancer. Prostate. 2007, 67(3):301-311.
[2]虞颂庭,臧美孚,夏溟.尿路上皮肿瘤概论.见:吴阶平,主编.吴阶平泌尿外科学.济南:山东科学技术出版社, 2004, 919-942.
[3]李宁忱,谢立平.膀胱癌诊断治疗指南.见:那彦群,孙光,主编. 2009版中国泌尿外科疾病诊断治疗指南.北京:人民卫生出版社, 2009, 16-46.
[4] Wrana JL, Attisano L, Mieser R, et al. Mechanism of activation of the TGF-beta receptor. Nature. 1994, 370:341-347.
[5] Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998, 67:753-791.
[6] Derynck R, Feng XH. TGF-beta receptor signaling. Biochim Biophys Acta. 1997, 1333:105 -150.
[7] Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006, 25(3):435-457.
[8] Levy L, Hill CS. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2006, 17(1-2):41-58.
[9] Tokunaga H, Lee DH, Kim IY, et al. Decreased expression of Transforming Growth Factor b Receptor Type 1 is associated with poor prognosis in bladder transitional cell carcinoma patients. Clin Cancer Res. 1999, 5(9):2520–2525.
[10] Van Tiborg AA, De Vries A, Zwarthoff EC.The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. J Pathol, 2001, 194(1):76-80.
[11] Chen T, Jackson C, Costello B, et al. An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. Int J Cancer. 2004, 112(3):420-425.
[12] Srinivas Veerla, Ioannis Panagopoulos, Yuesheng Jin, et al. Promoter Analysis of Epigenetically Controlled Genes in Bladder Cancer. Genes Chromosomes and Cancer. 2008, 47(5):368-378.
[13] Li Y, Yang K, Mao Q, et al. Inhibition of TGF-b receptor 1 by siRNA suppresses in the T24 bladder cancer cells via modulation of integrins and matrix metalloproteinase. Int Urol Nephrol. 2010, 42(2):315-323.
[14] Brait M, Begum S, Carvalho AL, et al. Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer. Cancer Epidemiol Biomarkers Prev. 2008, 17(10):2786-2794.
[15] Dong M, How T, Kirkbride KC, et al. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 2007, 117(1):206-217.
[16] Finger EC, Turley RS, Dong M, et al. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 2008, 29(3):528-535.
[17] Cooper SJ, Zou H, Legrand SN, et al. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010, 29(20):2905-2915.
[18] Gordon KJ, Dong M, Chislock EM, et al. Loss of type III transforming growth factorβreceptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis. 2008, 29(2): 252–262.
[19] Gatza CE, Oh SY, Blobe GC. Roles for the type III TGF-βreceptor in human cancer. Cellular Signalling, 2010, 22(8):1163–1174.
[20] S Markowitz, A Roberts, Tumor suppressor activity of the TGF-βpathway in human cancers, Cytokine Growth Factor Rev. 1996, 7:93–102.
[21] R Derynck, RJ Akhurst, A Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001, 29:117–129.
[22] I Shin, AV Bakin, U Rodeck, A Brunet, CL Arteaga, Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell. 2001, 12:3328–3339.
[23] ME Engel, PK Datta, HL Moses. Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. J Cell Biochem. 1998, Suppl 31:111–122.
[24] Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. PNAS. 2003, 100:8621–8623.
[25] Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005, 23:2078–2093.
[26] Wang XF, Lin HY, Ng-Eaton E, et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991, 15(4):797-805.
[27] López-Casillas F, Cheifetz S, Doody J, et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991, 67(4):785-795.
[28] López-Casillas F, Payne HM, Andres JL, et al. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors:mapping of ligand binding and GAG attachment sites. J Cell Biol. 1994, 124(4):557-568.
[29] Brown CB, Boyer AS, Runyan RB, et al. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999, 283:2080–2082.
[30] Reeves R, Edberg DD, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol. 2001, 21:575-594.
[31] Nakajima A, Ito Y, Asano M, et al. Functional role of transforming growth factor-beta type III receptorduring palatal fusion.Dev Dyn. 2007, 236:791–801.
[32] Sun L, Chen C. Expression of transforming grouth factor beta type III receptor suppresses tumorigenicity of human breast cancer. MDA-MB-231 cells. J Biol Chem. 1997, 272:25367-25372.
[33] Copland JA, Luxon BA, Ajani L, et al. Genomic profiling identifies alteration in TGF-beta signaling through loss of TGF-beta receptor and progression. Oncogene. 2003, 22:6109-6118.
[34] Chen W, Kirkbride KC, How T, et al. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 2003, 301:1394-1397.
[35] You HJ, How T, Blobe GC. The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis. 2009, 30(8): 1281-1287.
[36] Wu JT, Kral JG. The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J Surg Res. 2005, 123(1): 158–169.
[37] Criswell TL, Dumont N, Barnett JV, et al. Knockdown of the transforming growth factor-beta type III receptor impairs motility and invasion of metastatic cancer cells. Cancer Res. 2008, 68(18): 7304-7312.
[38] Iolascon A, Giordani L, Borriello A, et al. Reduced expression of transforming growth factor-beta receptor type III in high stage neuroblastomas, Br J Cancer. 2000, 82(6):1171-1176.
[39] Bristow RE, Baldwin RL, Yamada SD, et al. Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma. Cancer. 1999, 85(3):658-668.
[40] Bilandzic M, Chu S, Farnworth PG, et al. Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Mol Endocrinol. 2009, 23:539–548.
[41] Florio P, Ciarmela P, Reis FM, et al. Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. Eur J Endocrinol. 2005, 152(2):277-284.
[42] Sharifi N, Hurt EM, Kawasaki BT, et al. TGFBR3 loss and consequences in prostate cancer. Prostate. 2007, 67(3):301-311.
[43] Kapp JA, Honjo K, Kapp LM, et a1. TCR transgenic CD8+T cells activated in the presence of TGFbeta express FoxP3 and mediate linked suppression of primary immune responses and cardiac allografi rejection. Int Immunol. 2006, 18(11): 1549-1562.
[1] Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. Version 2.0. IARC Cancer Base No.5, 2004.
[2] Blobe GC, Schiemarm WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000, 342: 1350-1358.
[3] Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998, 67: 753-791.
[4] Sporn MB, Pwberts AB, Wakefield LM, et al. Transforming growt h factor -β: Biological function and chemical structure. Science. 1986, 233(4763):532 -534.
[5] Yamaguchi Y. Function, molecular structure and gene expression regulation of transforming growth factor-beta (TGF-beta). Nippon Rinsho. 1992, 50(8):1932-1938.
[6] Taipale J, Saharinen J, Keski-Oja J. Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Adv Cancer Res. 1998, 75: 87-134.
[7] Wrana JL, Attisano L, Wieser R, et al. Mechanism of activation of the TGF-beta receptor. Nature. 1994, 370(6488):341-347.
[8] Del Re E, Babitt JL, Pirani A, et al. In the absence of typeⅢreceptor,the transforming growth factor(TGF)-beta typeⅡreceptor requires the type I receptor to bind TGF-beta 2. J Biol Chem. 2004, 279(21): 22765-22772.
[9] López-Casillas F, Payne HM, Andres JL, et al. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol. 1994, 124(4):557-568.
[10] Wang XF, Lin HY, Ng-Eaton E, et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991, 15;(4) :797-805.
[11] Hempel N, How T, Cooper SJ, et al. Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 2008, 29(5):905-912.
[12] López-Casillas F, Cheifetz S, Doody J, et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991, 67(4):785-795.
[13] S Cheifetz, B Like, J Massague. Cellular distribution of type I and type II receptors for transforming growth factor-β. J Biol Chem. 1986, 261:9972–9978.
[14] J Massague′, B Like. Cellular receptors for type b transforming growth factor. Ligand binding and affinity labeling in human and rodent cell lines. J Biol Chem. 1985, 260:263–2645.
[15] Fanger BO, Wakefield LM, Sporn MB. Structure and properties of the cellular receptor for transforming growth factor type b. Biochemistry. 1986, 25:3083–3091.
[16] Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem. 2000, 267(24):6954-6967.
[17] Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signaling. Nature. 2003, 425(6958): 577-584.
[18] Masuyama N, Hanafusa H, Kusakabe M, et al. Identification of two Smad4 proteins in Xenopus. Their common and distinct properties. J Biol Chem. 1999, 274 (17): 12163-12170.
[19] Markowitz SD, Roberts AB. Tumor suppressor activity of the TGF-βpathway in human cancers. Cytokine Growth Factor Rev. 1996, 7:93-102.
[20] R Derynck, RJ Akhurst, A Balmain. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001, 29:117–129.
[21] I Shin, AV Bakin, U Rodeck, et al. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell 2001, 12:3328-3339.
[22] ME Engel, PK Datta, HL Moses. Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation.J Cell Biochem. 1998, Suppl 31:111-122.
[23] Roberts AB. Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. PNAS. 2003, 100:8621–8623.
[24] Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005, 23:2078–2093.
[25] Segerson EC, Beet hart PK. Suppressor activity of bone marrow cells and localization of fluorescent-labeled bone marrow cells within ovine endomet rial tissue. J Anita Sci, 2000, 78(3):709-717.
[26] Derynck R, Feng XH. TGF-beta receptor signaling. Biochim Biophys Acta. 1997, 1333(1):105-150.
[27] Kang SH, Bang YJ, Im YH, et a1. Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer. Oncogene, 1999, 18:7280-7286.
[28] Kim IY, Ahn HJ, Zelner DJ, et al. Genetic change in transforming growth factor beta(TGF-beta)receptor type I gene correlates with insensitivity to TGF-beta l in human prostate cancer cells. Cancer Res. 1996, 56:44-48.
[29] Zhang HT,Fei QY, Chen F, et a1. Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer. Lung Cancer. 2003, 40: 281-287.
[30] Bian Y, Caldes T, Wijnen J, et a1. TGFBRl*6A may contribute to hereditary colorectal cancer. J Clin Oncol, 2005, 23(13):3074-3078.
[31] Chen T, Jackson CR, Link A, et a1. Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Clin Cancer Res. 2006, 12(2): 392-397.
[32] Knaus PI, Lindemann D, DeCoteau JF. A dominant inhibitory mutant of the type II transforming growth factorβreceptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol. 1996, 16(7):3480-3489.
[33] De M, Yan W, de Jonge RR, et a1. Functional characterization of transforming growth factorβtype II receptor mutants in human cancer. Cancer Res. 1998, 58(9):1986-1992.
[34] Yasumi K, Guo R J, Hanai H, et a1. Transforming growth factorβtype II receptor(TGF-βR II) mutation in gastric lymphoma without mutator phenotype. Pathol Int. 1998, 48(2):134-137.
[35] Lynch MA, Nakashima R, Song H, et a1. Mutational analysis of the transforming growth factorβreceptor type II gene in human ovarian carcinoma. Cancer Res. 1998, 58(19):4227-4232.
[36] Zhang HT, Chen XF, Wang MH, et al. Defective expression of transforming growth factorβreceptor type II (TGFBR2) is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res. 2004, 10(7):2359-2367.
[37] Nadine Hempel, Tam How, Mei Dong, et al. Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion. Cancer Res. 2007, 67(11): 5231- 5238.
[38] Finger EC, Turley RS, Dong M, et al. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 2008, 29(3):528-535.
[39] Dong M, How T, Kirkbride KC, et al. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 2007, 117(1):206-217.
[40] Cooper SJ, Zou H, Legrand SN, et al. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010, 29(20):2905-2915.
[41] Sharifi N, Hurt EM, Kawasaki BT, et al. TGFBR3 loss and consequences in prostate cancer. Prostate. 2007, 67(3):301-311.
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