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GADD45A基因在人贲门腺癌组织中的异常甲基化和表达及其临床意义 被引量：1

Expression and aberrant methylation of growth arrest and DNA-damage-inducible 45 alpha gene in human gastric cardia adenocarcinoma tissues and its clinical significance
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摘要 目的:探讨生长阻滞和DNA损伤诱导45A(growth arrest and DNA-damage-inducible 45 alpha,GADD45A)基因在贲门腺癌(gastric cardia adenocarcinoma,GCA)中的异常甲基化及表达,并探讨其临床意义。方法:选取河北医科大学第四医院2004-2007年期间GCA患者组织标本(138例)。分别应用亚硫酸氢盐测序法(bisulfite sequencing,BS-Seq)、亚硫酸氢盐转换-甲基化特异性聚合酶链式反应(bisulfite conversion-methylation specific polymerase chain reaction,BS-MSP)、RT-PCR和免疫组织化学法检测GADD45A基因在GCA组织及癌旁正常组织中的甲基化、GADD45A mRNA及蛋白表达的情况。结果:GADD45A远端启动子区的4个CpG位点在GCA组织中的甲基化率[44.93%(62/138)]显著高于癌旁正常组织[0.00%(0/138)](P<0.01),且在Ⅲ期和Ⅳ期GCA组织中的甲基化率显著高于Ⅰ期和Ⅱ期GCA组织(P<0.05),但GADD45A在GCA组织中的甲基化与患者的年龄、性别及病理分化程度无关(P>0.05)。GADD45A近端启动子(region 2)及第一外显子区(region 3)的CpG岛在GCA及癌旁组织中均未检测到甲基化。GCA组织中GADD45A mRNA和蛋白阳性表达率显著低于癌旁正常组织[(0.35±0.15)vs(0.78±0.26),42.75%vs 71.01%,均P<0.05],且与其远端启动子区4个CpG位点的甲基化状态之间有明显的相关性(r=-0.52,P<0.01)。结论:GADD45A基因远端启动子区的4个CpG位点的高甲基化导致的基因沉默可能与GCA中GADD45A基因表达降低有关。 Objective：To investigate the expression and aberrant methylation of growth arrest and DNA-damage-inducible 45 alpha（GADD45A） gene in gastric cardia adenocarcinoma（GCA） and to explore its clinical significance.Methods： Tissue samples in GCA patients（138 cases） were selected from Fourth Hospital of Hebei University during 2004 to 2007.Bisulfite sequencing（BS-Seq）,bisulfite conversion-methylation specific polymerase chain reaction（BS-MSP）,reverse transcription-polymerase chain reaction（RT-PCR） and immunohistochemistry methods were used respectively to detect the methylation status,mRNA and protein expression of GADD45A gene in GCA tissues and the para-carcinoma normal tissues.Results： The methylation frequency of four CpG sites in distal promoter of GADD45A in GCA tissues（44.93%,[62/138]） was significantly higher than that in the para-carcinoma normal tissues（0.00%,0/138）（P0.01）.The methylation frequency of 4 CpG sites in stage Ⅲ and Ⅳ GCA tissues was significantly higher than that in stage Ⅰ and Ⅱ GCA tissues（P0.05）.However,the methylation status GADD45A in GCA tissues was not correltaed with age,gender and pathological differentiation（P0.05）.For GADD45A region 2 and 3 located in proximal promoter and exon 1,no methylation was detected in GCA and the para-carcinoma normal tissues.The expression of GADD45A mRNA and positive expression rate of GADD45A protein in GCA tissues were significantly lower than those in the para-carcinoma normal tissues（[0.35±0.15] vs [0.78±0.26],42.75% vs 71.01%,P0.05） and was associated with methylation status of 4 CpG sites in distal promoter（r=-0.52,P0.01）.Conclusion： Hypermethylation of four CpG sites in distal promoter of GADD45A gene may be responsible for the decreased expression of GADD45A in GCA.
作者 张清泉 董稚明 郭炜 张明慧 崔蕾
机构地区 衡水市哈励逊国际和平医院病理科 河北医科大学第四医院河北省肿瘤研究所病理研究室
出处 《中国肿瘤生物治疗杂志》 CAS CSCD 北大核心 2013年第3期317-322,共6页 Chinese Journal of Cancer Biotherapy
基金 国家自然科学基金资助项目(No.81101854) 河北省科技厅资助项目(No.072761223)~~
关键词 贲门腺癌 生长阻滞和DNA损伤诱导45A基因 甲基化 gastric cardia adenocarcinoma（GCA） GADD45A gene methylation
分类号 R735.2 [医药卫生—肿瘤] R730.2 [医药卫生—肿瘤]
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参考文献20

  • 1Fomace AJ Jr , Alamo I Jr, Hollander MC. DNA damage?inducible transcripts in mammalian cells [J]. Proc Nat! Acad Sci USA, 1988, 85 (23) : 8800-8804.
  • 2Rosemary Siafakas A, Richardson DR. Growth arrest and DNA damage45 alpha (GADD45alpha) [J]. Int J Biochem Cell Bioi, 2009, 41 (5) : 986-989.
  • 3Cretu A, Sha X, Tront J, et al. Stress sensor Gadd45 genes as therapeutic targets in cancer [J]. Cancer Ther, 2009, 7 ( A) : 268-276.
  • 4Wang W, Huper G, Guo Y, et al. Analysis of methylation-sensi?tive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer [J]. Oncogene, 2005, 24 (16 ): 2705- 2714.
  • 5Ramachandran K, Gopisetty G, Gordian E, et al. Methylation?mediated repression of GADD45alpha in prostate cancer and its role as a potential therapeutic target [J]. Cancer Res, 2009, 69 (4): 1527-1535.
  • 6Higashi H, Vallbohmer D, Wamecke-Eberz U, et al. Down-regu?lation of Gadd45 expression is associated with tumor differentiation in non-small cell lung cancer [J]. Anticancer Res, 2006, 26 (3A) : 2143-2147.
  • 7Wang Bx, Yin BL, He B, et ai, Overexpression of DNA damage?induced 45 (l gene contributes to esophageal squamous cell cancer by promoter hypomethylation [J]. J Exp Clin Cancer Res, 2012, 31: 11.
  • 8Schneider G, Weber A, Zechner U, et al. GADD45alpha is highly expressed in pancreatic ductal adenocarcinoma cells and re?quired for tumor cell viability [J]. Int J Cancer, 2006, 118 (10) : 2405-2411.
  • 9Reddy SP, Britto R, Vinnakota K, et al. Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis [J]. Clin Cancer Res, 2008, 14 ( 10) : 2978-2987.
  • 10Yamasawa K, Nio Y, Dong M, et al. Clinicopathological signifi?cance of abnormalities in Gadd45 expression and its relationship to p53 in human pancreatic cancer [J]. Clin Cancer Res, 2002, 8 (8) : 2563-2569.

二级参考文献13

  • 1DAMMANN R, LI C, YOON JH, et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3[J]. Nat Genet, 2000, 25(3) : 315-319.
  • 2SHIVAKUMAR L, MINNA J, SAKAMAKI T,et al. The RASSF1 A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation[J]. Mol Cell Biol, 2002, 22(12) :4309- 4318.
  • 3HERMAN J G, GRAFF J R, MYOHANEN S, et al. Methylationspecific PCR: a novel PCR assay for methylation status of CpG islands[ J]. Proc Natl Acad Sci USA,1996, 93(18) :9821-9826.
  • 4KHOKHLATCHEV A, RABIZADEH S, XAVIER R, et al. Identification of a novel Ras-regulated proapoptotic pathway [ J ]. Curr Biol,2002, 12 (4) : 253-265.
  • 5DAMMANN R, TAKAHASHI T, PFEIFER GP, et al. The CpG island of the novel tumor suppressor gene RASSF1A is intenselymethylated in primary small cell lung carcinomas [ J]. Orwogene, 2001, 20(27) : 3563-3567.
  • 6AGATHANGGELOU A, HONORIO S, MACARTNEY D P, et al. Methylation associated inactivation of RASSFIA from region 3p21.3 in lung, breast and ovarian tumours [ J]. Oncogene, 2001,20 (12) : 1509-1518.
  • 7LO K W, KWONG J, HUI A B, et al. High frequency of promoter hypermethylation of RASSF1A in nasopharyngeal carcinoma [ J ]. Cancer Res, 2001,61(10) : 3877-3881.
  • 8LI J Y, ERSHOW A G, CHEN Z J, et al. A case-control study of cancer of the esophageal and gastric cardia in Linxian [ J ]. Int J Cancer, 1989, 43 (5) : 755-761.
  • 9ZHANG YJ , AHSAN H , CHEN Y, et al. High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin BI2DNA adduct levels in human hepatocellular carcinoma[J]. Mol Carcinog, 2002 , 35 (2) : 85-92.
  • 10BYUN D S, LEE M G, CHAE K S,et al. Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma [ J ]. Cancer Res, 2001,61 (19) : 7034-7038.

共引文献8

同被引文献13

  • 1Bodine SC, Latres E, Baumhueter S, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy [J]. Science, 2001, 294(5547) : 1704-1708.
  • 2Hanai J, Cao P, Tanksale P, et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity [J]. J Clin Invest, 2007, 117(12) : 3940-3951.
  • 3Stitt TN, Drujan D, Clarke BA, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors [ J]. Mol Cell, 2004, 14(3) :395-403.
  • 4Tan J, Yang X, Zhuang L, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells [ J]. Genes Dev, 2007, 21(9) : 1050-1063.
  • 5Qin H, Chan MW, Liyanarachchi S, et al. An integrative ChiP-chip and gene expression profiling to model SMAD regulatory modules [J]. BMC Syst Biol, 2009, 3(1 ) : 73.
  • 6Chou JL, Su HY, Chen LY, et al. Promoter hypermethylation of FBXO32, a novel TGF-β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer [J]. Lab Invest, 2010, 90(3): 414-425.
  • 7Sasaki M, Anast J, Bassett W, et al. Bisulfite conversion-specific and methylation-specific PCR: A sensitive technique for accurate evaluation of CpG methylation [J]. Biochem Biophys Res Commnn, 2003, 309(2): 305-309.
  • 8Li HH, Kedar V, Zhang C, et al. Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex [J~. J Clin Invest, 2004, 114(8); 1058-1071.
  • 9Li J J, Zhang TP, Meng Y, et al. Stability of F-box protein atrogin-1 is regulated by p38 mitogen-activated protein kinase pathway in cardiac H9c2 ceils [J]. Cell Physiol Biochem, 2011, 27(5) : 463-470.
  • 10Gomes MD, Lecker SH, Jagoe RT, et al. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy [J]. Proc Natl Acad Sci U S A, 2001, 98(25): 14440-14445.

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中国肿瘤生物治疗杂志
2013年 第3期

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