胃癌的DNA甲基转移酶表达及基因组DNA甲基化谱
|
摘要
表观遗传研究不涉及DNA序列改变的，可随细胞分裂而遗传的基因组修饰作用，包括DNA甲基化（DNA methylation）、组蛋白修饰、染色质重塑、基因组印迹等。目前，DNA甲基化是表观遗传学在肿瘤领域的研究热点。肿瘤细胞基因组正常DNA甲基化模式异常改变，表现为全基因组广泛低甲基化及抑癌基因高甲基化。这些异常改变所导致的肿瘤相关基因功能异常可能参与肿瘤发生与发展。DNA甲基转移酶（DNAmethyltransferase, DNMT）是催化DNA甲基化修饰的生物酶，其异常表达可能是肿瘤基因组发生异常DNA甲基化的原因；特别是DNMT异常高表达所致的各种抑癌基因异常高甲基化并失活，可能直接参与肿瘤发生发展病理生理机制。5-氮杂-2’-脱氧胞苷是经典的DNMT抑制剂，其对DNMT功能的抑制可能通过逆转抑癌基因高甲基化而抑制肿瘤进展。本研究分析胃癌组织及细胞中各种DNMT表达特点及DNMT抑制剂对胃癌细胞的影响；并分析胃癌组织基因组异常DNA甲基化谱。期望本研究对胃癌表观遗传科研提供参考。
第一章胃癌及胃粘膜组织的DNMT蛋白表达
目的：分析胃癌与配对胃粘膜组织的DNA甲基转移酶（DNMT，包括DNMT1，DNMT2，DNMT3A，DNMT3B及DNMT3L）表达特点及差异。
方法：采用免疫组织化学法对30例胃癌及配对胃粘膜组织行5种DNMT蛋白表达研究。
结果：胃癌及配对胃粘膜组织均表达各种DNMT蛋白，其中胃粘膜组织增殖活跃区表达DNMTs较显著。胃癌中DNMT3A表达较配对胃粘膜组织减弱，余DNMT蛋白（DNMT1，DNMT2，DNMT3B及DNMT3L）在胃癌及胃粘膜的表达无显著差异。弥漫型胃癌的各种DNMT阳性表达率（除DNMT2外）较肠型胃癌增高。
结论：胃癌DNMT蛋白表达并未较配对胃粘膜增强；胃癌DNMT表达与Lauren分型相关。
第二章胃癌与胃上皮细胞DNMT蛋白表达及5-氮杂-2’-脱氧胞苷对胃癌细胞的影响
目的：分析胃癌细胞及胃上皮细胞的DNMT蛋白表达及DNMT抑制剂5-氮杂-2’-脱氧胞苷对胃癌细胞的影响。
方法：采用免疫荧光化学法及蛋白质免疫印迹法分析各种DNMT蛋白在胃癌细胞MKN-28，SGC-7901及胃上皮细胞GES-1的表达；采用噻唑兰比色法及流式细胞术分析DNMT抑制剂5-氮杂-2’-脱氧胞苷对胃癌与胃上皮细胞增殖率、细胞周期分布及凋亡率的影响。
结果：胃癌细胞MKN-28，SGC-7901表达各种DNMT蛋白，但DNMT1，DNMT3A表达较弱。DNMT1，DNMT2，DNMT3L蛋白在胃癌细胞以胞核表达为主；而DNMT3A，DNMT3B蛋白为胞核胞浆共表达。各种DNMT蛋白在胃癌细胞MKN-28，SGC-7901与胃上皮细胞GES-1间表达无显著差异。单独应用常规浓度（0.5-5μmol/L）的5-氮杂-2’-脱氧胞苷在短期内（5天）对胃癌细胞MKN-28，SGC-7901增值、凋亡或细胞周期的影响甚小。
结论：胃癌细胞表达DNMT蛋白未必较胃上皮细胞增强。单独使用DNMT抑制剂5-氮杂-2’-脱氧胞苷在短期内未必影响胃癌细胞增殖或凋亡。
第三章胃癌与胃粘膜组织的基因组DNA甲基化谱
目的：分析胃癌与配对胃粘膜组织的基因组DNA甲基化谱。
方法：采用甲基化DNA免疫共沉淀芯片（MeDIP-chip）分析胃癌与配对胃粘膜组织的基因组DNA甲基化谱差异；采用甲基化DNA免疫共沉淀实时定量PCR（MeDIP-qPCR）验证部分MeDIP-chip结果；采用实时定量逆转录PCR（qRT-PCR）分析胃癌组织中部分异常低甲基化基因（ABL2, FGF18, TRAF2, EGFL7和RAB33A）的转录。
结果：局部高甲基化及广泛低甲基化是胃癌与胃粘膜组织基因组DNA甲基化的共同特点。部分基因启动子只在胃癌组织呈高甲基化，但部分基因启动子却只在胃粘膜组织呈高甲基化。搜寻肿瘤相关基因后发现，胃癌组织基因组异常DNA甲基化特征既包括抑癌基因异常高甲基化，又包括癌基因或促癌基因异常低甲基化。MeDIP-qPCR证实促癌基因ABL2, FGF18, TRAF2, EGFL7和RAB33A确实在胃癌组织呈异常低甲基化（即在胃粘膜呈相对高甲基化）。qRT-PCR发现基因FGF18, TRAF2与EGFL7在胃癌组织转录较在配对胃粘膜组织增强，但ABL2与RAB33A在胃癌的转录却较胃粘膜减弱。
结论：胃癌基因组异常DNA甲基化特征具有复杂性，并非仅限于抑癌基因高甲基化。
Epigenetics is the study of inherited genetic changes that occurwithout changes to the DNA sequence. The mechanisms of epigeneticchange include DNA methylation—the most widely researched epigeneticalteration in human tumor cells—histone modification, and chromatinremodeling. Human tumor cells exhibit aberrant DNA methylation patternsincluding the hypermethylation of CpG islands in tumor-suppressor genes(TSGs) and a global loss of DNA methylation in the genome. Thesechanges, which are related to the inactivation of TSGs and the activation ofoncogenes or tumor-promoter genes (TPGs), may promote tumorprogression. Abnormal expressions of DNA methyltransferase (DNMT)may play important roles in the aberrant DNA methylation that occurs intumors. DNMT expression can be significantly higher in tumors than incontrol tissues, and the over-expression of DNMT may contribute to tumorprogression through the hypermethylation-mediated inactivation of TSGsin CpG islands. Because DNMT inhibitors can reverse themethylation-dependent TSG silencing,5-aza-2'-deoxycytidine (a DNMT inhibitor) should be useful for tumor treatment. In this study, we usedgastric cancer (GC) to analyze the expressions of DNMTs (DNMT1,DNMT2, DNMT3A, DNMT3B, and DNMT3L) and the effect of5-aza-2'-deoxycytidine on cell inhibition. And we studied the aberrantDNA methylation pattern of GC genome. We expect that this research willbe helpful for the future Epigenetics studies on GC.
CHAPTER1The Expressions of DNMT Proteins in GastricCancer and Matched Mucosa Tissues
Objective: To investigate the protein expressions of DNAmethyltransferases (DNMTs, including DNMT1, DNMT2, DNMT3A,DNMT3B and DNMT3L) in gastric cancer (GC) and matched gastricmucosa tissues.
Methods: Immunohistochemistry was performed to detect the DNMTexpressions in30pairs of GC and matched mucosa tissues.
Results: GC and matched mucosa tissues expressed all five kinds ofDNMT proteins. The proliferating zones of foveolar epithelia in gastricmucosa tissues expressed DNMT proteins significantly. The expression ofDNMT3A was weaker in GC tissues than in matched controls. Theexpressions of other DNMTs, however, did not differ significantly betweenthe GCs and controls. In GC tissues, the positive rates of DNMTexpressions (with the exception of DNMT2) were higher in diffuse type than in intestinal type.
Conclusion: GC did not necessarily show stronger expressions ofDNMT proteins than the matched mucosa tissues. The DNMT expressionsin GC were associated with the Lauren’s type.
CHAPTER2The Distributions of DNMT Proteins in Gastriccancer and the effect of5-aza-2'-deoxycytidine on Gastric cancercells
Objective: To investigate the protein expressions and distributions ofDNMTs in GC and gastric epithelial cells and to analyze the effect of5-aza-2'-deoxycytidine on GC’s growth rates, cell cycle distributions andapoptosis rates.
Methods: Immunofluorescence and western blotting were performedto detect the DNMT distributions and expressions in GC cells (SGC-7901and MKN-28) and gastric epithelial cell (GES-1). MTT assay and flowcytometry were performed to analyze the reactions of GC cells to5-aza-2'-deoxycytidine treatment.
Results: SGC-7901and MKN-28expressed5kinds of DNMTproteins. DNMT1, DNMT2and DNMT3L were distributed in the nuclei ofGC cells. DNMT3A and DNMT3B were distributed in both the nuclei andcytoplasm of GC cells. The DNMT expressions did not differ significantlybetween the GC cells (SGC-7901, MKN-28) and gastric epithelial cell (GES-1).5-Aza-2'-deoxycytidine with concentrations of0.5-5μmol/L(where it acts as a demethylation drug) had very little effect on the growthrates, cell cycle distributions, and apoptosis rates of SGC-7901or MKN-28cells when the drug was used alone in short term (5days).
Conclusion: GC cells didn’t necessarily express DNMT proteinsstronger than gastric epithelial cells.5-aza-2'-deoxycytidine (0.5-5μmol/L)didn’t necessarily inhibit GC cell proliferation when it was used alone inshort term.
CHAPTER3The aberrant DNA methylation pattern of Gastriccancer genome
Objective: To investigate the aberrant DNA methylation pattern of GCgenome.
Methods: Methylated DNA immunoprecipitation (MeDIP) microarray(MeDIP-chip) was performed to analyze the genomic DNA methylation ofa pair of GC and matched mucosa tissue. MeDIP-qRCR assay wasperformed to validate parts of the MeDIP-chip findings in5pairs of gastrictissues. qRT-PCR was performed to analyze the mRNA expressions ofvalidated genes (such as ABL2, FGF18, TRAF2, EGFL7and RAB33A) inthe5pairs of gastric tissues above.
Results: For both the GC and matched mucosa tissue, localhypermethylation and global hypomethylation of genomic DNA were the significant characteristics. And certain CpG islands and gene promoterswere hypermethylated only in GC tissue, whereas some other CpG islandsand gene promoters were hypermethylated only in matched mucosa tissue.After separating tumor related genes those showed differential DNAmethylation in promoters between the cancer and control from the genome,GC tissue was found to contain both aberrantly hypermethylated andhypomethylated TSGs, oncogenes, and tumor-promoter genes (TPGs).MeDIP-qPCR verified some tumor related genes (such as ABL2, FGF18,TRAF2, EGFL7and RAB33A) were aberrantly hypomethylated in GCtissues compared to in controls. And the qRT-PCR assay found that themRNA transcriptions of FGF18, TRAF2and EGFL7were significantlymore in GC tissues than in matched mucosa tissues, but the mRNAtranscriptions of ABL2and RAB33A were significantly less in GC than inmatched controls.
Conclusion: Aberrant DNA methylation pattern of GC genome iscomplex, but not limited to hypermethylation of TSG only.
第一章胃癌及胃粘膜组织的DNMT蛋白表达
目的：分析胃癌与配对胃粘膜组织的DNA甲基转移酶（DNMT，包括DNMT1，DNMT2，DNMT3A，DNMT3B及DNMT3L）表达特点及差异。
方法：采用免疫组织化学法对30例胃癌及配对胃粘膜组织行5种DNMT蛋白表达研究。
结果：胃癌及配对胃粘膜组织均表达各种DNMT蛋白，其中胃粘膜组织增殖活跃区表达DNMTs较显著。胃癌中DNMT3A表达较配对胃粘膜组织减弱，余DNMT蛋白（DNMT1，DNMT2，DNMT3B及DNMT3L）在胃癌及胃粘膜的表达无显著差异。弥漫型胃癌的各种DNMT阳性表达率（除DNMT2外）较肠型胃癌增高。
结论：胃癌DNMT蛋白表达并未较配对胃粘膜增强；胃癌DNMT表达与Lauren分型相关。
第二章胃癌与胃上皮细胞DNMT蛋白表达及5-氮杂-2’-脱氧胞苷对胃癌细胞的影响
目的：分析胃癌细胞及胃上皮细胞的DNMT蛋白表达及DNMT抑制剂5-氮杂-2’-脱氧胞苷对胃癌细胞的影响。
方法：采用免疫荧光化学法及蛋白质免疫印迹法分析各种DNMT蛋白在胃癌细胞MKN-28，SGC-7901及胃上皮细胞GES-1的表达；采用噻唑兰比色法及流式细胞术分析DNMT抑制剂5-氮杂-2’-脱氧胞苷对胃癌与胃上皮细胞增殖率、细胞周期分布及凋亡率的影响。
结果：胃癌细胞MKN-28，SGC-7901表达各种DNMT蛋白，但DNMT1，DNMT3A表达较弱。DNMT1，DNMT2，DNMT3L蛋白在胃癌细胞以胞核表达为主；而DNMT3A，DNMT3B蛋白为胞核胞浆共表达。各种DNMT蛋白在胃癌细胞MKN-28，SGC-7901与胃上皮细胞GES-1间表达无显著差异。单独应用常规浓度（0.5-5μmol/L）的5-氮杂-2’-脱氧胞苷在短期内（5天）对胃癌细胞MKN-28，SGC-7901增值、凋亡或细胞周期的影响甚小。
结论：胃癌细胞表达DNMT蛋白未必较胃上皮细胞增强。单独使用DNMT抑制剂5-氮杂-2’-脱氧胞苷在短期内未必影响胃癌细胞增殖或凋亡。
第三章胃癌与胃粘膜组织的基因组DNA甲基化谱
目的：分析胃癌与配对胃粘膜组织的基因组DNA甲基化谱。
方法：采用甲基化DNA免疫共沉淀芯片（MeDIP-chip）分析胃癌与配对胃粘膜组织的基因组DNA甲基化谱差异；采用甲基化DNA免疫共沉淀实时定量PCR（MeDIP-qPCR）验证部分MeDIP-chip结果；采用实时定量逆转录PCR（qRT-PCR）分析胃癌组织中部分异常低甲基化基因（ABL2, FGF18, TRAF2, EGFL7和RAB33A）的转录。
结果：局部高甲基化及广泛低甲基化是胃癌与胃粘膜组织基因组DNA甲基化的共同特点。部分基因启动子只在胃癌组织呈高甲基化，但部分基因启动子却只在胃粘膜组织呈高甲基化。搜寻肿瘤相关基因后发现，胃癌组织基因组异常DNA甲基化特征既包括抑癌基因异常高甲基化，又包括癌基因或促癌基因异常低甲基化。MeDIP-qPCR证实促癌基因ABL2, FGF18, TRAF2, EGFL7和RAB33A确实在胃癌组织呈异常低甲基化（即在胃粘膜呈相对高甲基化）。qRT-PCR发现基因FGF18, TRAF2与EGFL7在胃癌组织转录较在配对胃粘膜组织增强，但ABL2与RAB33A在胃癌的转录却较胃粘膜减弱。
结论：胃癌基因组异常DNA甲基化特征具有复杂性，并非仅限于抑癌基因高甲基化。
Epigenetics is the study of inherited genetic changes that occurwithout changes to the DNA sequence. The mechanisms of epigeneticchange include DNA methylation—the most widely researched epigeneticalteration in human tumor cells—histone modification, and chromatinremodeling. Human tumor cells exhibit aberrant DNA methylation patternsincluding the hypermethylation of CpG islands in tumor-suppressor genes(TSGs) and a global loss of DNA methylation in the genome. Thesechanges, which are related to the inactivation of TSGs and the activation ofoncogenes or tumor-promoter genes (TPGs), may promote tumorprogression. Abnormal expressions of DNA methyltransferase (DNMT)may play important roles in the aberrant DNA methylation that occurs intumors. DNMT expression can be significantly higher in tumors than incontrol tissues, and the over-expression of DNMT may contribute to tumorprogression through the hypermethylation-mediated inactivation of TSGsin CpG islands. Because DNMT inhibitors can reverse themethylation-dependent TSG silencing,5-aza-2'-deoxycytidine (a DNMT inhibitor) should be useful for tumor treatment. In this study, we usedgastric cancer (GC) to analyze the expressions of DNMTs (DNMT1,DNMT2, DNMT3A, DNMT3B, and DNMT3L) and the effect of5-aza-2'-deoxycytidine on cell inhibition. And we studied the aberrantDNA methylation pattern of GC genome. We expect that this research willbe helpful for the future Epigenetics studies on GC.
CHAPTER1The Expressions of DNMT Proteins in GastricCancer and Matched Mucosa Tissues
Objective: To investigate the protein expressions of DNAmethyltransferases (DNMTs, including DNMT1, DNMT2, DNMT3A,DNMT3B and DNMT3L) in gastric cancer (GC) and matched gastricmucosa tissues.
Methods: Immunohistochemistry was performed to detect the DNMTexpressions in30pairs of GC and matched mucosa tissues.
Results: GC and matched mucosa tissues expressed all five kinds ofDNMT proteins. The proliferating zones of foveolar epithelia in gastricmucosa tissues expressed DNMT proteins significantly. The expression ofDNMT3A was weaker in GC tissues than in matched controls. Theexpressions of other DNMTs, however, did not differ significantly betweenthe GCs and controls. In GC tissues, the positive rates of DNMTexpressions (with the exception of DNMT2) were higher in diffuse type than in intestinal type.
Conclusion: GC did not necessarily show stronger expressions ofDNMT proteins than the matched mucosa tissues. The DNMT expressionsin GC were associated with the Lauren’s type.
CHAPTER2The Distributions of DNMT Proteins in Gastriccancer and the effect of5-aza-2'-deoxycytidine on Gastric cancercells
Objective: To investigate the protein expressions and distributions ofDNMTs in GC and gastric epithelial cells and to analyze the effect of5-aza-2'-deoxycytidine on GC’s growth rates, cell cycle distributions andapoptosis rates.
Methods: Immunofluorescence and western blotting were performedto detect the DNMT distributions and expressions in GC cells (SGC-7901and MKN-28) and gastric epithelial cell (GES-1). MTT assay and flowcytometry were performed to analyze the reactions of GC cells to5-aza-2'-deoxycytidine treatment.
Results: SGC-7901and MKN-28expressed5kinds of DNMTproteins. DNMT1, DNMT2and DNMT3L were distributed in the nuclei ofGC cells. DNMT3A and DNMT3B were distributed in both the nuclei andcytoplasm of GC cells. The DNMT expressions did not differ significantlybetween the GC cells (SGC-7901, MKN-28) and gastric epithelial cell (GES-1).5-Aza-2'-deoxycytidine with concentrations of0.5-5μmol/L(where it acts as a demethylation drug) had very little effect on the growthrates, cell cycle distributions, and apoptosis rates of SGC-7901or MKN-28cells when the drug was used alone in short term (5days).
Conclusion: GC cells didn’t necessarily express DNMT proteinsstronger than gastric epithelial cells.5-aza-2'-deoxycytidine (0.5-5μmol/L)didn’t necessarily inhibit GC cell proliferation when it was used alone inshort term.
CHAPTER3The aberrant DNA methylation pattern of Gastriccancer genome
Objective: To investigate the aberrant DNA methylation pattern of GCgenome.
Methods: Methylated DNA immunoprecipitation (MeDIP) microarray(MeDIP-chip) was performed to analyze the genomic DNA methylation ofa pair of GC and matched mucosa tissue. MeDIP-qRCR assay wasperformed to validate parts of the MeDIP-chip findings in5pairs of gastrictissues. qRT-PCR was performed to analyze the mRNA expressions ofvalidated genes (such as ABL2, FGF18, TRAF2, EGFL7and RAB33A) inthe5pairs of gastric tissues above.
Results: For both the GC and matched mucosa tissue, localhypermethylation and global hypomethylation of genomic DNA were the significant characteristics. And certain CpG islands and gene promoterswere hypermethylated only in GC tissue, whereas some other CpG islandsand gene promoters were hypermethylated only in matched mucosa tissue.After separating tumor related genes those showed differential DNAmethylation in promoters between the cancer and control from the genome,GC tissue was found to contain both aberrantly hypermethylated andhypomethylated TSGs, oncogenes, and tumor-promoter genes (TPGs).MeDIP-qPCR verified some tumor related genes (such as ABL2, FGF18,TRAF2, EGFL7and RAB33A) were aberrantly hypomethylated in GCtissues compared to in controls. And the qRT-PCR assay found that themRNA transcriptions of FGF18, TRAF2and EGFL7were significantlymore in GC tissues than in matched mucosa tissues, but the mRNAtranscriptions of ABL2and RAB33A were significantly less in GC than inmatched controls.
Conclusion: Aberrant DNA methylation pattern of GC genome iscomplex, but not limited to hypermethylation of TSG only.
引文
[1]吴孟超,吴在德主编.黄家驷外科学(第7版)[M].人民卫生出版社.2008,p1440-1442.
[2] Harder J, Opitz OG, Brabender J, et al. Quantitative promoter methylation analysisof hepatocellular carcinoma, cirrhotic and normal liver[J]. Int J Cancer.2008,122(12):2800-2804.
[3] Yegnasubramanian S, Haffner MC, Zhang Y, et al. DNA hypomethylation ariseslater in prostate cancer progression than CpG island hypermethylation andcontributes to metastatic tumor heterogeneity[J]. Cancer Res.2008,68(21):8954-8967.
[4] Gao Q, Steine EJ, Barrasa MI, et al. Deletion of the de novo DNAmethyltransferase Dnmt3a promotes lung tumor progression[J]. Proc Natl AcadSci U S A.2011,108(44):18061-18066.
[5] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[6] Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structuralperspective[J]. Structure.2008,16(3):341-350.
[7] Rollins RA, Haghighi F, Edwards JR, et al. Large-scale structure of genomicmethylation patterns[J]. Genome Res.2006,16(2):157-163.
[8] Weber M, Hellmann I, Stadler MB, et al. Distribution, silencing potential andevolutionary impact of promoter DNA methylation in the human genome[J]. NatGenet.2007,39(4):457-466.
[9] Attwood JT, Yung RL, Richardson BC. DNA methylation and the regulation ofgene transcription[J]. Cell Mol Life Sci.2002,59(2):241-257.
[10] Trasler JM. Gamete imprinting: setting epigenetic patterns for the nextgeneration[J]. Reprod Fertil Dev.2006,18(1-2):63-69.
[11] Esteller M. Cancer epigenomics: DNA methylomes and histone-modificationmaps[J]. Nat Rev Genet.2007,8(4):286-298.
[12] Chim SS, Jin S, Lee TY, et al. Systematic search for placental DNA-methylationmarkers on chromosome21: toward a maternal plasma-based epigenetic test forfetal trisomy21[J]. Clin chem.2008,54(3):500-511.
[13] Daniel FI, Cherubini K, Yurgel LS, et al. The role of epigenetic transcriptionrepression and DNA methyltransferases in cancer[J]. Cancer.2011,117(4):677-687.
[14] Robertson KD, Uzvolgyi E, Liang G, et al. The human DNA methyltransferases(DNMTs)1,3a and3b: coordinate mRNA expression in normal tissues andoverexpression in tumors[J]. Nucleic Acids Res.1999,27(11):2291-2298.
[15] Schaefer M, Hagemann S, Hanna K, et al. Azacytidine inhibits RNA methylationat DNMT2target sites in human cancer cell lines[J]. Cancer Res.2009,69(20):8127-8132.
[16] Ooi SK, Qiu C, Bernstein E, et al. DNMT3L connects unmethylated lysine4ofhistone H3to de novo methylation of DNA[J]. Nature.2007,448(7154):714-717.
[17] Bourc'his D, Xu GL, Lin CS, et al. Dnmt3L and the establishment of maternalgenomic imprints[J]. Science.2001,294(5551):2536-2539.
[18] Jia D, Jurkowska RZ, Zhang X, et al. Structure of Dnmt3a bound to Dnmt3Lsuggests a model for de novo DNA methylation[J]. Nature.2007,449(7159):248-251.
[19] Wang N, Jin F, Huang HF. DNA methylation and imprinted gene[J].International genetical journal.2007,30(4):272-274.
[20] Goll MG, Kirpekar F, Maggert KA, et al. Methylation of tRNAAsp by the DNAmethyltransferase homolog Dnmt2[J]. Science.2006,311(5759):395-398.
[21] Schaefer M, Hagemann S, Hanna K, et al. Azacytidine inhibits RNA methylationat DNMT2target sites in human cancer cell lines[J]. Cancer Res.2009,69(20):8127-8132.
[22] Phalke S, Nickel O, Walluscheck D, et al. Retrotransposon silencing and telomereintegrity in somatic cells of Drosophila depends on the cytosine-5methyltransferase DNMT2[J]. Nat Genet.2009,41(6):696-702.
[23] Rai K, Chidester S, Zavala CV, et al. Dnmt2functions in the cytoplasm topromote liver, brain, and retina development in zebrafish[J]. Genes Dev.2007,21(3):261-266.
[24] Schaefer M, Pollex T, Hanna K, et al. RNA methylation by Dnmt2protectstransfer RNAs against stress-induced cleavage[J]. Genes Dev.2010,24(15):1590-1595.
[25] Kato Y, Kaneda M, Hata K, et al. Role of the Dnmt3family in de novomethylation of imprinted and repetitive sequences during male germ celldevelopment in the mouse[J]. Hum Mol Genet.2007,16(19):2272–2280.
[26] Kim H, Park J, Jung Y, et al. DNA methyltransferase3-like affects promotermethylation of thymine DNA glycosylase independently of DNMT1andDNMT3B in cancer cells[J]. Int J Oncol.2010,36(6):1563-1572
[27] Choi MS, Shim YH, Hwa JY, et al. Expression of DNA methyltransferases inmultistep hepatocarcinogenesis[J]. Hum Pathol.2003,34(1):11-17.
[28] Kim H, Kwon YM, Kim JS, et al. Elevated mRNA levels of DNAmethyltransferase-1as an independent prognostic factor in primary nonsmall celllung cancer[J]. Cancer.2006,107(5):1042-1049.
[29] Rojas A, Meherem S, Kim Y H, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[30] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[31] Cui M, Wen Z, Chen J, et al.5-Aza-2'-deoxycytidine is a potent inhibitor ofDNA methyltransferase3B and induces apoptosis in human endometrial cancercell lines with the up-regulation of hMLH1[J]. Med Oncol.2010,27(2):278-285.
[32] Deng G, Li ZQ, Zhao C, et al. WNT5A expression is regulated by the status of itspromoter methylation in leukaemia and can inhibit leukemic cell malignantproliferation[J]. Oncol Rep.2011,25(2):367-376.
[33] Fu HY, Shen JZ, Wu Y, et al. Arsenic trioxide inhibits DNA methyltransferaseand restores expression of methylation-silenced CDKN2B/CDKN2A genes inhuman hematologic malignant cells[J]. Oncol Rep.2010,24(2):335-343.
[34] Tang SC, Wu MF, Wong RH, et al. Epigenetic mechanisms for silencingglutathione S-transferase m2expression by hypermethylated specificity protein1binding in lung cancer[J]. Cancer.2011,117(14):3209-3221.
[35] Xiong Y, Dowdy SC, Xue A, et al. Opposite alterations of DNAmethyltransferase gene expression in endometrioid and serous endometrialcancers[J]. Gynecol Oncol.2005,96(3):601-609.
[36] Stefanska B, Huang J, Bhattacharyya B, et al. Definition of the landscape ofpromoter DNA hypomethylation in liver cancer[J]. Cancer Res.2011,71(17):5891-5903.
[37] Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment[J].Eur J Pharmacol.2009,625(1-3):131-142.
[38] Oshimo Y, Nakayama H, Ito R, et al. Promoter methylation of cyclin D2gene ingastric carcinoma[J]. Int J Oncol.2003,23(6):1663-1670.
[39] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[40] Oue N, Kuraoka K, Kuniyasu H, et al. DNA methylation status of hMLH1, p16(INK4a), and CDH1is not associated with mRNA expression levels of DNAmethyltransferase and DNA demethylase in gastric carcinomas[J]. Oncol Rep.2001,8(5):1085-1089.
[41] Etoh T, Kanai Y, Ushijima S, et al. Increased DNA methyltransferase1(DNMT1)protein expression correlates significantly with poorer tumor differentiation andfrequent DNA hypermethylation of multiple CpG islands in gastric cancers[J].Am J Pathol.2004,164(2):689-699.
[42] Ding WJ, Fang JY, Chen XY, et al. The expression and clinical significance ofDNA methyltransferase proteins in human gastric cancer[J]. Dig Dis Sci.2008,53(8):2083-2089.
[1] Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancertherapy[J]. Clin Epigenetics.2013,5(1):3.
[2] Jung Y, Park J, Kim TY, et al. Potential advantages of DNA methyltransferase1(DNMT1)-targeted inhibition for cancer therapy[J]. J Mol Med.2007,85(10):1137-1148.
[3] Momparler RL, Bouchard J, Samson J. Induction of differentiation and inhibitionof DNA methylation in HL-60myeloid leukemic cells by5-AZA-2'-deoxycytidine[J]. Leuk Res.1985,9(11):1361-1366.
[4] Gomyo Y, Sasaki J, Branch C, et al.5-aza-2'-deoxycytidine upregulates caspase-9expression cooperating with p53-induced apoptosis in human lung cancer cells[J].Oncogene.2004,23(40):6779-6787.
[5] Chiam K, Centenera MM, Butler LM, et al. GSTP1DNA Methylation andExpression Status Is Indicative of5-aza-2'-Deoxycytidine Efficacy in HumanProstate Cancer Cells[J]. PLoS One.2011,6(9): e25634.
[6] Chik F, Szyf M. Effects of specific DNMT gene depletion on cancer celltransformation and breast cancer cell invasion; toward selective DNMTinhibitors[J]. Carcinogenesis.2011,32(2):224-232.
[7] Mutze K, Langer R, Schumacher F, et al. DNA methyltransferase1as a predictivebiomarker and potential therapeutic target for chemotherapy in gastric cancer[J].Eur J Cancer.2011,47(12):1817-1825.
[8]刘丽乔，罗达亚，付晶晶，等.5-Aza-CdR对人结肠癌Caco-2细胞系P16基因甲基化状态及其生物学表型的影响[J].基础医学与临床.2011,31(2):161-165.
[9]马千回，侯琳，宋金莲.乳腺癌中NDRG-1基因甲基化及其体外逆转研究[J].肿瘤.2010,30(4):310-313.
[10] Deng G, Li ZQ, Zhao C, et al. WNT5A expression is regulated by the status of itspromoter methylation in leukaemia and can inhibit leukemic cell malignantproliferation[J]. Oncol Rep.2011,25(2):367-376.
[11] Pliml J, Sorm F. Synthesis of2`-deoxy-D-ribofuranosyl-5-azacytosine[J]. CollCzech Chem Commun.1964,29:2576–2577.
[12] Rius M, Keller D, Brom M, et al. Vectorial transport of nucleoside analogs fromthe apical to the basolateral membrane in double-transfected cells expressing thehuman concentrative nucleoside transporter hCNT3and the export pumpABCC4[J]. Drug Metab Dispos.2010,38(7):1054-1063.
[13] Baldwin SA, Beal PR, Yao SY, et al. The equilibrative nucleoside transporterfamily, SLC29[J]. Pflugers Arch.2004,447(5):735-743.
[14] Bouchard J, Momparler RL. Incorporation of5-Aza-2'-deoxycytidine-5'-triphosphate into DNA. Interactions with mammalian DNA polymerase alphaand DNA methylase[J]. Mol Pharmacol.1983,24(1):109-114.
[15] Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in L1210leukemic cells by5-aza-2'-deoxycytidine as a possible mechanism ofchemotherapeutic action[J]. Cancer Res.1983,43(8):3493-3496.
[16] Hagemann S, Heil O, Lyko F, et al. Azacytidine and decitabine inducegene-specific and non-random DNA demethylation in human cancer cell lines[J].PLoS One.2011,6(3): e17388.
[17] Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment[J].Eur J Pharmacol.2009,625(1-3):131-142.
[18] Sorm F, Vesely J. Effect of5-aza-2'-deoxycytidine against leukemic andhemopoietic tissues in AKR mice[J]. Neoplasma.1968,15(4):339-343.
[19] Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNAmethylation[J]. Cell.1980,20(1):85-93.
[20] Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained exposure to theDNA demethylating agent,2'-deoxy-5-azacytidine, leads to apoptotic cell deathin chronic myeloid leukemia by promoting differentiation, senescence, andautophagy[J]. Biochem Pharmacol.2011,81(3):364-378.
[21] Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylatedP15/INK4B gene in patients with myelodysplastic syndrome by5-Aza-2'-deoxycytidine (decitabine) treatment[J]. Blood.2002,100(8):2957-2964.
[22] Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of theDAP-kinase CpG island is a common alteration in B-cell malignancies[J]. Blood.1999,93(12):4347-4353.
[23] Jabbour E, Issa JP, Garcia-Manero G, et al. Evolution of decitabine development:accomplishments, ongoing investigations, and future strategies[J]. Cancer.2008,112(11):2341-2351.
[24] Choi MS, Shim YH, Hwa JY, et al. Expression of DNA methyltransferases inmultistep hepatocarcinogenesis[J]. Hum Pathol.2003,34(1):11-17.
[25] Eads CA, Danenberg KD, Kawakami K, et al. CpG island hypermethylation inhuman colorectal tumors is not associated with DNA methyltransferaseoverexpression[J]. Cancer Res.1999,59(10):2302-2306.
[26] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[27] Csepregi A, Ebert MP, R cken C, et al. Promoter methylation of CDKN2A andlack of p16expression characterize patients with hepatocellular carcinoma[J].BMC Cancer.2010,10:317.
[28] Otterson GA, Khleif SN, Chen W, et al. CDKN2gene silencing in lung cancerby DNA hypermethylation and kinetics of p16INK4protein induction by5-aza2'deoxycytidine[J]. Oncogene.1995,11(6):1211-1216.
[29] Numoto K, Yoshida A, Sugihara S, et al. Frequent methylation of RASSF1A insynovial sarcoma and the anti-tumor effects of5-aza-2'-deoxycytidine againstsynovial sarcoma cell lines[J]. J Cancer Res Clin Oncol.2010,136(1):17-25.
[30] Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitorsazacitidine, decitabine and zebularine exert differential effects on cancer geneexpression in acute myeloid leukemia cells[J]. Leukemia.2009,23(6):1019-1028.
[31] Zhu WG, Dai Z, Ding H, et al. Increased expression of unmethylated CDKN2Dby5-aza-2'-deoxycytidine in human lung cancer cells[J]. Oncogene.2001,20(53):7787-7796.
[32] Zhu WG, Hileman T, Ke Y, et al.5-aza-2'-deoxycytidine activates thep53/p21Waf1/Cip1pathway to inhibit cell proliferation[J]. J Biol Chem.2004,279(15):15161-15166.
[33] Jüttermann R, Li E, Jaenisch R. Toxicity of5-aza-2'-deoxycytidine to mammaliancells is mediated primarily by covalent trapping of DNA methyltransferase ratherthan DNA demethylation[J]. Proc Natl Acad Sci U S A.1994,91(25):11797-11801.
[1] Esteller M. Cancer Epigenetics for the21st Century: What’s Next[J]? GenesCancer.2011,2(6):604–606.
[2] Klotz DM, Nelson SA, Kroboth K, et al. The microtubule poison vinorelbine killscells independently of mitotic arrest and targets cells lacking the APC tumoursuppressor more effectively[J]. J Cell Sci.2012,125(Pt4):887-895.
[3] Ohta S, Lai EW, Pang AL, et al. Downregulation of metastasis suppressor genes inmalignant pheochromocytoma[J]. Int J Cancer.2005,114(1):139-143.
[4] Gilham DE, Debets R, Pule M, et al. CAR-T cells and solid tumors: tuning T cellsto challenge an inveterate foe[J]. Trends Mol Med.2012,18(7):377-384.
[5] Riccio A, Cubellis MV. Gain of function in CDKN1C[J]. Nat Genet.2012,44(7):737-738.
[6] Harinck F, Kluijt I, van der Stoep N, et al. Indication for CDKN2A-mutationanalysis in familial pancreatic cancer families without melanomas[J]. J MedGenet.2012,49(6):362-365.
[7] Guan CN, Zhang PW, Lou HQ, et al. DLC-1Expression Levels in Breast CancerAssessed by qRT-PCR are Negatively Associated with Malignancy[J]. Asian PacJ Cancer Prev.2012,13(4):1231-1233.
[8] Liu J, Lin Y, Yang H, et al. The expression of p33(ING1), p53, andautophagy-related gene Beclin1in patients with non-small cell lung cancer[J].Tumour Biol.2011,32(6):1113-1121.
[9] Schultz DC, Vanderveer L, Berman DB, et al. Identification of two candidatetumor suppressor genes on chromosome17p13.3[J]. Cancer Res.1996,56(9):1997-2002.
[10] Vaidyanathan G, Cismowski MJ, Wang G, et al. The Ras-related proteinAGS1/RASD1suppresses cell growth[J]. Oncogene.2004,23(34):5858-5863.
[11] Berman SD, Calo E, Landman AS, et al. Metastatic osteosarcoma induced byinactivation of Rb and p53in the osteoblast lineage[J]. Proc Natl Acad Sci U S A.2008,105(33):11851-11856.
[12] Kanwal S, Kayani MA, Faryal R. Identification of novel SNPs in SYK gene ofbreast cancer patients: computational analysis of SNPs in the5'UTR[J]. Mol BiolRep.2012,39(8):8345-8351.
[13] Takahashi M, Fujita M, Furukawa Y, et al. Isolation of a novel human gene,APCDD1, as a direct target of the beta-Catenin/T-cell factor4complex withprobable involvement in colorectal carcinogenesis[J]. Cancer Res.2002,62(20):5651-5656.
[14] Agueli C, Cammarata G, Salemi D, et al.14q32/miRNA clusters loss ofheterozygosity in acute lymphoblastic leukemia is associated with up-regulationof BCL11a[J]. Am J Hematol.2010,85(8):575-578.
[15] Zhang X, Liu H, Li B, et al. Tumor suppressor BLU inhibits proliferation ofnasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminalkinase and the cyclin D1promoter[J]. BMC Cancer.2012,12(1):267.
[16] Wheeler SE, Morariu EM, Bednash JS, et al. Lyn kinase mediates cell motilityand tumor growth in EGFRvIII-expressing head and neck cancer[J]. Clin CancerRes.2012,18(10):2850-2860.
[17] Persson M, Andrén Y, Moskaluk CA, et al. Clinically significant copy numberalterations and complex rearrangements of MYB and NFIB in head and neckadenoid cystic carcinoma[J]. Genes Chromosomes Cancer.2012,51(8):805-817.
[18] Xiong F, Wu C, Chang J, et al. Genetic variation in an miRNA-1827binding sitein MYCL1alters susceptibility to small-cell lung cancer[J]. Cancer Res.2011,71(15):5175-5181.
[19] Gilmore TD, Gerondakis S. The c-Rel Transcription Factor in Development andDisease[J]. Genes Cancer.2011,2(7):695-711.
[20] Zhang L, Teng Y, Zhang Y, et al. C-Src-mediated RANKL-induced breast cancercell migration by activation of the ERK and Akt pathway[J]. Oncol Lett.2012,3(2):395-400.
[21] Memarian A, Hojjat-Farsangi M, Asgarian-Omran H, et al. Variation in WNTgenes expression in different subtypes of chronic lymphocytic leukemia[J]. LeukLymphoma.2009,50(12):2061-2070.
[22] Dwyer MA, Joseph JD, Wade HE, et al. WNT11expression is induced byestrogen-related receptor alpha and beta-catenin and acts in an autocrine mannerto increase cancer cell migration[J]. Cancer Res.2010,70(22):9298-9308.
[23] Tanic M, Yanowsky K, Rodriguez-Antona C, et al. Deregulated miRNAs inHereditary Breast Cancer Revealed a Role for miR-30c in Regulating KRASOncogene[J]. PLoS One.2012,7(6): e38847.
[24] Qiu JF, Zhang ZQ, Wang Y, et al. Lentivirus-mediated RNAi knockdown ofVEGFA in RKO colorectal cancer cells decreases tumor formation and growth invitro and in vivo[J]. Int J Clin Exp Pathol.2012,5(4):290-298.
[25] Seyhan AA, Varadarajan U, Choe S, et al. A genome-wide RNAi screen identifiesnovel targets of neratinib resistance leading to identification of potential drugresistant genetic markers[J]. Mol Biosyst.2012,8(5):1553-1570.
[26] Shen DW, Gottesman MM. RAB8enhances TMEM205-mediated cisplatinresistance[J]. Pharm Res.2012,29(3):643-650.
[27] Wang JS, Wang FB, Zhang QG, et al. Enhanced expression of Rab27A gene bybreast cancer cells promoting invasiveness and the metastasis potential bysecretion of insulin-like growth factor-II[J]. Mol Cancer Res.2008,6(3):372-382.
[28] Shibata D, Mori Y, Cai K, et al. RAB32hypermethylation and microsatelliteinstability in gastric and endometrial adenocarcinomas[J]. Int J Cancer.2006,119(4):801-806.
[29] Behjati R, Kawai K, Inadome Y, et al. APAF-1is related to an undifferentiatedstate in the testicular germ cell tumor pathway[J]. Cancer Sci.2011,102(1):267-274.
[30] Chêne L, Giroud C, Desgrandchamps F, et al. Extensive analysis of the7q31region in human prostate tumors supports TES as the best candidate tumorsuppressor gene[J]. Int J Cancer.2004,111(5):798-804.
[31] da Costa Prando E, Cavalli LR, Rainho CA. Evidence of epigenetic regulation ofthe tumor suppressor gene cluster flanking RASSF1in breast cancer cell lines[J].Epigenetics.2011,6(12):1413-1424.
[32] Cong XL, Li B, Yang RC, et al. Enhanced growth suppression of Philadephia1leukemia cells by targeting bcr3/abl2and VEGF through antisense strategy[J].Leukemia.2005,19(9):1517-1524.
[33] Sonvilla G, Allerstorfer S, St ttner S, et al. FGF18in colorectal tumour cells:autocrine and paracrine effects[J]. Carcinogenesis.2008,29(1):15-24.
[34] Delfortrie S, Pinte S, Mattot V, et al. Egfl7promotes tumor escape fromimmunity by repressing endothelial cell activation[J]. Cancer Res.2011,71(23):7176-7186.
[35] Schenone S, Brullo C, Musumeci F, et al. Fyn kinase in brain diseases and cancer:the search for inhibitors[J]. Curr Med Chem.2011,18(19):2921-2942.
[36] Jacobs JF, van Bokhoven H, van Leeuwen FN, et al. Regulation of MYCNexpression in human neuroblastoma cells[J]. BMC Cancer.2009,9:239.
[37] Lankat-Buttgereit B, Fehmann HC, Hering BJ, et al. Expression of the ras-relatedrab3a gene in human insulinomas and normal human pancreatic islets[J].Pancreas.1994,9(4):434-438.
[38] Jang KW, Lee KH, Kim SH, et al. Ubiquitin ligase CHIP induces TRAF2proteasomal degradation and NF-κB inactivation to regulate breast cancer cellinvasion[J]. J Cell Biochem.2011,112(12):3612-3620.
[39] Kawaguchi-Ihara N, Murohashi I, Nara N, et al. Promotion of the self-renewalcapacity of human acute leukemia cells by Wnt3A[J]. Anticancer Res.2008,28(5A):2701-2704.
[40] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[41] Rojas A, Meherem S, Kim Y H, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[42] Stefanska B, Huang J, Bhattacharyya B, et al. Definition of the landscape ofpromoter DNA hypomethylation in liver cancer[J]. Cancer Res.2011,71(17):5891-5903.
[43] Tan AC, Jimeno A, Lin SH, et al. Characterizing DNA methylation patterns inpancreatic cancer genome[J]. Mol Oncol.2009,3(5-6):425-438.
[44] He Y, Cui Y, Wang W, et al. Hypomethylation of the hsa-miR-191locus causeshigh expression of hsa-mir-191and promotes the epithelial-to-mesenchymaltransition in hepatocellular carcinoma[J]. Neoplasia.2011,13(9):841-853.
[45] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[46] Gil-Henn H, Patsialou A, Wang Y, et al. Arg/Abl2promotes invasion andattenuates proliferation of breast cancer in vivo[J]. Oncogene.2012, doi:10.1038/onc.2012.284.[Epub ahead of print]
[47] Peng C, Zhu F, Wen W, et al. Tumor necrosis factor receptor-associated factorfamily protein2is a key mediator of the epidermal growth factor-inducedribosomal S6kinase2/cAMP-responsive element-binding protein/Fos proteinsignaling pathway[J]. J Biol Chem.2012,287(31):25881-25892.
[1] Esteller M. Epigenetics in cancer[J]. N Engl J Med.2008,358(11):1148-1159.
[2]何苗,王子卫.肿瘤中DNA甲基化和小RNA的关联研究现状[J].医学综述.2011,17(15):2296-2299.
[3] Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structuralperspective[J]. Structure.2008,16(3):341-350.
[4] Chim SS, Jin S, Lee TY, et al. Systematic search for placental DNA-methylationmarkers on chromosome21:toward a maternal plasma-based epigenetic test forfetal trisomy21[J]. Clin chem.2008,54(3):500-511.
[5] Tong JD, Jiao NL, Wang YX, et al. Downregulation of fibulin-3gene by promotermethylation in colorectal cancer predicts adverse prognosis[J]. Neoplasma.2011,58(5):441-448.
[6] Yoshioka M, Kikuta H, Ishiguro N, et al. Unique Epstein-Barr virus(EBV) latentgene expression, EBNA promoter usage and EBNA promoter methylation statusin chronic active EBV infection[J]. J Gen Virol.2003,84(Pt5):1133-1140.
[7] Hong SJ, Oh JH, Jung YC, et al. DNA methylation patterns of ulcer-healing genesassociated with the normal gastric mucosa of gastric cancers[J]. J Korean Med Sci.2010,25(3):405-417.
[8] Simmen MW. Genome-scale relationships between cytosine methylation anddinucleotide abundances in animals[J]. Genomics.2008,92(1):33-40.
[9] Schuebel KE, Chen W, Cope L, et al. Comparing the DNA hypermethylome withgene mutations in human colorectal cancer[J]. PLoS Genet.2007,3(9):1709-1723.
[10] Goll MG, Kirpekar F, Maggert KA, et al. Methylation of tRNAAsp by the DNAmethyltransferase homolog Dnmt2[J]. Science.2006,311(5759):395-398.
[11] Fu HY, Shen JZ, Wu Y, et al. Arsenic trioxide inhibits DNA methyltransferaseand restores expression of methylation-silenced CDKN2B/CDKN2A genes inhuman hematologic malignant cells[J]. Oncol Rep.2010,24(2):335-343.
[12] Linhart HG, Troen A, Bell GW, et al. Folate deficiency induces genomic uracilmisincorporation and hypomethylation but does not increase DNA pointmutations[J]. Gastroenterology.2009,136(1):227-235.
[13] Wen XZ, Akiyama Y, Pan KF, et al. Methylation of GATA-4and GATA-5anddevelopment of sporadic gastric carcinomas[J]. World J Gastroenterol.2010,16(10):1201-1208.
[14] Perri F, Cotugno R, Piepoli A, et al. Aberrant DNA methylation innon-neoplastic gastric mucosa of H. pylori infected patients and effect oferadication[J]. Am J Gastroenterol.2007,102(7):1361-1371.
[15] Ferrasi AC, Pinheiro NA, Rabenhorst SH, et al. Helicobacter pylori and EBV ingastric carcinomas: Methylation status and microsatellite instability[J]. World JGastroenterol.2010,16(3):312-319.
[16]郑长青,季守平,章扬培. MGMT基因甲基化在肿瘤发生及个体性化疗中的意义[J].医学分子生物学杂志.2008,5(4):373-376.
[17] Erdamar S, Ucaryilmaz E, Dogusoy G. Importance of MutL homologue MLH1and MutS homologue MSH2expression in Turkish patients with sporadiccolorectal cancer[J]. World J Gastroenterol.2007,13(33):4437-4444.
[18] Csepregi A, Ebert MP, Rocken C, et al. Promoter methylation of CDKN2A andlack of p16expression characterize patients with hepatocellular carcinoma[J].BMC Cancer.2010,10:317.
[19] Rojas A, Meherem S, Kim YH, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[20] Issa JP. DNA Methylation as a therapeutic target in cancer[J]. Clin Cancer Res.2007,13(6):1634-1637.
[21] Liu R, Gong M, Li X, et al. Induction, regulation, and biologic function of Axlreceptor tyrosine kinase in Kaposi sarcoma[J]. Blood.2010,116(2):297-305.
[22] Suzuki H, Yamamoto E, Nojima M, et al. Methylation-associated silencing ofmicroRNA-34b/c in gastric cancer and its involvement in an epigenetic fielddefect[J]. Carcinogenesis.2010,31(12):2066-2073.
[23] Sunami E, Vu AT, Nguyen SL, et al. Analysis of methylated circulating DNA incancer patients' blood[J]. Methods Mol Biol.2009,507:349-356.
[24] Svrcek M, Buhard O, Colas C, et al. Methylation tolerance due to anO6-methylguanine DNA methyltransferase (MGMT) field defect in the colonicmucosa: an initiating step in the development of mismatch repair-deficientcolorectal cancers[J]. Gut.2010,59(11):1516-1526.
[25] Wakabayashi T, Natsume A, Hatano H, et al. p16promoter methylation in theserum as a basis for the molecular diagnosis of gliomas[J]. Neurosurgery.2009,64(3):455-462.
[26] Kamiyama H, Noda H, Takata O, et al. Promoter hypermethylation oftumor-related genes in peritoneal lavage and the prognosis of patients withcolorectal cancer[J]. J Surg Oncol.2009,100(1):69-74.
[27] Nagasaka T, Tanaka N, Cullings HM, et al. Analysis of fecal DNA methylation todetect gastrointestinal neoplasia[J]. J Natl Cancer Inst.2009,101(18):1244-1258.
[28] Kim JH, Choi YD, Lee JS, et al. Assessment of DNA methylation for thedetection of cervical neoplasia in liquid-based cytology specimens[J]. GynecolOncol.2010,116(1):99-104.
[29] Hibi K, Goto T, Kitamura YH, et al. Methylation of the TFPI2gene is frequentlydetected in advanced gastric carcinoma[J]. Anticancer Res.2010,30(10):4131-4133.
[30] Hildebrandt MA, Gu J, Lin J, et al. Hsa-miR-9methylation status is associatedwith cancer development and metastatic recurrence in patients with clear cellrenal cell carcinoma[J]. Oncogene.2010,29(42):5724-5728.
[31] Formeister EJ, Tsuchiya M, Fujii H, et al. Comparative analysis of promotermethylation and gene expression endpoints between tumorous and non-tumoroustissues from HCV-positive patients with hepatocellular carcinoma[J]. Mutat Res.2010,692(1-2):26-33.
[32] Park SY, Kook MC, Kim YW, et al. CpG island hypermethylator phenotype ingastric carcinoma and its clinicopathological features[J]. Virchows Arch.2010,457(4):415-422.
[33] Wang H, Zhao Y, Li L, et al. An ATM-and Rad3-related (ATR) signalingpathway and aphosphorylation-acetylation cascade are involved in activation ofp53/p21Waf1/Cip1in response to5-aza-2'-deoxycytidine treatment[J]. J BiolChem.2008,283(5):2564-2574.
[34] Jung Y, Park J, Kim TY, et al. Potential advantages of DNA methyltransferase1(DNMT1)-targeted inhibition for cancer therapy[J]. J Mol Med.2007,85(10):1137-1148.
[2] Harder J, Opitz OG, Brabender J, et al. Quantitative promoter methylation analysisof hepatocellular carcinoma, cirrhotic and normal liver[J]. Int J Cancer.2008,122(12):2800-2804.
[3] Yegnasubramanian S, Haffner MC, Zhang Y, et al. DNA hypomethylation ariseslater in prostate cancer progression than CpG island hypermethylation andcontributes to metastatic tumor heterogeneity[J]. Cancer Res.2008,68(21):8954-8967.
[4] Gao Q, Steine EJ, Barrasa MI, et al. Deletion of the de novo DNAmethyltransferase Dnmt3a promotes lung tumor progression[J]. Proc Natl AcadSci U S A.2011,108(44):18061-18066.
[5] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[6] Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structuralperspective[J]. Structure.2008,16(3):341-350.
[7] Rollins RA, Haghighi F, Edwards JR, et al. Large-scale structure of genomicmethylation patterns[J]. Genome Res.2006,16(2):157-163.
[8] Weber M, Hellmann I, Stadler MB, et al. Distribution, silencing potential andevolutionary impact of promoter DNA methylation in the human genome[J]. NatGenet.2007,39(4):457-466.
[9] Attwood JT, Yung RL, Richardson BC. DNA methylation and the regulation ofgene transcription[J]. Cell Mol Life Sci.2002,59(2):241-257.
[10] Trasler JM. Gamete imprinting: setting epigenetic patterns for the nextgeneration[J]. Reprod Fertil Dev.2006,18(1-2):63-69.
[11] Esteller M. Cancer epigenomics: DNA methylomes and histone-modificationmaps[J]. Nat Rev Genet.2007,8(4):286-298.
[12] Chim SS, Jin S, Lee TY, et al. Systematic search for placental DNA-methylationmarkers on chromosome21: toward a maternal plasma-based epigenetic test forfetal trisomy21[J]. Clin chem.2008,54(3):500-511.
[13] Daniel FI, Cherubini K, Yurgel LS, et al. The role of epigenetic transcriptionrepression and DNA methyltransferases in cancer[J]. Cancer.2011,117(4):677-687.
[14] Robertson KD, Uzvolgyi E, Liang G, et al. The human DNA methyltransferases(DNMTs)1,3a and3b: coordinate mRNA expression in normal tissues andoverexpression in tumors[J]. Nucleic Acids Res.1999,27(11):2291-2298.
[15] Schaefer M, Hagemann S, Hanna K, et al. Azacytidine inhibits RNA methylationat DNMT2target sites in human cancer cell lines[J]. Cancer Res.2009,69(20):8127-8132.
[16] Ooi SK, Qiu C, Bernstein E, et al. DNMT3L connects unmethylated lysine4ofhistone H3to de novo methylation of DNA[J]. Nature.2007,448(7154):714-717.
[17] Bourc'his D, Xu GL, Lin CS, et al. Dnmt3L and the establishment of maternalgenomic imprints[J]. Science.2001,294(5551):2536-2539.
[18] Jia D, Jurkowska RZ, Zhang X, et al. Structure of Dnmt3a bound to Dnmt3Lsuggests a model for de novo DNA methylation[J]. Nature.2007,449(7159):248-251.
[19] Wang N, Jin F, Huang HF. DNA methylation and imprinted gene[J].International genetical journal.2007,30(4):272-274.
[20] Goll MG, Kirpekar F, Maggert KA, et al. Methylation of tRNAAsp by the DNAmethyltransferase homolog Dnmt2[J]. Science.2006,311(5759):395-398.
[21] Schaefer M, Hagemann S, Hanna K, et al. Azacytidine inhibits RNA methylationat DNMT2target sites in human cancer cell lines[J]. Cancer Res.2009,69(20):8127-8132.
[22] Phalke S, Nickel O, Walluscheck D, et al. Retrotransposon silencing and telomereintegrity in somatic cells of Drosophila depends on the cytosine-5methyltransferase DNMT2[J]. Nat Genet.2009,41(6):696-702.
[23] Rai K, Chidester S, Zavala CV, et al. Dnmt2functions in the cytoplasm topromote liver, brain, and retina development in zebrafish[J]. Genes Dev.2007,21(3):261-266.
[24] Schaefer M, Pollex T, Hanna K, et al. RNA methylation by Dnmt2protectstransfer RNAs against stress-induced cleavage[J]. Genes Dev.2010,24(15):1590-1595.
[25] Kato Y, Kaneda M, Hata K, et al. Role of the Dnmt3family in de novomethylation of imprinted and repetitive sequences during male germ celldevelopment in the mouse[J]. Hum Mol Genet.2007,16(19):2272–2280.
[26] Kim H, Park J, Jung Y, et al. DNA methyltransferase3-like affects promotermethylation of thymine DNA glycosylase independently of DNMT1andDNMT3B in cancer cells[J]. Int J Oncol.2010,36(6):1563-1572
[27] Choi MS, Shim YH, Hwa JY, et al. Expression of DNA methyltransferases inmultistep hepatocarcinogenesis[J]. Hum Pathol.2003,34(1):11-17.
[28] Kim H, Kwon YM, Kim JS, et al. Elevated mRNA levels of DNAmethyltransferase-1as an independent prognostic factor in primary nonsmall celllung cancer[J]. Cancer.2006,107(5):1042-1049.
[29] Rojas A, Meherem S, Kim Y H, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[30] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[31] Cui M, Wen Z, Chen J, et al.5-Aza-2'-deoxycytidine is a potent inhibitor ofDNA methyltransferase3B and induces apoptosis in human endometrial cancercell lines with the up-regulation of hMLH1[J]. Med Oncol.2010,27(2):278-285.
[32] Deng G, Li ZQ, Zhao C, et al. WNT5A expression is regulated by the status of itspromoter methylation in leukaemia and can inhibit leukemic cell malignantproliferation[J]. Oncol Rep.2011,25(2):367-376.
[33] Fu HY, Shen JZ, Wu Y, et al. Arsenic trioxide inhibits DNA methyltransferaseand restores expression of methylation-silenced CDKN2B/CDKN2A genes inhuman hematologic malignant cells[J]. Oncol Rep.2010,24(2):335-343.
[34] Tang SC, Wu MF, Wong RH, et al. Epigenetic mechanisms for silencingglutathione S-transferase m2expression by hypermethylated specificity protein1binding in lung cancer[J]. Cancer.2011,117(14):3209-3221.
[35] Xiong Y, Dowdy SC, Xue A, et al. Opposite alterations of DNAmethyltransferase gene expression in endometrioid and serous endometrialcancers[J]. Gynecol Oncol.2005,96(3):601-609.
[36] Stefanska B, Huang J, Bhattacharyya B, et al. Definition of the landscape ofpromoter DNA hypomethylation in liver cancer[J]. Cancer Res.2011,71(17):5891-5903.
[37] Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment[J].Eur J Pharmacol.2009,625(1-3):131-142.
[38] Oshimo Y, Nakayama H, Ito R, et al. Promoter methylation of cyclin D2gene ingastric carcinoma[J]. Int J Oncol.2003,23(6):1663-1670.
[39] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[40] Oue N, Kuraoka K, Kuniyasu H, et al. DNA methylation status of hMLH1, p16(INK4a), and CDH1is not associated with mRNA expression levels of DNAmethyltransferase and DNA demethylase in gastric carcinomas[J]. Oncol Rep.2001,8(5):1085-1089.
[41] Etoh T, Kanai Y, Ushijima S, et al. Increased DNA methyltransferase1(DNMT1)protein expression correlates significantly with poorer tumor differentiation andfrequent DNA hypermethylation of multiple CpG islands in gastric cancers[J].Am J Pathol.2004,164(2):689-699.
[42] Ding WJ, Fang JY, Chen XY, et al. The expression and clinical significance ofDNA methyltransferase proteins in human gastric cancer[J]. Dig Dis Sci.2008,53(8):2083-2089.
[1] Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancertherapy[J]. Clin Epigenetics.2013,5(1):3.
[2] Jung Y, Park J, Kim TY, et al. Potential advantages of DNA methyltransferase1(DNMT1)-targeted inhibition for cancer therapy[J]. J Mol Med.2007,85(10):1137-1148.
[3] Momparler RL, Bouchard J, Samson J. Induction of differentiation and inhibitionof DNA methylation in HL-60myeloid leukemic cells by5-AZA-2'-deoxycytidine[J]. Leuk Res.1985,9(11):1361-1366.
[4] Gomyo Y, Sasaki J, Branch C, et al.5-aza-2'-deoxycytidine upregulates caspase-9expression cooperating with p53-induced apoptosis in human lung cancer cells[J].Oncogene.2004,23(40):6779-6787.
[5] Chiam K, Centenera MM, Butler LM, et al. GSTP1DNA Methylation andExpression Status Is Indicative of5-aza-2'-Deoxycytidine Efficacy in HumanProstate Cancer Cells[J]. PLoS One.2011,6(9): e25634.
[6] Chik F, Szyf M. Effects of specific DNMT gene depletion on cancer celltransformation and breast cancer cell invasion; toward selective DNMTinhibitors[J]. Carcinogenesis.2011,32(2):224-232.
[7] Mutze K, Langer R, Schumacher F, et al. DNA methyltransferase1as a predictivebiomarker and potential therapeutic target for chemotherapy in gastric cancer[J].Eur J Cancer.2011,47(12):1817-1825.
[8]刘丽乔，罗达亚，付晶晶，等.5-Aza-CdR对人结肠癌Caco-2细胞系P16基因甲基化状态及其生物学表型的影响[J].基础医学与临床.2011,31(2):161-165.
[9]马千回，侯琳，宋金莲.乳腺癌中NDRG-1基因甲基化及其体外逆转研究[J].肿瘤.2010,30(4):310-313.
[10] Deng G, Li ZQ, Zhao C, et al. WNT5A expression is regulated by the status of itspromoter methylation in leukaemia and can inhibit leukemic cell malignantproliferation[J]. Oncol Rep.2011,25(2):367-376.
[11] Pliml J, Sorm F. Synthesis of2`-deoxy-D-ribofuranosyl-5-azacytosine[J]. CollCzech Chem Commun.1964,29:2576–2577.
[12] Rius M, Keller D, Brom M, et al. Vectorial transport of nucleoside analogs fromthe apical to the basolateral membrane in double-transfected cells expressing thehuman concentrative nucleoside transporter hCNT3and the export pumpABCC4[J]. Drug Metab Dispos.2010,38(7):1054-1063.
[13] Baldwin SA, Beal PR, Yao SY, et al. The equilibrative nucleoside transporterfamily, SLC29[J]. Pflugers Arch.2004,447(5):735-743.
[14] Bouchard J, Momparler RL. Incorporation of5-Aza-2'-deoxycytidine-5'-triphosphate into DNA. Interactions with mammalian DNA polymerase alphaand DNA methylase[J]. Mol Pharmacol.1983,24(1):109-114.
[15] Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in L1210leukemic cells by5-aza-2'-deoxycytidine as a possible mechanism ofchemotherapeutic action[J]. Cancer Res.1983,43(8):3493-3496.
[16] Hagemann S, Heil O, Lyko F, et al. Azacytidine and decitabine inducegene-specific and non-random DNA demethylation in human cancer cell lines[J].PLoS One.2011,6(3): e17388.
[17] Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment[J].Eur J Pharmacol.2009,625(1-3):131-142.
[18] Sorm F, Vesely J. Effect of5-aza-2'-deoxycytidine against leukemic andhemopoietic tissues in AKR mice[J]. Neoplasma.1968,15(4):339-343.
[19] Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNAmethylation[J]. Cell.1980,20(1):85-93.
[20] Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained exposure to theDNA demethylating agent,2'-deoxy-5-azacytidine, leads to apoptotic cell deathin chronic myeloid leukemia by promoting differentiation, senescence, andautophagy[J]. Biochem Pharmacol.2011,81(3):364-378.
[21] Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylatedP15/INK4B gene in patients with myelodysplastic syndrome by5-Aza-2'-deoxycytidine (decitabine) treatment[J]. Blood.2002,100(8):2957-2964.
[22] Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of theDAP-kinase CpG island is a common alteration in B-cell malignancies[J]. Blood.1999,93(12):4347-4353.
[23] Jabbour E, Issa JP, Garcia-Manero G, et al. Evolution of decitabine development:accomplishments, ongoing investigations, and future strategies[J]. Cancer.2008,112(11):2341-2351.
[24] Choi MS, Shim YH, Hwa JY, et al. Expression of DNA methyltransferases inmultistep hepatocarcinogenesis[J]. Hum Pathol.2003,34(1):11-17.
[25] Eads CA, Danenberg KD, Kawakami K, et al. CpG island hypermethylation inhuman colorectal tumors is not associated with DNA methyltransferaseoverexpression[J]. Cancer Res.1999,59(10):2302-2306.
[26] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[27] Csepregi A, Ebert MP, R cken C, et al. Promoter methylation of CDKN2A andlack of p16expression characterize patients with hepatocellular carcinoma[J].BMC Cancer.2010,10:317.
[28] Otterson GA, Khleif SN, Chen W, et al. CDKN2gene silencing in lung cancerby DNA hypermethylation and kinetics of p16INK4protein induction by5-aza2'deoxycytidine[J]. Oncogene.1995,11(6):1211-1216.
[29] Numoto K, Yoshida A, Sugihara S, et al. Frequent methylation of RASSF1A insynovial sarcoma and the anti-tumor effects of5-aza-2'-deoxycytidine againstsynovial sarcoma cell lines[J]. J Cancer Res Clin Oncol.2010,136(1):17-25.
[30] Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitorsazacitidine, decitabine and zebularine exert differential effects on cancer geneexpression in acute myeloid leukemia cells[J]. Leukemia.2009,23(6):1019-1028.
[31] Zhu WG, Dai Z, Ding H, et al. Increased expression of unmethylated CDKN2Dby5-aza-2'-deoxycytidine in human lung cancer cells[J]. Oncogene.2001,20(53):7787-7796.
[32] Zhu WG, Hileman T, Ke Y, et al.5-aza-2'-deoxycytidine activates thep53/p21Waf1/Cip1pathway to inhibit cell proliferation[J]. J Biol Chem.2004,279(15):15161-15166.
[33] Jüttermann R, Li E, Jaenisch R. Toxicity of5-aza-2'-deoxycytidine to mammaliancells is mediated primarily by covalent trapping of DNA methyltransferase ratherthan DNA demethylation[J]. Proc Natl Acad Sci U S A.1994,91(25):11797-11801.
[1] Esteller M. Cancer Epigenetics for the21st Century: What’s Next[J]? GenesCancer.2011,2(6):604–606.
[2] Klotz DM, Nelson SA, Kroboth K, et al. The microtubule poison vinorelbine killscells independently of mitotic arrest and targets cells lacking the APC tumoursuppressor more effectively[J]. J Cell Sci.2012,125(Pt4):887-895.
[3] Ohta S, Lai EW, Pang AL, et al. Downregulation of metastasis suppressor genes inmalignant pheochromocytoma[J]. Int J Cancer.2005,114(1):139-143.
[4] Gilham DE, Debets R, Pule M, et al. CAR-T cells and solid tumors: tuning T cellsto challenge an inveterate foe[J]. Trends Mol Med.2012,18(7):377-384.
[5] Riccio A, Cubellis MV. Gain of function in CDKN1C[J]. Nat Genet.2012,44(7):737-738.
[6] Harinck F, Kluijt I, van der Stoep N, et al. Indication for CDKN2A-mutationanalysis in familial pancreatic cancer families without melanomas[J]. J MedGenet.2012,49(6):362-365.
[7] Guan CN, Zhang PW, Lou HQ, et al. DLC-1Expression Levels in Breast CancerAssessed by qRT-PCR are Negatively Associated with Malignancy[J]. Asian PacJ Cancer Prev.2012,13(4):1231-1233.
[8] Liu J, Lin Y, Yang H, et al. The expression of p33(ING1), p53, andautophagy-related gene Beclin1in patients with non-small cell lung cancer[J].Tumour Biol.2011,32(6):1113-1121.
[9] Schultz DC, Vanderveer L, Berman DB, et al. Identification of two candidatetumor suppressor genes on chromosome17p13.3[J]. Cancer Res.1996,56(9):1997-2002.
[10] Vaidyanathan G, Cismowski MJ, Wang G, et al. The Ras-related proteinAGS1/RASD1suppresses cell growth[J]. Oncogene.2004,23(34):5858-5863.
[11] Berman SD, Calo E, Landman AS, et al. Metastatic osteosarcoma induced byinactivation of Rb and p53in the osteoblast lineage[J]. Proc Natl Acad Sci U S A.2008,105(33):11851-11856.
[12] Kanwal S, Kayani MA, Faryal R. Identification of novel SNPs in SYK gene ofbreast cancer patients: computational analysis of SNPs in the5'UTR[J]. Mol BiolRep.2012,39(8):8345-8351.
[13] Takahashi M, Fujita M, Furukawa Y, et al. Isolation of a novel human gene,APCDD1, as a direct target of the beta-Catenin/T-cell factor4complex withprobable involvement in colorectal carcinogenesis[J]. Cancer Res.2002,62(20):5651-5656.
[14] Agueli C, Cammarata G, Salemi D, et al.14q32/miRNA clusters loss ofheterozygosity in acute lymphoblastic leukemia is associated with up-regulationof BCL11a[J]. Am J Hematol.2010,85(8):575-578.
[15] Zhang X, Liu H, Li B, et al. Tumor suppressor BLU inhibits proliferation ofnasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminalkinase and the cyclin D1promoter[J]. BMC Cancer.2012,12(1):267.
[16] Wheeler SE, Morariu EM, Bednash JS, et al. Lyn kinase mediates cell motilityand tumor growth in EGFRvIII-expressing head and neck cancer[J]. Clin CancerRes.2012,18(10):2850-2860.
[17] Persson M, Andrén Y, Moskaluk CA, et al. Clinically significant copy numberalterations and complex rearrangements of MYB and NFIB in head and neckadenoid cystic carcinoma[J]. Genes Chromosomes Cancer.2012,51(8):805-817.
[18] Xiong F, Wu C, Chang J, et al. Genetic variation in an miRNA-1827binding sitein MYCL1alters susceptibility to small-cell lung cancer[J]. Cancer Res.2011,71(15):5175-5181.
[19] Gilmore TD, Gerondakis S. The c-Rel Transcription Factor in Development andDisease[J]. Genes Cancer.2011,2(7):695-711.
[20] Zhang L, Teng Y, Zhang Y, et al. C-Src-mediated RANKL-induced breast cancercell migration by activation of the ERK and Akt pathway[J]. Oncol Lett.2012,3(2):395-400.
[21] Memarian A, Hojjat-Farsangi M, Asgarian-Omran H, et al. Variation in WNTgenes expression in different subtypes of chronic lymphocytic leukemia[J]. LeukLymphoma.2009,50(12):2061-2070.
[22] Dwyer MA, Joseph JD, Wade HE, et al. WNT11expression is induced byestrogen-related receptor alpha and beta-catenin and acts in an autocrine mannerto increase cancer cell migration[J]. Cancer Res.2010,70(22):9298-9308.
[23] Tanic M, Yanowsky K, Rodriguez-Antona C, et al. Deregulated miRNAs inHereditary Breast Cancer Revealed a Role for miR-30c in Regulating KRASOncogene[J]. PLoS One.2012,7(6): e38847.
[24] Qiu JF, Zhang ZQ, Wang Y, et al. Lentivirus-mediated RNAi knockdown ofVEGFA in RKO colorectal cancer cells decreases tumor formation and growth invitro and in vivo[J]. Int J Clin Exp Pathol.2012,5(4):290-298.
[25] Seyhan AA, Varadarajan U, Choe S, et al. A genome-wide RNAi screen identifiesnovel targets of neratinib resistance leading to identification of potential drugresistant genetic markers[J]. Mol Biosyst.2012,8(5):1553-1570.
[26] Shen DW, Gottesman MM. RAB8enhances TMEM205-mediated cisplatinresistance[J]. Pharm Res.2012,29(3):643-650.
[27] Wang JS, Wang FB, Zhang QG, et al. Enhanced expression of Rab27A gene bybreast cancer cells promoting invasiveness and the metastasis potential bysecretion of insulin-like growth factor-II[J]. Mol Cancer Res.2008,6(3):372-382.
[28] Shibata D, Mori Y, Cai K, et al. RAB32hypermethylation and microsatelliteinstability in gastric and endometrial adenocarcinomas[J]. Int J Cancer.2006,119(4):801-806.
[29] Behjati R, Kawai K, Inadome Y, et al. APAF-1is related to an undifferentiatedstate in the testicular germ cell tumor pathway[J]. Cancer Sci.2011,102(1):267-274.
[30] Chêne L, Giroud C, Desgrandchamps F, et al. Extensive analysis of the7q31region in human prostate tumors supports TES as the best candidate tumorsuppressor gene[J]. Int J Cancer.2004,111(5):798-804.
[31] da Costa Prando E, Cavalli LR, Rainho CA. Evidence of epigenetic regulation ofthe tumor suppressor gene cluster flanking RASSF1in breast cancer cell lines[J].Epigenetics.2011,6(12):1413-1424.
[32] Cong XL, Li B, Yang RC, et al. Enhanced growth suppression of Philadephia1leukemia cells by targeting bcr3/abl2and VEGF through antisense strategy[J].Leukemia.2005,19(9):1517-1524.
[33] Sonvilla G, Allerstorfer S, St ttner S, et al. FGF18in colorectal tumour cells:autocrine and paracrine effects[J]. Carcinogenesis.2008,29(1):15-24.
[34] Delfortrie S, Pinte S, Mattot V, et al. Egfl7promotes tumor escape fromimmunity by repressing endothelial cell activation[J]. Cancer Res.2011,71(23):7176-7186.
[35] Schenone S, Brullo C, Musumeci F, et al. Fyn kinase in brain diseases and cancer:the search for inhibitors[J]. Curr Med Chem.2011,18(19):2921-2942.
[36] Jacobs JF, van Bokhoven H, van Leeuwen FN, et al. Regulation of MYCNexpression in human neuroblastoma cells[J]. BMC Cancer.2009,9:239.
[37] Lankat-Buttgereit B, Fehmann HC, Hering BJ, et al. Expression of the ras-relatedrab3a gene in human insulinomas and normal human pancreatic islets[J].Pancreas.1994,9(4):434-438.
[38] Jang KW, Lee KH, Kim SH, et al. Ubiquitin ligase CHIP induces TRAF2proteasomal degradation and NF-κB inactivation to regulate breast cancer cellinvasion[J]. J Cell Biochem.2011,112(12):3612-3620.
[39] Kawaguchi-Ihara N, Murohashi I, Nara N, et al. Promotion of the self-renewalcapacity of human acute leukemia cells by Wnt3A[J]. Anticancer Res.2008,28(5A):2701-2704.
[40] Du YY, Dai DQ, Yang Z. Role of RECK methylation in gastric cancer and itsclinical significance[J]. World J Gastroenterol.2010,16(7):904-908.
[41] Rojas A, Meherem S, Kim Y H, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[42] Stefanska B, Huang J, Bhattacharyya B, et al. Definition of the landscape ofpromoter DNA hypomethylation in liver cancer[J]. Cancer Res.2011,71(17):5891-5903.
[43] Tan AC, Jimeno A, Lin SH, et al. Characterizing DNA methylation patterns inpancreatic cancer genome[J]. Mol Oncol.2009,3(5-6):425-438.
[44] He Y, Cui Y, Wang W, et al. Hypomethylation of the hsa-miR-191locus causeshigh expression of hsa-mir-191and promotes the epithelial-to-mesenchymaltransition in hepatocellular carcinoma[J]. Neoplasia.2011,13(9):841-853.
[45] Radhakrishnan VM, Jensen TJ, Cui H, et al. Hypomethylation of the14-3-3σpromoter leads to increased expression in non-small cell lung cancer[J]. GenesChromosomes Cancer.2011,50(10):830-836.
[46] Gil-Henn H, Patsialou A, Wang Y, et al. Arg/Abl2promotes invasion andattenuates proliferation of breast cancer in vivo[J]. Oncogene.2012, doi:10.1038/onc.2012.284.[Epub ahead of print]
[47] Peng C, Zhu F, Wen W, et al. Tumor necrosis factor receptor-associated factorfamily protein2is a key mediator of the epidermal growth factor-inducedribosomal S6kinase2/cAMP-responsive element-binding protein/Fos proteinsignaling pathway[J]. J Biol Chem.2012,287(31):25881-25892.
[1] Esteller M. Epigenetics in cancer[J]. N Engl J Med.2008,358(11):1148-1159.
[2]何苗,王子卫.肿瘤中DNA甲基化和小RNA的关联研究现状[J].医学综述.2011,17(15):2296-2299.
[3] Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structuralperspective[J]. Structure.2008,16(3):341-350.
[4] Chim SS, Jin S, Lee TY, et al. Systematic search for placental DNA-methylationmarkers on chromosome21:toward a maternal plasma-based epigenetic test forfetal trisomy21[J]. Clin chem.2008,54(3):500-511.
[5] Tong JD, Jiao NL, Wang YX, et al. Downregulation of fibulin-3gene by promotermethylation in colorectal cancer predicts adverse prognosis[J]. Neoplasma.2011,58(5):441-448.
[6] Yoshioka M, Kikuta H, Ishiguro N, et al. Unique Epstein-Barr virus(EBV) latentgene expression, EBNA promoter usage and EBNA promoter methylation statusin chronic active EBV infection[J]. J Gen Virol.2003,84(Pt5):1133-1140.
[7] Hong SJ, Oh JH, Jung YC, et al. DNA methylation patterns of ulcer-healing genesassociated with the normal gastric mucosa of gastric cancers[J]. J Korean Med Sci.2010,25(3):405-417.
[8] Simmen MW. Genome-scale relationships between cytosine methylation anddinucleotide abundances in animals[J]. Genomics.2008,92(1):33-40.
[9] Schuebel KE, Chen W, Cope L, et al. Comparing the DNA hypermethylome withgene mutations in human colorectal cancer[J]. PLoS Genet.2007,3(9):1709-1723.
[10] Goll MG, Kirpekar F, Maggert KA, et al. Methylation of tRNAAsp by the DNAmethyltransferase homolog Dnmt2[J]. Science.2006,311(5759):395-398.
[11] Fu HY, Shen JZ, Wu Y, et al. Arsenic trioxide inhibits DNA methyltransferaseand restores expression of methylation-silenced CDKN2B/CDKN2A genes inhuman hematologic malignant cells[J]. Oncol Rep.2010,24(2):335-343.
[12] Linhart HG, Troen A, Bell GW, et al. Folate deficiency induces genomic uracilmisincorporation and hypomethylation but does not increase DNA pointmutations[J]. Gastroenterology.2009,136(1):227-235.
[13] Wen XZ, Akiyama Y, Pan KF, et al. Methylation of GATA-4and GATA-5anddevelopment of sporadic gastric carcinomas[J]. World J Gastroenterol.2010,16(10):1201-1208.
[14] Perri F, Cotugno R, Piepoli A, et al. Aberrant DNA methylation innon-neoplastic gastric mucosa of H. pylori infected patients and effect oferadication[J]. Am J Gastroenterol.2007,102(7):1361-1371.
[15] Ferrasi AC, Pinheiro NA, Rabenhorst SH, et al. Helicobacter pylori and EBV ingastric carcinomas: Methylation status and microsatellite instability[J]. World JGastroenterol.2010,16(3):312-319.
[16]郑长青,季守平,章扬培. MGMT基因甲基化在肿瘤发生及个体性化疗中的意义[J].医学分子生物学杂志.2008,5(4):373-376.
[17] Erdamar S, Ucaryilmaz E, Dogusoy G. Importance of MutL homologue MLH1and MutS homologue MSH2expression in Turkish patients with sporadiccolorectal cancer[J]. World J Gastroenterol.2007,13(33):4437-4444.
[18] Csepregi A, Ebert MP, Rocken C, et al. Promoter methylation of CDKN2A andlack of p16expression characterize patients with hepatocellular carcinoma[J].BMC Cancer.2010,10:317.
[19] Rojas A, Meherem S, Kim YH, et al. The aberrant methylation of TSP1suppresses TGF-beta1activation in colorectal cancer[J]. Int J Cancer.2008,123(1):14-21.
[20] Issa JP. DNA Methylation as a therapeutic target in cancer[J]. Clin Cancer Res.2007,13(6):1634-1637.
[21] Liu R, Gong M, Li X, et al. Induction, regulation, and biologic function of Axlreceptor tyrosine kinase in Kaposi sarcoma[J]. Blood.2010,116(2):297-305.
[22] Suzuki H, Yamamoto E, Nojima M, et al. Methylation-associated silencing ofmicroRNA-34b/c in gastric cancer and its involvement in an epigenetic fielddefect[J]. Carcinogenesis.2010,31(12):2066-2073.
[23] Sunami E, Vu AT, Nguyen SL, et al. Analysis of methylated circulating DNA incancer patients' blood[J]. Methods Mol Biol.2009,507:349-356.
[24] Svrcek M, Buhard O, Colas C, et al. Methylation tolerance due to anO6-methylguanine DNA methyltransferase (MGMT) field defect in the colonicmucosa: an initiating step in the development of mismatch repair-deficientcolorectal cancers[J]. Gut.2010,59(11):1516-1526.
[25] Wakabayashi T, Natsume A, Hatano H, et al. p16promoter methylation in theserum as a basis for the molecular diagnosis of gliomas[J]. Neurosurgery.2009,64(3):455-462.
[26] Kamiyama H, Noda H, Takata O, et al. Promoter hypermethylation oftumor-related genes in peritoneal lavage and the prognosis of patients withcolorectal cancer[J]. J Surg Oncol.2009,100(1):69-74.
[27] Nagasaka T, Tanaka N, Cullings HM, et al. Analysis of fecal DNA methylation todetect gastrointestinal neoplasia[J]. J Natl Cancer Inst.2009,101(18):1244-1258.
[28] Kim JH, Choi YD, Lee JS, et al. Assessment of DNA methylation for thedetection of cervical neoplasia in liquid-based cytology specimens[J]. GynecolOncol.2010,116(1):99-104.
[29] Hibi K, Goto T, Kitamura YH, et al. Methylation of the TFPI2gene is frequentlydetected in advanced gastric carcinoma[J]. Anticancer Res.2010,30(10):4131-4133.
[30] Hildebrandt MA, Gu J, Lin J, et al. Hsa-miR-9methylation status is associatedwith cancer development and metastatic recurrence in patients with clear cellrenal cell carcinoma[J]. Oncogene.2010,29(42):5724-5728.
[31] Formeister EJ, Tsuchiya M, Fujii H, et al. Comparative analysis of promotermethylation and gene expression endpoints between tumorous and non-tumoroustissues from HCV-positive patients with hepatocellular carcinoma[J]. Mutat Res.2010,692(1-2):26-33.
[32] Park SY, Kook MC, Kim YW, et al. CpG island hypermethylator phenotype ingastric carcinoma and its clinicopathological features[J]. Virchows Arch.2010,457(4):415-422.
[33] Wang H, Zhao Y, Li L, et al. An ATM-and Rad3-related (ATR) signalingpathway and aphosphorylation-acetylation cascade are involved in activation ofp53/p21Waf1/Cip1in response to5-aza-2'-deoxycytidine treatment[J]. J BiolChem.2008,283(5):2564-2574.
[34] Jung Y, Park J, Kim TY, et al. Potential advantages of DNA methyltransferase1(DNMT1)-targeted inhibition for cancer therapy[J]. J Mol Med.2007,85(10):1137-1148.