新疆哈萨克族食管癌早期相关基因甲基化分析及功能研究
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摘要
目的： DNA甲基化是肿瘤发生的早期分子事件，CpG岛局部甲基化异常早于细胞的恶性增生，因此基因启动子区高甲基化或低甲基化是肿瘤发生早期的一个高度灵敏的肿瘤生物标志物，可通过检测肿瘤相关基因的甲基化状态，为肿瘤的早期诊断、疗效观察及预后判断提供极为重要的信息。新疆哈萨克族食管癌是我区的特高发疾病，基于目前尚无系统的，在肿瘤发生前即可操作的早期预警体系，本课题拟从研究消化道肿瘤早期相关的原癌基因survivin，cdc42与抑癌基因p16，FHIT在哈萨克族食管癌组织中的mRNA差异表达入手，探讨其启动子区CpG岛甲基化状态与基因表达的关系，在此基础上进一步研究基因启动子区甲基化状态的改变对基因表达的调控及对细胞生物学功能的影响，为新疆哈萨克族食管癌早期预警指标体系的建立，早期诊断，治疗和预后提供理论依据。方法：1）哈萨克族食管癌组织中survivin、cdc42、p16和FHIT基因mRNA水平的表达检测：采集新疆哈萨克族食管癌组织及远端无癌组织标本48对，Trizol法提取总RNA，应用半定量RT-PCR技术检测4个消化道肿瘤早期相关基因在食管癌组织及远端无癌组织中的表达；2）哈萨克族食管癌中survivin、cdc42、p16和FHIT基因启动子区CpG岛的甲基化检测：应用Methprimer软件查找survivin、cdc42、p16和FHIT基因启动子区第一个CpG岛，并设计甲基化引物及非甲基化引物，用亚硫酸氢钠修饰基因组DNA之后运用甲基化特异性PCR技术(MSP)检测survivin、cdc42甲基化状态；利用高分辨率熔解曲线技术（HRM）检测p16和FHIT基因启动子区CpG岛甲基化程度，进而探究甲基化状态或程度差异与基因表达的关系；3）survivin及cdc42启动子区CpG岛重组载体的构建及甲基化状态对报告基因CAT活性的影响：重组体的构建：PCR扩增包含survivin、cdc42基因启动子区第一个CpG岛的DNA片段，及任意一段不含CpG岛的random序列，酶切后分组，一组体外甲基化酶修饰，另一组不修饰，分别与酶切的pCAT3-Enhancer载体相连，构建CpG island-pCAT3-Enhancer重组载体，将未甲基化修饰的重组体及pCAT3-Enhancer空载体转化至甲基化酶缺陷的大肠杆菌ER1793（Mcr-、Mrr-）中，将甲基化修饰的重组载体及pCAT3-Enhancer空载体转化至可持续甲基化状态的大肠杆菌JM109中。挑选阳性克隆，测序并检测甲基化程度；重组载体转染至食管癌细胞株Eca109中：将8种载体转染至食管癌细胞株Eca109中，37℃孵育48小时；报告基因氯霉素乙酰基转移酶（CAT）活性的检测：收获细胞，提取CAT基因表达产物，加C~(14)标记的氯霉素后，用薄层层析法测定CAT活性，以此分析survivin，cdc42启动子区CpG岛甲基化对下游CAT活性调控能力的影响，确定基因启动子区甲基化差异对基因表达的影响。结果：1）在48对食管癌组织标本中，癌组织中survivin，cdc42，p16，FHIT阳性表达率分别为87.50%，97.92%，75.00，83.33%，远端无癌组织中阳性表达率分别为58.33%，100.00%，77.08%，85.42%。癌组织与远端无癌组织比较，survivin阳性表达率明显增高，差异有统计学意义（P＜0.05）。cdc42，p16，FHIT阳性表达率癌组织与远端无癌组织之间差异无统计学意义（P＞0.05）。survivin mRNA表达水平癌组织明显高于远端无癌组织，差异有统计学意义（P＜0.05）。cdc42，p16，FHIT mRNA表达水平癌组织与远端无癌组织差异无统计学意义（P＞0.05）；2）在48例食管癌癌组织中，survivin mRNA的表达与淋巴结转移、临床分期、肿瘤侵犯深度具有相关性（r=0.379、0.488、0.393；P=0.017、0.002、0.019），与分化程度无相关性（P＞0.05）。cdc42mRNA表达与临床分期，肿瘤分化程度具有相关性（r=0.452，r=0.325；P=0.003P=0.034），与淋巴结转移及侵润程度之间均无相关性（P＞0.05）。p16mRNA表达与临床分期、分化程度、淋巴结转移及侵润程度之间均无相关性（P＞0.05）。FHITmRNA表达与肿瘤临床分期具有相关性（r=0.338，P=0.035），而与分化程度、淋巴结转移及侵润程度之间均无相关性（P＞0.05）。3）在20对食管癌标本中，癌组织中70%的survivin基因启动子区CpG岛为杂合型甲基化，远端无癌组织中75%的survivin基因启动子区CpG岛为杂合型甲基化，组织间杂合型甲基化状态无明显差异（P＞0.05）。癌组织中有4例甲基化，其对应的mRNA表达水平均大于远端无癌组织；远端无癌组织中有4例甲基化，其对应的mRNA均未表达；4）在20对食管癌标本中，癌组织中有90%c的dc42启动子区CpG岛呈现出甲基化状态，远端无癌组织中有80%呈现为甲基化状态，组织间甲基化状态无明显差异（P＞0.05）。且cdc42启动子区CpG岛甲基化状态与mRNA水平的表达无相关性；5）在20对食管癌标本中，癌组织及远端无癌组织中p16启动子区CpG岛甲基化例数均为20例，甲基化比例100%。p16启动子区CpG岛甲基化水平在癌组织及远端无癌组织无明显差异（P＞0.05）。p16启动子区CpG岛甲基化水平与食管癌组织TNM分期具相关性（r=0.511，P=0.030），与组织分化，侵润程度，淋巴结转移均无相关性（P＞0.05）。与其mRNA高阳性表达相比，甲基化与mRNA水平的表达无相关性；6）在20对标本中，FHIT启动子区CpG岛呈现低甲基化比例及水平。癌组织及远端无癌组织甲基化比例分别为35.00%和30%。甲基化水平均小于10%，且在癌组织及远端无癌组织无明显差异（P＞0.05），甲基化水平与食管癌组织TNM分期，组织分化，侵润程度，淋巴结转移均无相关性（P＞0.05）。与其mRNA高表达比较，提示低甲基化水平可能未影响基因的表达；7）甲基化及非甲基化的pCAT3-Enhancer载体，转染至食管癌细胞株中，甲基化的载体下游报告基因CAT酶的活性显著低于非甲基化的载体；8）甲基化及非甲基化的Random-pCAT3-Enhancer重组载体，转染至食管癌细胞株中，CAT酶的活性均接近阴性水平；9）甲基化及非甲基化的survivin启动子区CpG岛-pCAT3-Enhancer重组载体，转染至食管癌细胞株中，CAT酶的活性均接近阴性水平；10）甲基化及非甲基化的cdc42启动子区CpG岛-pCAT3-Enhancer重组载体，转染至食管癌细胞株中，甲基化的重组载体CAT酶的活性显著低于非甲基化的重组载体CAT酶的活性。结论：1）哈萨克族食管癌癌组织中survivin mRNA水平表达的增高在哈萨克族食管癌的发生、发展过程中起到了一定的作用。4例远端无癌组织中survivin启动子区CpG岛甲基化对应了mRNA的沉默表达，提示在正常组织中启动子区CpG岛甲基化具备调控基因表达的能力。在食管癌细胞株中，survivin启动子区CpG岛的甲基化及非甲基化均导致了CAT的失活。提示在癌组织或癌细胞中，启动子区CpG岛的甲基化可能与基因表达无直接关系，在癌变过程中可能有更多的机制调控了该基因的表达。2）哈萨克族食管癌中cdc42基因mRNA在癌组织和远端无癌组织中阳性表达率及表达水平无差异，提示该基因可能不是参与食管癌发生发展的主要机制。其启动子区CpG岛甲基化状态的阳性率在癌组织和远端无癌组织中也无差异，且甲基化状态与该基因mRNA水平的表达无关。在食管癌细胞株中，cdc42启动子区CpG岛的甲基化降低了下游报告基因CAT酶的活性，而非甲基化使酶保持较高活性。提示cdc42启动子区CpG岛甲基化本身具有调控基因表达的能力，而在哈萨克族食管癌中其启动子区CpG岛甲基化与基因表达无直接关系，说明在癌变过程中可能存在更多的调控机制参与了该基因的表达；3）哈萨克族食管癌中p16mRNA在癌组织和远端无癌组织中均为高表达，p16启动子区CpG岛甲基化比例高达100%，提示p16可能未参与哈萨克族食管癌的发生发展，且甲基化可能不是调控该基因表达的主要分子机制。4）哈萨克族食管癌中，FHIT mRNA在癌组织及远端无癌组织中表达无差异，其启动子区CpG岛甲基化比例及程度均较低，提示FHIT可能未参与哈萨克族食管癌的发生发展，同时低甲基化水平可能未影响FHIT基因的表达。
Objective: DNA methylation occurs in the early stage of tumorigenesis, CpGislands aberrant methylation earlier than the malignant cell proliferation, so genepromoter region hypomethylation or hypermethylation is a highly sensitive tumorbiomarker in early stage of tumorigenesis. Detection of tumor-associated genemethylation status can provide extremely important information in the early diagnosis,effect observation and prognosis judgment of the tumor. Kazak Esophageal cancer (EC)is one of the highest prevalence disease in Xinjiang. Based on there are no systematicearly warning indicator before tumorigenesis, the project intends to screen the digestivetract tumors early related genes, research the different expression of oncogenes and tumorsuppressor genes in EC tissue, then explore their promoter CpG island methylation state,and further study the change of promoter methylation affect on gene expression andbiological functions. All these can provide a theoretical basis in the early diagnosis, theearly warning indicators establishment, as well as tumor treatment and prognosis inXinjiang Kazak's EC. Methods:1) Detection of the mRNA expression of survivin, cdc42,p16and FHIT in EC: Collected48pairs specimens in the Kazak EC tissues and distalnon-cancerous tissue, extracted the total RNA by Trizol, used reverse transcription obtaincDNA, amplified by PCR technique, then detected the expression of the four genes in ECcancer tissues and distal non-cancerous tissues;2) Detection of the methylation state ofsurvivin, cdc42, p16and FHIT genes CpG island in promoter region in EC: UsingMethprimer software to got survivin, cdc42, p16and FHIT genes CpG islands inpromoter region, and design the methylated primers and normal primers. Modificated thegenomic DNA by sodium bisulfite, and then used methylation-specific PCR (MSP) todetect the survivin and cdc42methylation status, used high-resolution melting curve(HRM)to detect p16and FHIT gene promoter CpG island methylation level. Based onthese, further explore the relationship of the mRNA expression and the methylation status or level;3) Construction of recombinant vector: Using Primer5design primers, thenamplified survivin, cdc42gene promoter CpG island, and one random sequence withoutCpG islands by PCR, divided these sequeces into two groups, one group are methylatedmodification in vitro, another group are not modified. Then connected these sixfragments with the pCAT3-Enhancer vector, constructed the recombinants which containthe methylated or unmethylated CpG island-pCAT3-Enhancer vector. Then therecombinants which contain methylated CpGisland-pCAT3-Enhancer vector andpCAT3-Enhancer empty vector were transformed into E.coli ER1793(Mcr-, Mrr-, whichdefect methylase), the recombinants which contain unmethylatedCpGisland-pCAT3-Enhancer vector and pCAT3-Enhancer empty vector weretransformed into E.coli JM109which can maintain methylation status. Then selectedpositive recombinants, identificated by PCR and sequencing, and detected themethylation degree of the three CpG islands which in methylated CpG island-pCAT3-Enhancer vector recombinants;4) The eight recombinants were transfected into Eca109:The recombinants were transfected into Eca109cell lines respectively, then cultured at37℃for48hours;5) Detection of Chloramphenicol acetyl enzyme (CAT) activity: the cellswere harvested after48hours, then extracted the CAT gene products by disrupt the cell,after label it with the14C chloramphenicol, determined the CAT activity by thin layerchromatography(TLC), analyzed the CAT enzyme activity, determined the impact of genepromoter CpG island methylation on gene expression. Results:1) In the48pairs of ECtissues, survivin，cdc42，p16，FHIT positive expression ratio are87.50%,97.92%,75.00%,83.33%respectively in cancer tissues, positive expression ratio are58.33%,100.00%,77.08%,85.42%respectively in distal non-cancerous tissues. Survivin mRNA expressionlevel and positive ratio in cancer tissues significantly higher than distal non-canceroustissues, the difference has statistically significant (P＜0.05). The positive expression ratioand mRNA expression levels of cdc42, p16, FHIT have no difference between cancertissues and distal non-cancerous tissues(P＞0.05).2) In the48pairs of EC tissues,survivin mRNA expression has a positive correlation with lymph node metastasis, clinicalstage and tumor invasion(r=0.379,0.488,0.393; P=0.017,0.002,0.019), and has nocorrelation with the degree of differentiation(P＞0.05). Cdc42mRNA expression haspositive correlation with the clinical stage and tumor differentiation(r=0.452, r=0.325；P=0.003, P=0.034), and has no correlation with lymph node metastasis and tumorinvasion degree(P＞0.05). P16mRNA expression has no correlation with the clinicalstage, the degree of differentiation, lymph node metastasis and tumor invasion degree(P ＞0.05). FHIT mRNA expression positive correlated with clinical stage (r=0.338,P=0.035), but has no correlation with the degree of differentiation, lymph nodemetastasis and invasion degree(P＞0.05).3) In20paired cases of EC,70%of survivingene promoter CpG islands are heterozygous methylated in the cancer tissues,75%of thesurvivin gene promoter region CpG islands are heterozygous methylated in distalnon-cancerous tissues, there are no significant difference between the cancerous tissuesand distal non-cancerous tissues in methylation status(P＞0.05). Four cases of highmethylation in cancer tissues, which corresponding to survivin mRNA expression levelswere higher than distal non-cancerous tissues, four cases of high methylation in distalnon-cancerous tissues, which corresponding to negative mRNA expression.4) In20paired cases of EC,90%of cdc42promoter CpG islands show methylation status incancer tissues,80%of the cdc42promoter CpG islands show the methylation status indistal non-cancerous tissues, there were no significant difference in the cancer and distalnon-cancerous tissues methylation status(P＞0.05). Compare to the high expression ofcdc42mRNA, cdc42promoter CpG island methylation status has no relation to cdc42mRNA levels in cancer tissues and distal non-cancerous tissues.5) In20paired cases ofEC,100%p16promoter CpG islands show methylated in cancer tissues and distalnon-cancerous tissues. The methylation level has correlation with clinical stage (P＜0.05),but has no correlation with lymph node metastasis, tumor invasion tissues anddifferentiation level(P＞0.05). Compare to the expression of its mRNA, there were norelation between high methylation level and expression level.6) In20paired cases of EC,35%FHIT promoter CpG islands show methylated in cancer tissues and30%in distalnon-cancerous tissues. The methylation level has no correlation with clinical stage, lymphnode metastasis, tumor invasion tissues and differentiation level(P＞0.05). Compare tothe expression of its mRNA, perhaps there are little effect of low methylation level onexpression level.7) The reporter gene CAT enzyme activity in methylated null vector wassignificantly lower than non-methylated null vector after transfected into EC cell line.8)The CAT activity were both decrease to zero both in methylated and unmethlatedRandom region-pCAT3-Enhancer recombinants after transfected into EC cell line.9)TheCAT activity were both decrease to zero after methylated and unmethylated survivinpromoter region CpG island-pCAT3-Enhancer recombinant transfected into EC cell line.10) The CAT activity in methylated cdc42promoter region CpG island-pCAT3-Enhancerrecombinant was significantly lower than unmethylated recombinants after transfectedinto EC cell line. Conclusion:1) High expression of survivin suggests it was involved in the apoptosis and cell cycle regulation in the occurrence and development of EC.4casesin distal non-cancerous tissues have negative expression corresponding to promotermethylated, which means methylated promoter has the ability of regulation on theexpression. The CAT activity were both decrease to zero after methylated andunmethylated survivin promoter region CpG island-pCAT3-Enhancer recombinanttransfected into EC cell line. All these notes survivin promoter methylation in cancertissue has no relation to the gene expression, which may be involved in other mechanismin EC development.2) Cdc42high expression and high positive ratio both in cancer anddistal non-cancerous tissues tips the expression is not a mechanism in EC development.Cdc42promoter CpG islands are both methylated in cancer and distal non-canceroustissues, which has a clue that cdc42promoter region CpG island methylation has norelation to the high gene expression. Methylated CpG island of cdc42, which in EC cellline Eca109, can reduces the expression of the downstream reporter gene CAT activity,rather than the unmethyled can maintain CAT high activity. This tips cdc42promoterCpG island methylation has the ability to regulate the expression in Eca109. But in KazakEC, its expression was not affected by the promoter region methylation, which suggestedthere are may have more regulatory mechanisms involved in gene expression in thedevelopment of EC.3) P16mRNA in cancer tissues and distal non-cancerous tissues arehighly expressed. P16promoter region CpG island methylation ratio is100%. These notep16expression has no relation to the development of EC.4) FHIT mRNA in cancertissues and distal non-cancerous tissues are highly expressed, this means FHIT are notparticipates in the occurrence of the tumor. The low level and ratio of FHIT promoterCpG island methylation perhaps has no effect on the gene expression.
Objective: DNA methylation occurs in the early stage of tumorigenesis, CpGislands aberrant methylation earlier than the malignant cell proliferation, so genepromoter region hypomethylation or hypermethylation is a highly sensitive tumorbiomarker in early stage of tumorigenesis. Detection of tumor-associated genemethylation status can provide extremely important information in the early diagnosis,effect observation and prognosis judgment of the tumor. Kazak Esophageal cancer (EC)is one of the highest prevalence disease in Xinjiang. Based on there are no systematicearly warning indicator before tumorigenesis, the project intends to screen the digestivetract tumors early related genes, research the different expression of oncogenes and tumorsuppressor genes in EC tissue, then explore their promoter CpG island methylation state,and further study the change of promoter methylation affect on gene expression andbiological functions. All these can provide a theoretical basis in the early diagnosis, theearly warning indicators establishment, as well as tumor treatment and prognosis inXinjiang Kazak's EC. Methods:1) Detection of the mRNA expression of survivin, cdc42,p16and FHIT in EC: Collected48pairs specimens in the Kazak EC tissues and distalnon-cancerous tissue, extracted the total RNA by Trizol, used reverse transcription obtaincDNA, amplified by PCR technique, then detected the expression of the four genes in ECcancer tissues and distal non-cancerous tissues;2) Detection of the methylation state ofsurvivin, cdc42, p16and FHIT genes CpG island in promoter region in EC: UsingMethprimer software to got survivin, cdc42, p16and FHIT genes CpG islands inpromoter region, and design the methylated primers and normal primers. Modificated thegenomic DNA by sodium bisulfite, and then used methylation-specific PCR (MSP) todetect the survivin and cdc42methylation status, used high-resolution melting curve(HRM)to detect p16and FHIT gene promoter CpG island methylation level. Based onthese, further explore the relationship of the mRNA expression and the methylation status or level;3) Construction of recombinant vector: Using Primer5design primers, thenamplified survivin, cdc42gene promoter CpG island, and one random sequence withoutCpG islands by PCR, divided these sequeces into two groups, one group are methylatedmodification in vitro, another group are not modified. Then connected these sixfragments with the pCAT3-Enhancer vector, constructed the recombinants which containthe methylated or unmethylated CpG island-pCAT3-Enhancer vector. Then therecombinants which contain methylated CpGisland-pCAT3-Enhancer vector andpCAT3-Enhancer empty vector were transformed into E.coli ER1793(Mcr-, Mrr-, whichdefect methylase), the recombinants which contain unmethylatedCpGisland-pCAT3-Enhancer vector and pCAT3-Enhancer empty vector weretransformed into E.coli JM109which can maintain methylation status. Then selectedpositive recombinants, identificated by PCR and sequencing, and detected themethylation degree of the three CpG islands which in methylated CpG island-pCAT3-Enhancer vector recombinants;4) The eight recombinants were transfected into Eca109:The recombinants were transfected into Eca109cell lines respectively, then cultured at37℃for48hours;5) Detection of Chloramphenicol acetyl enzyme (CAT) activity: the cellswere harvested after48hours, then extracted the CAT gene products by disrupt the cell,after label it with the14C chloramphenicol, determined the CAT activity by thin layerchromatography(TLC), analyzed the CAT enzyme activity, determined the impact of genepromoter CpG island methylation on gene expression. Results:1) In the48pairs of ECtissues, survivin，cdc42，p16，FHIT positive expression ratio are87.50%,97.92%,75.00%,83.33%respectively in cancer tissues, positive expression ratio are58.33%,100.00%,77.08%,85.42%respectively in distal non-cancerous tissues. Survivin mRNA expressionlevel and positive ratio in cancer tissues significantly higher than distal non-canceroustissues, the difference has statistically significant (P＜0.05). The positive expression ratioand mRNA expression levels of cdc42, p16, FHIT have no difference between cancertissues and distal non-cancerous tissues(P＞0.05).2) In the48pairs of EC tissues,survivin mRNA expression has a positive correlation with lymph node metastasis, clinicalstage and tumor invasion(r=0.379,0.488,0.393; P=0.017,0.002,0.019), and has nocorrelation with the degree of differentiation(P＞0.05). Cdc42mRNA expression haspositive correlation with the clinical stage and tumor differentiation(r=0.452, r=0.325；P=0.003, P=0.034), and has no correlation with lymph node metastasis and tumorinvasion degree(P＞0.05). P16mRNA expression has no correlation with the clinicalstage, the degree of differentiation, lymph node metastasis and tumor invasion degree(P ＞0.05). FHIT mRNA expression positive correlated with clinical stage (r=0.338,P=0.035), but has no correlation with the degree of differentiation, lymph nodemetastasis and invasion degree(P＞0.05).3) In20paired cases of EC,70%of survivingene promoter CpG islands are heterozygous methylated in the cancer tissues,75%of thesurvivin gene promoter region CpG islands are heterozygous methylated in distalnon-cancerous tissues, there are no significant difference between the cancerous tissuesand distal non-cancerous tissues in methylation status(P＞0.05). Four cases of highmethylation in cancer tissues, which corresponding to survivin mRNA expression levelswere higher than distal non-cancerous tissues, four cases of high methylation in distalnon-cancerous tissues, which corresponding to negative mRNA expression.4) In20paired cases of EC,90%of cdc42promoter CpG islands show methylation status incancer tissues,80%of the cdc42promoter CpG islands show the methylation status indistal non-cancerous tissues, there were no significant difference in the cancer and distalnon-cancerous tissues methylation status(P＞0.05). Compare to the high expression ofcdc42mRNA, cdc42promoter CpG island methylation status has no relation to cdc42mRNA levels in cancer tissues and distal non-cancerous tissues.5) In20paired cases ofEC,100%p16promoter CpG islands show methylated in cancer tissues and distalnon-cancerous tissues. The methylation level has correlation with clinical stage (P＜0.05),but has no correlation with lymph node metastasis, tumor invasion tissues anddifferentiation level(P＞0.05). Compare to the expression of its mRNA, there were norelation between high methylation level and expression level.6) In20paired cases of EC,35%FHIT promoter CpG islands show methylated in cancer tissues and30%in distalnon-cancerous tissues. The methylation level has no correlation with clinical stage, lymphnode metastasis, tumor invasion tissues and differentiation level(P＞0.05). Compare tothe expression of its mRNA, perhaps there are little effect of low methylation level onexpression level.7) The reporter gene CAT enzyme activity in methylated null vector wassignificantly lower than non-methylated null vector after transfected into EC cell line.8)The CAT activity were both decrease to zero both in methylated and unmethlatedRandom region-pCAT3-Enhancer recombinants after transfected into EC cell line.9)TheCAT activity were both decrease to zero after methylated and unmethylated survivinpromoter region CpG island-pCAT3-Enhancer recombinant transfected into EC cell line.10) The CAT activity in methylated cdc42promoter region CpG island-pCAT3-Enhancerrecombinant was significantly lower than unmethylated recombinants after transfectedinto EC cell line. Conclusion:1) High expression of survivin suggests it was involved in the apoptosis and cell cycle regulation in the occurrence and development of EC.4casesin distal non-cancerous tissues have negative expression corresponding to promotermethylated, which means methylated promoter has the ability of regulation on theexpression. The CAT activity were both decrease to zero after methylated andunmethylated survivin promoter region CpG island-pCAT3-Enhancer recombinanttransfected into EC cell line. All these notes survivin promoter methylation in cancertissue has no relation to the gene expression, which may be involved in other mechanismin EC development.2) Cdc42high expression and high positive ratio both in cancer anddistal non-cancerous tissues tips the expression is not a mechanism in EC development.Cdc42promoter CpG islands are both methylated in cancer and distal non-canceroustissues, which has a clue that cdc42promoter region CpG island methylation has norelation to the high gene expression. Methylated CpG island of cdc42, which in EC cellline Eca109, can reduces the expression of the downstream reporter gene CAT activity,rather than the unmethyled can maintain CAT high activity. This tips cdc42promoterCpG island methylation has the ability to regulate the expression in Eca109. But in KazakEC, its expression was not affected by the promoter region methylation, which suggestedthere are may have more regulatory mechanisms involved in gene expression in thedevelopment of EC.3) P16mRNA in cancer tissues and distal non-cancerous tissues arehighly expressed. P16promoter region CpG island methylation ratio is100%. These notep16expression has no relation to the development of EC.4) FHIT mRNA in cancertissues and distal non-cancerous tissues are highly expressed, this means FHIT are notparticipates in the occurrence of the tumor. The low level and ratio of FHIT promoterCpG island methylation perhaps has no effect on the gene expression.
引文
[1] Li JY. Epidemiology of esophageal cancer in China[J]. Natl Cancer Inst Monogr,1982,62:113-120.
[2] Munoz N. Epidemiological aspects of oesophageal cancer[J]. Endoscopy,1993,25:609-612.
[3] Pisani P, Parkin DM, Ferlay J. Estimate of the worldwide mortality from eighteenmajor cancers in1985:implications for prevention and projection of futureburden[J]. Int J Cancer,1993,55:891-903.
[4] Bai SX.原发性食管腺癌-附19例报告[J].中华肿瘤杂志,1989,11(5):383-385.
[5] Sales, Levin. DeMeester TR, Levin B. Cancer of the esophagus[M]. Grune andStratun,1985:8~17.
[6] Sandoval J, Esteller M. Cancer epigenomics: beyond genomics[J]. Curr Opin GenetDev,2012,22(1):50-55.
[7] Wu CT, Morris JR. Genes, genetics and epigenetics:a correspondence[J]. Science,2001,293(5532):1103-1105.
[8]王树人.基因的表达与Epigenetics[J].四川生理科学杂志,2006,28(1):29-33.
[9] Jaenisch R, Bird A. Epigenetic regulation of gene expression:how the genomeintegrates intrinsic and environmental signals[J]. Not Rev Genet,2003,33(3):245-254.
[10]黄庆,郭颖,府伟灵.人类表观基因组计划[J].生命的化学,2004,24(2):101-102.
[11] Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joinsgenetics[J]. Trends Genet,2000,16(4):168-174.
[12] Bird AP. CpG-rich islands and the function of DNA methylation[J]. Nature,1986,321(6067):209-213.
[13] Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer[J]. NatRev Genet,2002,3(6):415-428.
[14] Robertson KD. DNA methylation and human disease[J]. Nat Rev Genet,2005,6(8):597-610.
[15] Narayan A, Ji W, Zhang XY, et al. Hypomethylation of pericent romeric DNA inbreast adenocarcinomas[J]. Int J Cancer,1998,77(6):833-838.
[16] Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human disease[J].Biochim Bio phys Acta,2007,1775(01):138-162.
[17] Wajed SA, Laird PW, DeMeester T R. DNA methylation:An alternative pathway toCancer[J]. Ann Surg,2001,234(1):10-20.
[18] Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of16, MGMT, and hMLH1genes in combination with MTHFRC677T genetic polymorphism in esophagealsquamous cell carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[19] Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[20] Jones PA, Baylin SB. The fundamental role of epigenetic events in carcer[J]. NatRev Genet,2002,3(6):415-428.
[21] Shin CM, Kim N, Park JH, et al. Prediction of the risk for gastric cancer usingcandidate methylation markers in the non-neoplastic gastric mucosa[J]. J Pathol,2012,226(4):654-665.
[22] Sameer AS, Abdullah S, Nissar S, et al. The blues of P(16)INK(4a):Aberrantpromoter methylation and association with colorectal cancer in the Kashmirvalley[J]. Mol Med Report,2012,5(4):1053-1057.
[23] Johanning GL, Heimburger DC, Piyathilake CJ. DNA methylation and diet incancer[J]. J Nutr,2002,132(12):3814S-3818S.
[24]姚群峰.基因启动子异常甲基化及其作为肿瘤生物标志物的研究进展[J].国外医学分子生物学分册,2003,25(3):162-165.
[25]陆嵘,房静远.人消化道肿瘤的表观遗传学研究[J].自然科学进展,2007,17(5):568-572.
[26] Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: whyXIAP is the black sheep of the family[J]. EMBO Rep,2006,7(10):988-994.
[27] Dohi T, Beltrami E, Wall NR, et al. Mitochondrial survivin inhibits apoptosis andpromotes tumorigenesis[J]. J Clin Invest,2004,114(8):1117-1127.
[28]朱红霞,王益华,周翠琦,等.抗凋亡基因survivin在食管癌中的表达及其意义[J].中华肿瘤杂志,2005,27(1):22-24.
[29] Johnson DI. Cdc42: An essential Rho-type GTPase controlling eukaryotic cellpolarity[J]. Microbiol Mol Biol Rev,1999,63(1):54-105.
[30] Cerione RA. Cdc42: new roads to travel[J]. Trends Cell Biol,2004,14(3):127-132.
[31] Chen QY, Jiao DM, Yao QH, et al. Expression analysis of Cdc42in lung cancer andmodulation of its expression by curcumin in lung cancer cell lines[J]. Int J Oncol,2012,40(5):1561-1568.
[32] Yao R, Wang Y, Lubet RA,et al. Differentially Expressed Genes Associated withMouse Lung Tumor Progression[J]. Oncogene,2002,21(37):5814-5821.
[33] Serrano M, Hannon GJ. Beach D. A new regulatory motif in cell cycle controlcausing specific inhibition of cyclinD/CDK4[J]. Nature,1993,366(6456):704-707.
[34] Kamb A, Gruis NA, Weave FJ, et al. A cell cycle regulator potentially involved ingenesis of many tumor types[J]. Science,1994,264((5157):436-440.
[35] Caldas C, Halm SA, Costa D, et al. Frequent somatic mutation and homozygousdeletions of the MTSI gene in pancreatic adenocarcinoma[J]. Nature Geret,1994,8(1):27-32.
[36] Okamoto A, Demetrick DJ, Spillare EA. Mutations and altered expression ofp16INK4in human cancer[J]. Proc Natl Acad Sci USA,1994,91(23):11045-11049.
[37] Lukas J, Parry D, Aagaard L, et al. Retinoblastoma-protein dependent cell-cycleinhibition by the tumour suppressor p16[J]. Nature,1995,75(6531):503-506.
[38] Chen YW, Kao SY, Yang MH. Analysis of p16(INK4A)expression of oral squamouscell carcinomas in Taiwan:Prognostic correlation without relevance to betel quidconsumption[J]. J Surg Oncol,2012,21. doi:10.1002/jso.23067.
[39] Ohta M, Inoue H, Cotticelli MG, et a1. The FHIT gene, spanning the chromosome3P14.2fragile site and renal carcinoma-associated t(3;8)breakpoint is abnormal indigestive tract cancers[J]. Cell,1996,84(4):587-597.
[40] Barnes LD, Garrison PN, Siprashvili Z, et a1. Fhit, a putative tumor suppressor inhumans is a dinucleoside5',5"'-P1, P3-triphosphate hydrolase[J]. Biochemistry,1996,35(36):11529-11535.
[41] Huebner K, Garrison PN, Barnes LD, et al. The role of the FHIT/FRA3B locus incancer[J]. Annu Rev Genet,1998,32:7-31.
[42] Siprashvili Z, Sozzi G, Barnes LD, et al. Replacement of Fhit in cancer cellssuppresses tumorigenicity[J]. Proc Natl Acad Sci USA,1997,94(25):13771-13776.
[43] Chaudhuri AR, Khan IA, Prasad V, et al. The tumor suppressor protein Fhit, A novelinteraction with tubulin[J]. Biol Chem,1999,274(34):24378-24382.
[44] Chava S, Mohan V, Shetty PJ, et al. Immunohistochemical evaluation of p53, FHIT,and IGF2gene expression in esophageal cancer[J]. Dis Esophagus,2012,25(1):81-87.
[45] Keeney S, Bauer TL. Epidemiology of adenocarcinoma of the esophagogastricjunction[J]. Surg Oncol Clin N Am,2006,15(4):687-96.
[46]张月明.新疆哈萨克族食管癌的分布[J].新疆医学院学报,1988,11(2):139-145.
[47] Whelan SL. Cancer Incidence in Five Continents. Coding practices[J]. IARC SciPubl,1992,(120):31-38.
[48] Mu oz N. Epidemiological aspects of oesophageal cancer[J]. Endoscopy,1993,25(9):609-612.
[49]居来提·艾尼瓦尔,李德生,张力为,等.新疆2005~2008年伊犁地区食管癌患病情况调查研究[J].新疆医学,2011,41:112-114.
[50] Yang D, Welm A, Bishop JM. Cell division and cell survival in the absence ofsurvivin[J]. Proc Natl Acad Sci USA,2004,101(42):15100-15105.
[51] Li S, Tian D, Fei P, et al. A cyclooxygase-2inhibitor NS-398-enhanced apoptosis ofesophageal carcinoma cell EC9706by adjusting expression of survivin andcaspase-3[J]. Cancer Invest,2011,29(2):102-106.
[52] Kato J, Kuwabara Y, Mitani M, et al. Expression of Survivin in esophagealcancer:correlation with the prognosis and response to chemotherapy[J]. Int J Cancer,2001,95(2):92-95.
[53] Grabowski P, Kuhnel T, Muhr W, et al. Prognostic value of nuclear survivinexpression in oesophageal squamous cell carcinoma[J]. Br J Cancer,2003,88(1):115.
[54] Ikeguchi M, Yamaguchi K, Kaibara N. Survivin gene expression positivelycorrelates with proliferative activity of cancer cells in esophageal cancer[J]. TumourBiol,2003,24(1):40-45.
[55]钱志英,何流.荧光定量PCR法检测食管癌中survivin基因的临床研究[J].肿瘤研究与临床,2005,17(2):86-88.
[56] Grimminger P, Vallb hmer D, Hoffmann A, et al. Quantitative analysis of survivinRNA expression in blood as a non-invasive predictor of response to neoadjuvantradiochemotherapy in esophageal cancer[J]. J Surg Oncol,2009,100(6):447-451.
[57] Cao M, Yie SM, Wu SM, et al. Detection of survivin-expressing circulating cancercells in the peripheral blood of patients with esophageal squamous cell carcinomaand its clinical significance[J]. Clin Exp Metastasis,2009,26(7):751-758.
[58] Hsu KF, Lin CK, Yu CP, et al. Cortactin, fascin, and survivin expression associatedwith clinicopathological parameters in esophageal squamous cell carcinoma[J]. DisEsophagus,2009,22(5):402-408.
[59] Hoffmann AC, Vallb hmer D, Grimminger P, et al. Preoperative survivin mRNAdetection in peripheral blood is an independent predictor of outcome in esophagealcarcinoma[J]. Pharmacogenomics,2010,11(3):341-347.
[60] Takeno S, Yamashita S, Takahashi Y, et al. Survivin expression in oesophagealsquamous cell carcinoma:its prognostic impact and splice variant expression[J]. EurJ Cardiothorac Surg,2010,37(2):440-445.
[61] Zhu H, Wang Q, Hu C, et al. High expression of survivin predicts poor prognosis inesophageal squamous cell carcinoma following radiotherapy[J]. Tumour Biol,2011,32(6):1147-1153.
[62]王会恩,张霄鹏,王志康.食管鳞状细胞癌中Survivin的表达[J].河北医药,2011,33(22):3413-3414.
[63]杜媛鲲,王雷,李月牛,等.食管鳞癌组织VCAM-1和Survivin的表达及意义[J].山东医药,2008,48(16):1-2.
[64]张砚,陈卫刚,郑勇.哈萨克族食管鳞癌组织中CyclinD1survivin的表达[J].山东医药,2011,51(16):22-24.
[65]李卉,卢晓梅,赵学信,等. Survivin CyclinD1基因在哈萨克族食管癌中表达及其意义的研究[J].新疆医科大学学报,2007,30(6):560-562.
[66] Adams AE, Johnson DI, Longnecker RM, et al. CDC42and CDC43, two additionalgenes involved in budding and the establishment of cell polarity in the yeastSaccharomyces cerevisiae[J]. J Cell Biol,1990,111(1):131-142.
[67] Sinha S, Yang W. Cellular signaling for activation of Rho GTPase Cdc42[J].2008,20(11):1927-1934.
[68] Peterson FC, Penkert RR, Volkman BF, et al. Cdc42regulates the Par-6PDZ domainthrough an allosteric CRIB-PDZ transition[J]. Mol Cell,2004,13(5):665-676.
[69] Tcherkezian J, Lamarche-Vane N. Current knowledge of the large RhoGAP familyof proteins[J]. Biol Cell,2007,99(2):67-86.
[70] Olofsson B. Rho guanine dissociation inhibitors: pivotal molecules in cellularsignalling[J]. Cell Signal,1999,11(8):545-554.
[71] Moon SY, Zheng Y. Rho GTPase-activating proteins in cell regulation[J].Trends CellBiol,2003,13(1):13-22.
[72] Stengel K, Zheng Y. Cdc42in oncogenic transformation, invasion, andtumorigenesis[J]. Cell Signal,2011,23(9):1415-23.
[73]江隆昌,张勇,屈新才.细胞分裂周期蛋白42高表达在雌激素诱导的乳腺细胞耐药性增强过程中的作用[J].中华肿瘤杂志,2011,33(7):489-493.
[74] Melendez J, Grogg M, Zheng Y. Signaling role of Cdc42in regulating mammalianphysiology[J]. J Biol Chem,2011,286(4):2375-2381.
[75] Zhang JY, Zhang D, Wang EH. Overexpression of small GTPases directly correlateswith expression of δ-catenin and their coexpression predicts a poor clinical outcomein nonsmall cell lung cancer[J]. Mol Carcinog,2011,2:27.doi:10.1002/mc.21854.
[76] Chen QY, Jiao DM, Yao QH, et al. Expression analysis of Cdc42in lung cancer andmodulation of its expression by curcumin in lung cancer cell lines[J]. Int J Oncol,2012,40(5):1561-1568.
[77] Yeh YM, Pan YT, Wang TC. Cdc42/Rac1participates in the control of telomeraseactivity in human nasopharyngeal cancer cells[J]. Cancer Lett,2005,218(2):207-213.
[78] Oliver AW, He X, Borthwick K, et al. The HPV16E6binding protein Tip-1interactswith ARHGEF16, which activates Cdc42[J]. Br J Cancer,2011,104(2):324-331.
[79] Marques CA, H hnel PS, W lfel C, et al. An immune escape screen reveals Cdc42as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression[J].Blood,2008,111(3):1413-1419.
[80] Adithi M, Venkatesan N, Kandalam M. Expressions of Rac1, Tiam1and Cdc42inretinoblastoma[J]. Exp Eye Res,2006,83(6):1446-1452.
[81] Kamai T, Yamanishi T, Shirataki H, et al. Overexpression of RhoA, Rac1, and Cdc42GTPases is associated with progression in testiular cancer[J]. Clin Cancer Res,2004,10(14):4799-4805.
[82] Zuo Y, Wu Y, Chakraborty C. Cdc42negatively regulates intrinsic migration ofhighly aggressive breast cancer cells[J]. J Cell Physiol,2012,227(4):1399-1407.
[83] Gómez Del Pulgar T, Valdés-Mora F, Bandrés E, et al. Cdc42is highly expressed incolorectal adenocarcinoma and downregulates ID4through an epigeneticmechanism[J]. Int J Oncol,2008,33(1):185-193.
[84]瓦热斯江﹒衣不拉音,李惠武,王洪江,等. Cdc42基因在维吾尔族食管癌中表达的研究[J].地方病通报,2009,24(6):12-14.
[85]冯国军,卢晓梅. AnnexinAZ Cdc42在食管鳞状细胞癌中的表达及与浸润转移的关系.新疆医科大学硕士学位论文.
[86]刘赞,李卉,马文静,等. Cdc42, Rb基因在哈萨克族食管癌中的表达及其意义的研究[J].地方病通报,2008,23(4):1-3.
[87] Shapiro GI, Edwards CD, Ewen ME. P16INK4A participates in a G1arrestcheckpoint in response to DNA damage[J]. Mol Cell Biol,1998,18(1):378-387.
[88] Lydiatt WM, Murty VV, Davidson BJ, et al. Homozygous deletions and loss ofexpression of the CDKN2gene occur frequently in head and neck squamous cellcarcinoma cell lines but infrequently in primary tumors[J]. Genes ChromosomesCancer,1995,13(2):94-96.
[89] Hayashi K, Metzger R, Sslonga D, et al. High frequency of simultaneous loss of p16and p16beta gene expression in squamous cell carcinoma of the esophagus but notin adenocarcinoma of the esophagus or stomach[J]. Oncogene,1997,15(12):1481-1488.
[90] Takamura H, Fushida S, Hashimoto T, et al. Analysis of the p16INK4, p15INK4Bgenes abnormality and the amplification of cyclin D1gene in esophageal cancer[J].Nippon Rinsho,1996,54(4):1043-1048.
[91] Suzuki H, Zhou X, Yin J, et al. Intragenic mutations of CDKN2B and CDKN2A inprimary human esophageal cancers[J]. Hum Mol Genet,1995,4(10):1883-1887.
[92] Maesawa C, Tamura G, Nishizuka S, et al. Inactivation of the CDKN2gene byhomozygous deletion and de novo methylation is associated with advanced stageesophageal squamous cell carcinoma[J]. Cancer Res,1996,56(17):3875-3877.
[93] Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A)and their relevance to cancer[J]. Biochemistry,2011,50(25):5566-5582.
[94] Kamb A. Cell-cycle regulators and cancer[J]. Trends Genet,1995,11(4):136-140.
[95] Kamb A. Cyclin-dependent kinase inhibitors and human cancer[J]. Curr TopMicrobiol Immunol,1998,227(2):139-148.
[96] Felin IP, Grivicich I, Felin CR, et al. p53, p16E COX-2expression in esophagealsquamous cell carcinoma and histopathological association[J]. Arq Gastroenterol,2008,45(4):308-312.
[97] Sharpless NE. INK4a/ARF:A multifunctional tumor suppressor locus[J]. Mutat Res,2005,576(1-2):22-38.
[98] Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4inhibitorsand cancer[J]. Biochim Biophys Acta,2002,1602(1):73-87.
[99] Forbes S, Clements J, Dawson E, et al. COSMIC2005[J]. Br J Cancer,2006,4(2):318-322.
[100]Li J, Byeon IJ, Ericson K, et al. Tumor suppressor INK4:determination of thesolution structure of p18INK4C and demonstration of the functional significance ofloops in p18INK4C and p16INK4A[J]. Biochemistry,1999,38(10):2930-2940.
[101]Kim SG, Hong SJ, Kwon KW, et al. The expression of p53, p16, cyclin D1inesophageal squamous cell carcinoma and esophageal dysplasia[J]. Korean JGastroenterol,2006,48(4):269-276.
[102]刘海明. p16在食管癌变过程中的表达[J].中国医疗前沿,2011,6(12):14-15.
[103]谢有科,钟雪云,陈少湖. P16, CDK4及cyclin D1在粤东地区食管癌中的表达及意义[J].广东医学,2008,29(2):280-282.
[104]宋长山,谭家驹,赵建亭,等. p16与survivin蛋白在食管癌中的表达及意义[J].中国肿瘤,2007,16(8):625-627.
[105]Liu YS, Yu CH, Li L, et al. Expression of p53, p16and cyclooxygenase-2inesophageal cancer with tissue microarray[J]. J Dig Dis,2007,8(3):133-138.
[106]Jung A, Schrauder M, Oswald U, et al. The invasion front of human colorectaladenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, andp16INK4A and is a region of low proliferation[J]. Am J Pathol,2001,159(5):1613-1617.
[107]Natarajan E, Saeb M, Crum CP, et al. Co-expression of p16(INK4A)and laminin5gamma2by microinvasive and superficial squamous cell carcinomas in vivo and bymigrating wound and senescent keratinocytes in culture[J]. Am JPathol,2003,163(2):477-491.
[108]Svensson S, Nilsson K, Ringberg A, et al. Invade or proliferate? Two contrastingevents in malignant behavior governed by p16(INK4a)and an intact Rb pathwayillustrated by a model system of basal cell carcinoma[J]. Cancer Res,2003,63(8):1737-1742.
[109]Horree N, van Diest PJ, Sie-Go DM, et al. The invasive front in endometrialcarcinoma:higher proliferation and associated derailment of cell cycle regulators[J].Hum Pathol,2007,38(8):1232-1238.
[110]Palmqvist R, Rutegard JN, Bozoky B, et al. Human colorectal cancers with an intactp16/cyclinD1/pRb pathway have up-regulated p16expression and decreased-proliferation in small invasive tumor clusters[J]. Am J Pathol,2000,157(6):1947-1953.
[111]Mulvany NJ, Allen DG, Wilson SM. Diagnostic utility of p16INK4a:a reappraisal ofits use in cervical biopsies[J]. Pathology,2008,40(4):335–344.
[112]Chen JH, Ozanne SE, Hales CN. Heterogeneity in premature senescence byoxidative stress correlates with differential DNA damage during the cell cycle[J].DNA Repair(Amst),2005,4(10):1140–1148.
[113]Guida M, Sanguedolce F, Bufo P, et al. Aberrant DNA hypermethylation of hMLH-1and CDKN2A/p16genes in benign, premalignant and malignant endometriallesions[J]. Eur J Gynaecol Oncol,2009,30(3):267-270.
[114]Carnero A, Lleonart ME. Epigenetic mechanisms in senescence, immortalisationand cancer[J]. Biol Rev Camb Philos Soc,2011,86(2):443-455.
[115]Krishnamurthy J, Torrice C, Ramsey MR. et al. Ink4a/Arf expression is a biomarkerof aging[J]. J Clin Invest,2004,114(9):1299-1307.
[116]Gray-Schopfer VC, Cheong SC, Chong H, et al. Cellular senescence in naevi andimmortalisation in melanoma:a role for p16[J]. Br J Cancer,2006,95(4):496-505.
[117]Di Vinci A, Perdelli, Banelli, et al. p16(INK4a)promoter methylation and proteinexpression in breast fibroadenomaand carcinoma[J]. Int J Cancer,2005,114(3):414-421.
[118]Hilliard NJ, Krahl D, Sellheyer K. p16expression differentiates betweendesmoplastic Spitz nevus and desmoplastic melanoma[J]. J Cutan Pathol,2009,36(7):753-759.
[119]Zhao P, Mao X, Talbot IC. Aberrant cytological localization of p16and CDK4incolorectal epithelia in the normal adenoma carcinoma sequence[J]. World JGastroenterol,2006,12(39):6391-6396.
[120]Dai CY, Furth EE, Mick R, et al. p16(INK4a)expression begins early in humancolon neoplasia and correlates inversely with markers of cell proliferation[J].Gastroenterology,2000,119(4):929-942.
[121]Herschkowitz JI, He X, Fan C, et al. The functional loss of the retinoblastoma tumorsuppressor is a common event in basal-like and luminal B breast carcinomas[J].Breast Cancer Res,2008,10(5):R75.
[122]Kerlikowske K, Molinaro AM, Gauthier ML, et al. Biomarker expression and riskof subsequent tumors after initial ductal carcinoma in situ diagnosis[J]. J NatlCancer Inst,2010,102(9):627-637.
[123]Lam AK, Ong K, Giv MJ, et al. p16expression in colorectal adenocarcinoma:marker of aggressiveness and morphological types[J]. Pathology,2008,40(6):580-585.
[124]杨春梅,陈卫刚,郑义,等.新疆哈萨克族食管鳞癌中p16蛋白的表达及其意义[J].肿瘤防治研究,2012,39(3):289-291.
[125]Ohta M, Inoue H, Cotticelli MG, et al. The FHIT gene, spanning the chromosome3p14.2fragile site and renal cell carcinoma associated translocation breakpoint, isabnormal in digestive tract cancers[J]. Cell,1996,84(4):587-597.
[126]Pekarsky Y, Zanesi N, Palamarchuk A, et al. FHIT:from gene discovery to cancertreatment and prevention[J]. Lancet Oncol,2002,3(12):748-754.
[127]Druck T, Hadaczek P, Fu TB, et al. Structure and expression of the human FHITgene in normal and tumor cells[J]. Cancer Res,1997,57(3):504-512.
[128]Sozzi G, Tornielli S, Tagliabue E, et al. Absence of Fhit protein in primary lungtumors and cell lines with FHIT gene abnormalities[J]. Cancer Res,1997,57(23):5207-5212.
[129]Baffa R, Veronese ML, Santoro R, et al. Loss of FHIT expression in gastriccarcinoma[J]. Cancer Res,1998,58(20):4708-4714.
[130]Sozzi G, Pastorino U, Moiraghi L, et al. Loss of FHIT function in lung cancer andpreinvasive bronchial lesions[J]. Cancer Res,1998,58(22):5032-5037.
[131]Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of currentand former smokers[J]. J Natl Cancer Inst,1997,89(12):857-862.
[132]Hadaczek P, Siprashvili Z, Markiewski M, et al. Absence or reduction of Fhitexpression in most clear cell renal carcinomas[J]. Cancer Res,1998,58(14):2946-2951.
[133]Greenspan DL, Connolly DC, Wu R, et al. Loss of FHIT expression in cervicalcarcinoma cell lines and primary tumors[J]. Cancer Res,1997,57(21):4692-4698.
[134]Simon B, Bartsch D, Barth P, et al. Frequent abnormalities of the putative tumorsuppressor gene FHIT at3p14.2in pancreatic carcinoma cell lines[J]. Cancer Res,1998,58(3):1583-1587.
[135]Negrini M, Monaco C, Vorechovsky I, et al. The FHIT gene at3p14.2is abnormalin breast carcinomas[J]. Cancer Res,1996,56(14):3173-3179.
[136]Ingvarsson S, Agnarsson BA, Sigbjornsdottir BI, et al. Reduced Fhit expression insporadic and BRCA2-linked breast carcinomas[J]. Cancer Res,1999,59(11):2682-2689.
[137]Campiglio M, Pekarsky Y, Menard S, et al. FHIT loss of function in human primarybreast cancer correlates with advanced stage of the disease[J]. Cancer Res,1999,59(16):3866-3869.
[138]Yang QF, Nakamura M, Nakamura Y, et al. Two-hit inactivation of FHIT by loss ofheterozygosity and hypermethylation in breast cancer[J]. Clin Cancer Res,2002,8(9):2890-2893.
[139]Siprashvili Z, Sozzi G, Barnes LD,et al.Replacement of Fhit in cancer cellssuppresses tumorigenicity[J].Proc Natl Acad Sci USA,1997,94(25):13771-13776.
[140]Pace HC, Garrison PN, Robinson AK, et al.Genetic, biochemical, and crystallo-graphic characterization of Fhit-substrate complexes as the active signaling form ofFhit[J]. Proc Natl Acad Sci USA,1998,95(10):5484-5489.
[141]冯艳玲,李冬霞,张红旗.脆性组氨酸三联体(FHIT)基因外显子5,8纯合性缺失及突变与胃癌的关系[J].中国临床医学,2007,14(16):822-824.
[142]Zhao P, Liu W, Lu YL, et al. Clinicopathological significance of FHIT proteinexpression in gastric adenocarcinoma patients[J]. World J Gastroenterol,2005,11(36):5735-5738.
[143]Arun B, Kilic G, Yen C. Loss of FHIT expression in breast cancer is correlated withpoor prognostic marker[J]. Cancer Epidemiol Biomarkers Prev,2005,14(7):1681-1685.
[144]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究[J].癌变畸变突变,2007,1(3):242-245.
[145]Huang Q, Xie F, Tang Z, et al. FHIT promotes the apoptosis of QBC939byreducing the expression of cyclin D1[J]. Hepatogastroenterology,2011,58(107-108):713-718.
[146]Gatalica Z, Lele SM, Rampy BA, et al. The expression of FHIT protein is relatedinversely to disease progression in patients with breast carcinoma[J]. Cancer,2000,88(6):1378-1383.
[147]张德庆,陈东育,宋兆峰. FHIT蛋白及mRNA在食管癌组织中的表达及意义[J].中国诊断实验学,2011,15(1):83-85.
[148]Fang JM, Arlt MF, Burgess AC, et al. Translocation breakpoints in FHIT andFRA3B in both homologs of chromosome3in an esophageal adenocarcinoma[J].Genes Chromosomes Cancer,2001,30(3):292-298.
[149]赵坡,吕亚莉,钟梅.食管癌Fhit蛋白表达丢失的临床病理研究[J].肿瘤防治研究,2002,29(6):463-464.
[150]刘复兴,黄晓平,王明荣.食管鳞癌FHIT基因等位缺失及其表达下调[J].中国癌症杂志,2004,23(9):992-998.
[151]Derek J. Nancarrow, Herlina Y. et al, Genome-Wide Copy Number Analysis inEsophageal Adenocarcinoma Using High-Density Single-Nucleotide PolymorphismArrays[J]. Cancer Res,2008,68(11):4163-4172.
[152]常志伟,王立东,高珊珊.家族性食管癌组织中FHIT, p53蛋白的表达[J].郑州大学学报(医学版),2006,41(1):24-26.
[153]Wierzbicki PM, Adrych K, Kartanowicz D, et al. Fragile histidine triad(FHIT)geneis overexpressed in colorectal cancer[J]. J Physiol Pharmacol,2009,60(4):63-70.
[154]郭向东.食管癌组织中基因蛋白的表达变化及意义[J].山东医药,2007,47(18):44.
[155]杨国涛,闫召华,周玉汀,等. MMP10FHIT基因在食管癌中的表达及临床意义[J].山东大学学报(医学版),2005,43(12):1159-1162.
[156]李吉学,李燕杰,秦艳茹,等.河南食管癌高发区食管癌和癌旁正常组织中FHIT蛋白及其mRNA的表达[J].世界华人消化杂志,2005,13(12):1417-1420.
[157]张松法,叶枫,陈怀增,等.基因组CpG岛甲基化检测技术研究进展[J].国际遗传学杂志,2006,29(3):201-203.
[158]武立鹏,朱卫国. DNA甲基化的生物学应用及检测方法进展[J].中国检验医学杂志,2004,27(7):468-474.
[159]白丽荣,时丽冉.表观遗传学及其相关研究进展[J].安徽农业科学,2007,35(20):6056-6057.
[160]南克俊,魏永长.肿瘤患者血清DNA甲基化的研究进展[J].癌变畸变突变,2003,15(4):249-253.
[161]宋长山,杨光,谭家驹. DNA甲基化与食管癌的关系[J].中华肿瘤防治杂志,2007,14(1):71-74.
[162]McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer[J]. IntImmunopharmacol,2005,5(7-8):1113-1130.
[163]沈望珍,赵学信,王丽蓉,等.食管癌患者染色体3p14-24等位基因杂合缺失的研究[J].中华医学杂志,1995,75(9):560.
[164]赵学信,王丽蓉,沈望珍.哈萨克族食管癌患者3号染色体短臂3p24等位基因杂合缺失的研究[J].新疆医学院学报,1996,19(3):143-145.
[165沈望珍,王丽蓉,赵学信,等.食管癌组织p53抑癌基因等位基因杂合缺失及突变的研究[J].新疆医学院学报,1998,21(1):10-14.
[166]库热西·玉努斯,王丽容,赵学信,等.新疆哈萨克族食管癌APC抑癌基因等位基因杂合缺失和点突变研究[J].新疆医科大学学报,1999,22(2):79-81.
[167]沈望珍,赵学信,王丽容.新疆地区食管癌组织ras基因突变的研究[J].新疆医科大学学报,1999,22(4):233-235.
[168]库热西·玉努斯,王丽容,斯坎德尔·白克力,等.新疆哈萨克族食管癌p16抑癌基因缺失及其表达的研究[J].新疆医科大学学报,2000,23(1):10-12.
[169]陈健,王炳宇,斯坎德尔·白克力,等.食管癌中3p24和11p15.5染色体位点潜在抑癌基因的研究[J].新疆医科大学学报,2000,23(3):213-215.
[170]李涛,吴明拜,赵学信,等.食管癌3p24等位基因LOH及其扩增产物克隆的研究[J].新疆医科大学学报,2003,26(3):224-226.
[171]胡燕荣,吴明拜,赵学信,等.食管癌患者3p25等位基因杂合缺失的初步研究[J].新疆医科大学学报,2003,26(3):238-240.
[172]郭伟鹏,卢晓梅,赵学信,等.新疆哈萨克族食管癌患者HPV16E6基因的克隆及序列分析[J].新疆医科大学学报,2005,28(4):318-320.
[173]伊利亚尔·夏合丁,李卉,霍奇,等.基质金属蛋白酶-7在哈萨克族食管癌中的表达及其意义[J].地方病通报,2008,23(4):7-9.
[174]李卉,陈艳,秦永德,等.新疆哈萨克族食管癌cDNA表达文库的建立[J].地方病通报,2008,23(4):10-13.
[175]李卉,姜孝芳,李惠武.食管癌发生早期相关基因研究进展[J].地方病通报,2008,23(4):14-17.
[176]李海燕,李惠武,陈艳,等. MTA1及nm23H1基因在新疆哈萨克族食管癌组织中的表达及临床意义[J].新疆医科大学学报,2008,31(8):943-945.
[177]王树人.基因的表达与Epigenetics[J].四川生理科学杂志,2006,28(1):29-33.
[178]朱卫国. DNA甲基化,基因调控和癌症[J].世界华人消化杂志,2002,10(6):680-683.
[179]Dahl C, Guldberg P. DNA methylation analysis techniques[J]. Biogerontology,2003,4(4):233-250.
[180]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生命的化学,2005,22(1):1-3.
[181]Cottrell S E. Molecular diagnostic applications of DNA methylation technology[J].Clin Biochem,2004,37(7):595-604.
[182]Jones PA, Baylin SB. The fundamental role of epigenetic events in carcinoma[J].Nat Rev Gene,2002,3(6):415-428.
[183]Esteller M. DNA methylation and cancer therapy:new developments andexpectations[J]. Curr Opin Onco,2005,17(1):55-60.
[184]Das PM, Singal R. DNA methylation and cancer[J]. JClin Oncol,2004,22(22):4632-4642.
[185]Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrientinteractions[J]. Exp Biol Med(Maywood),2004,229(10):988-995.
[186]Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genesoverexpressed in pancreatic ductal adenocarcinoma[J]. Cancer Res,2003,63(14):4158-4166.
[187]Grunau C, Sanchez C, Ehrlich M, et al. Frequent DNA hypomethylation of humanjuxtacentromeric BAGE loci in cancer[J]. Genes Chromosomes Cancer,2005,43(1):11-24.
[188]Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases[J].Biochin Biophys Acta,2007,1775(1):138-162.
[189]Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR:a novel PCRassay for methylation status of CpG islands[J]. Proc Natl Acad Sci USA,1996,93(18):9821-9826.
[190]Liu ZJ, Maekawa M. Polymerase chain reaction-based methods of DNAmethylation analysis[J]. Anal Biochem,2003,317(2):259-265.
[191]Gundry C, Vandersteen J, Reed G, et al. Amplicon melting analysis with labeledprimers:A closed-tube method for differentiating homozygotes and heterozygotes[J].Clinical Chemistry,2003,49(3):396-406.
[192]White HE, Hall VJ, Cross NC. Methylation-sensitive high resolution melting-curveanalysis of the SNRPN gene as a diagnostic screen for Prader-Willi and Angelmansyndromes[J]. Clinical Chemistry,2007,53(11):1960-1962.
[193]Reed GH, Kent JO, Wittwer CT. High-resolution DNA melting analysis for simpleand efficient molecular diagnostics[J]. Pharmacogenomics,2007,8(6):597-608.
[194]Wojdacz TK, Dobrovic A, Algar EM. Rapid detection of methylation change at H19in human imprinting disorders using methylation-sensitive high-resolutionmelting[J]. Human Mutation,2008,29(10):1-6.
[195]Wojdacz TK, Dobrovic A. Methylation-sensitive high resolution melting(MS-HRM): a new approach for sensitive and high-throughput assessment ofmethylation[J]. Nucleic Acids Res,2007,35(6):e41(4-7).
[196]Adams L, Roth MJ, Abnet CC, et al. Promoter methylation in cytology specimensas an early detection marker for esophageal squamous dysplasia and earlyesophageal squamous cell carcinoma[J]. Cancer Prev Res(Phila),2008,1(5):357-361.
[197]Li B, Wang B, Niu LJ, et al. Hypermethylation of multiple tumor-related genesassociated with DNMT3b up-regulation served as a biomarker for early diagnosis ofesophageal squamous cell carcinoma[J]. Epigenetics,2011,6(3):307-316.
[198]Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, survivin, expressedin cancer and lymphoma[J]. Nat Med,1997,3(8):917-921.
[199]Hattori M, Sakamoto H, Satoh K, et al. DNA demethylase is expressed in ovariancancers and the expression correlates with demethylation of CpG sites in thepromoter region of c-erbB-2and survivin genes[J]. Cancer Lett,2001,169(2):155-164.
[200]付文荣,程正江. SYBR GreenⅠ实时荧光PCR检测survivin甲基化状态[J].国际检验医学杂志,2008,29(11):992-994.
[201]胡华梅,杨晓亚,熊刚,等.食管鳞状细胞癌survivin表达与其CpG岛甲基化的研究[J].第三军医大学学报,2010,32(1):13-15.
[202]Osmani N, Peglion F, Chavrier P, et al. Cdc42localization and cell polarity dependon membrane traffic[J]. J Cell Biol,2010,191(7):1261-1269.
[203]Bae JM, Shin SH, Kwon HJ, et al. ALU and LINE-1hypomethylations in multistepgastric carcinogenesis and their prognostic implications[J]. Int J Cancer,2011,28.doi:10.1002/ijc.27369.
[204] Jones PL, Veenstra GJ, Wade PA,et al. Methylated DNA and MeCP2recruit histonedeacetylase to repress transcription[J].Nat Genet,1998,19(2):187-191.
[205]Bird AP, Wolffe AP. Methylation-induced repression-belts, braces, and chromatin[J].Cell,1999,99(5):451-454.
[206]Wade PA, Jones PL, Vermaak D, et al.Histone deacetylase directs the dominantsilencing of transcription in chromatin: association with MeCP2and the Mi-2chromodomain SWI/SNF ATPase[J].Cold Spring Harb Symp QuantBiol,1998,63:435-445.
[207]国丽,王洪江,李卉,等.新疆哈萨克族食管癌中cdc42基因启动子区甲基化与其mRNA表达改变的研究[J].地方病通报,2009,24(2):21-23.
[208]Kamb A, Gruis WA, Weaver-Feldhaus J, et al. A cell cycle regulatory potentiallyinvolved in genesis of many tumor types[J]. Science,1994,264(2):436-440.
[209]Roth MJ, Abnet CC, Hu N, et al. p16, MGMT, RARbeta2, CLDN3, CRBP andMT1G gene methylation in esophageal squamous cell carcinoma and its precursorlesions[J]. Oncol Rep,2006,15(6):1591-1597.
[210]Abbaszadegan MR, Raziee HR, Ghafarzadegan K, et al. Aberrant p16methylation,a possible epigenetic risk factor in familial esophageal squamous cell carcinoma[J].Int J Gastrointest Cancer,2005,36(1):47-54.
[211]Taghavi N, Biramijamal F, Sotoudeh M, et al. p16INK4a hypermethylation and p53,p16and MDM2protein expression in esophageal squamous cell carcinoma[J].BMC Cancer,2010,13(10):138.
[212]Mohammad GS, Miotto E, Callegari E, et al. Associations of risk factors obesityand occupational airborne exposures with CDKN2A/p16aberrant DNA methylationin esophageal cancer patients[J]. Dis Esophagus,2010,23(7):597-602.
[213]Salam I, Hussain S, Mir MM, et al. Aberrant promoter methylation and reducedexpression of p16gene in esophageal squamous cell carcinoma from Kashmirvalley:a high-risk area[J]. Mol Cell Biochem,2009,332(1-2):51-58.
[214]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[215]Guo XQ, Wang SJ, Zhang LW, et al. DNA methylation and loss of proteinexpression in esophageal squamous cell carcinogenesis of high-risk area[J]. J ExpClin Cancer Res,2007,26(4):587-594.
[216]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of16, MGMT, andhMLH1genes in combination with MTHFRC677T genetic polymorphism inesophageal squamous cellar cinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[217]郭晓青,王士杰,张健慧,等.食管癌前病变组织p16及FHIT基因甲基化探讨[J].中国肿瘤临床,2005,32(10):554-557.
[218]余炜伟,王立东,李醒亚.食管鳞癌组织p16基因调控区甲基化及其蛋白表达研究[J].山东医药,2005,45(31):5-7.
[219]宋长山,谭家驹,崔金环,等.食管鳞癌中p16基因启动子区甲基化及其表达[J].肿瘤防治研究,2008,35(1):14-17.
[220]HaoXP, Willis JE, Pretlow TG, et al. Loss of fragile histidine triad expression incolorectal carcinomas and premalignant lesions[J]. Cancer Res,2000,60(1):18-21.
[221]Mori M, Mimori K, Masuda T, et al. Absence of MSH2protein expression isassociated with alteration in the FHIT locus and FHIT protein expression incolorectal carcinoma[J]. Cancer Res,2001,61(20):7379-7382.
[222]Glover TW, Stein CK. Chromosome breakage and recombination at fragile sites[J].Am J Hum Genet,1988,43(3):265-273.
[223]Leal MF, Lima EM, Silva PN. Promoter hypermethylationof CDH1, FH IT, MTAPand PLAGL1in gastric adenocarcinoma in individuals from Northern Brazil[J].World J Gastroenterol,2007,13(18):2568-2574.
[224]Carolina B, Macarena V. DNA methylation profile in diffuse type gastriccancer:evidence for hypermethylation of the BRCA1promoterregion in early-onsetgastric carcinogenesis[J]. Biol Res,2008,41(3):303-315.
[225]Noguchi T, akeno S, Kimnta Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. International Journal of MolecularMedicine,2003,11(4):441-447.
[226]Kuroki T, Trapasso F, Yendamuri S, et al. Allele loss and promoterhypermethylation of VHL, RAR-B, RASSF1A, and FHIT tumor suppressor geneson chromosome3p in esophageal squamous cell carcinoma[J]. Cancer Res,2003,63(13):3724-3728.
[227]Lee EJ, Lee BB, Kim JW, et al. Aberrant methylation of Fragile Histidine Triadgene is associated with poor prognosis in early stage esophageal squamous cellcarcinoma[J]. Eur J Cancer,2006,42(7):972-980.
[228]Noguchi T, Takeno S, Kimura Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. Int J MolMed,2003,11(4):441-447.
[229]Schildhaus HU, Krochel I, Lippert H, et al. Promoter hypermethylation of p16INK4a, E2cadherin, O62MGMT, DAPK and FHIT in adenocarcinomas of theesophagus, esophagogastric junction and proximal stomach[J]. Int J Oncol,2005,26(6):1493-1500.
[230]Tsao I, Atramentova LA. Genetic and epigenetic changes of FHIT gene in patientswith esophageal cancer[J]. Tsitol Genet,2009,43(6):40-44.
[231]Silveira AP, Da Silva Manoel-Caetano F, Aoki S, et al. Gene mutations andpolymorphisms of TP53and FHIT in chronic esophagitis and esophagealcarcinoma[J]. Anticancer Res,2011,31(5):1685-1690.
[232]Worm J, Guldberg P. DNA methylation:an epigenetic pathway to cancer and apromising target for anticancer therapy[J]. J Oral Pathol Med,2002,31(8):443-449.
[233]Zingg JM, Jones PA. Genetic and epigenetic aspects of DNA methylation ongenome expression, evolution, mutation and carcinogenesis[J]. Carcinogenesis,1997,18(5):869-882.
[234]Tao L, Yang S, Xie M, et al. Hypomethylation and overexpression of c-jun andc-myc protooncogenes and increased DNA methyltransferase activity indichloroacetic and trichloroacetic acid-promoted mouse liver tumors[J]. Cancer Let,2000,58(2):185-193.
[235]Greger V, Passarge E, H pping W, et al. Epigenetic changes may contribute to theformation and spontaneous regression of retinoblastoma[J]. Hum Genet,1989,83(2):155-158.
[236]Sakai T. Molecular cancer epidemiology-the present status and futurepossibilities[J]. Nihon Eiseigaku Zasshi,1996,50(6):1036-1046.
[237]Szyf M. The DNA methylation machinery as a target for anticancer therapy[J].Pharmacol Ther,1996,70(1):1-37.
[238]Vachtenheim J, Horakova I, Novotna H. Hypomethylation of CCGG sites in the3'region of H-ras protooncogene is frequent and is associated with H-ras allele lossin non-small cell lung cancer[J]. Cancer Res,1994,54(5):1145-1148.
[239]Cheah MS, Wallace CD, Hoffman RM. Hypomethylation of DNA in human cancercells:a site-specific change in the c-myc oncogene[J]. J Natl Cancer Inst,1984,73(5):1057-1065.
[240]吴莺,王世宣,马丁. FHIT基因在宫颈癌细胞中的表达及其甲基化调控[J].医药导报,2007,26(6):600-603.
[241]吴燕飞,张乐鸣. CDH13基因在乳腺癌细胞株MCF-7中表达及甲基化调控[J].现代实用医学,2010,22(8):855-858.
[242]司徒镇强,吴军正.细胞培养[M].世界图书出版社,2004:78-88.
[243]张耀洲,物相甫,李载平.氯霉素乙酰基转移酶基因在家蚕核型多角体病毒P10基因启动子控制下得表达[J].病毒学报,1998,9(4):361-366.
[244]武建秋,秦松,邓田,等.氯霉素乙酰转移酶(CAT)基因在海带中的表达[J].海洋与湖沼,1999,30(1):28-32.
[245]Alam J, Cook JL. Reporter genes: application to the study of mammalian genetranscription[J]. Anal Biochem,1990,188(2):245-254.
[246]Bronstein I, Fortin J, Stanley PE, et al. Chemiluminescent and bioluminescentreporter gene assays[J]. Anal Biochem,1994,219(2):169-181.
[247]Schwartz O, Virelizier JL, Montagnier L, et al. A microtransfection method usingthe luciferase-encoding reporter gene for the assay of human immunodeficiencyvirus LTR promoter activity[J]. Gene,1990,88(2):197-205.
[248]Gorman G. DNA Cloning: A Practical Approach[M].2nd ed, IRL Press at OxfordUniversity Press,1995:143-l90.
[249]Shaw WV. Chloramphenicol acetyltrasferase from chloramphenicol-resistantbacteria. Methods enzymol[M]. Methods Enzymol,1975,43:737-755.
[250]Schenborn E, Titus D. Detection of eukaryotic transcription DNA regulatorysequences with the CAT reporter gene assay. Promega Notes21,1989:1-3.
[251]Wu H, Tao J, Sun YE. Regulation and function of mammalian DNA methylationpatterns:a genomic perspective[J]. Brief Funct Genomics,2012,3:7.doi:10.1093/bfgp/els011.
[252]Okano M, Bell DW, Haber DA, et al. DNA methyltransferases Dnmt3a and Dnmt3bare essential for de novo methylation and mammalian development[J]. Cell,1999,99(3):247-257.
[253]Lyko F, Ramsahoye BH, Kashevsky H, et al. Mammalian (cytosine-5)methyltransferases cause genomic DNA methylation and lethality in Drosophila[J].Nat Genet,1999,23(3):363-366.
[254]Kawai J, Hirose K, Fushiki S, et al. Comparison of DNA methylation patternsamong mouse cell lines by restriction landmark genomic scanning[J]. Mol Cell Biol,1994,14(11):7421-7427.
[255]Yamagata Y, Szabó P, Szüts D, et al. Rapid turnover of DNA methylation in humancells[J]. Epigenetics,2012,7(2):141-145.
[256]白坚石,王萍,马晴,等. S-腺苷酰-L-甲硫氨酸(SAM)对HL-60细胞生长与分化的影响[J].北京师范大学学报(自然科学版),2000,36(6):826-829.
[257]Pascale RM, Marras V, Simile MM, et al. Chemprevention of rat livercarcinogenesis by S-adenosyl-L-methionine:a long-term study[J]. Cancer Res,1992,52(18):4979-4986.
[258]Luo J, Li YN, Wang F, et al. S-adenosylmethionine inhibits the growth of cancercells by reversing the hypomethylation status of c-myc and H-ras in human gastriccancer and colon cancer[J]. Int J Biol Sci,2010,6(7):784-795.
[259]Wang BX, Yin BL, He B, et al. Overexpression of DNA damage-induced45alphagene contributes to esophageal squamous cell cancer by promoterhypomethylation[J]. J Exp Clin Cancer Res,2012,31(1):11.
[260]Tokizane T, Shiina H, Igawa M, et al. Cytochrome P4501B1is overexpressed andregulated by hypomethylation in prostate cancer[J]. Clin Cancer Res,2005,11(16):5793-5801.
[261]Kinzler KW, Vogelstein B. Landscaping the cancer terrain[J]. Science,1998,280(5366):1036-1037.
[262]Jones PA, Laird PW. Cancer epigenetics comes of age[J]. Nat Genet,1999,21(2):163-167.
[263]Paredes J, Albergaria A, Oliveira JT, et al. P-cadherin overexpression is an indicatorof clinical outcome in invasive breast carcinomas and is associated with CDH3promoter hypomethylation[J]. Clin Cancer Res,2005,11(16):5869-5877.
[264] Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genesoverexpressed in pancreatic ductal adenocarcinoma[J]. Cancer Res,2003,63(14):4158-4166.
[265] Litkouhi B, Kwong J, Lo CM, et al. Claudin-4overexpression in epithelial ovariancancer is associated with hypomethylation and is a potential target for modulationof tight junction barrier function using a C-terminal fragment of Clostridiumperfringens enterotoxin[J]. Neoplasia,2007,9(4):304-314.
[266]Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics[J].Science,2001,293(5532):1068-1070.
[1]张松法,叶枫,陈怀增,等.基因组CpG岛甲基化检测技术研究进展[J].国际遗传学杂志,2006,29(3):201-203.
[2]武立鹏,朱卫国. DNA甲基化的生物学应用及检测方法进展[J].中国检验医学杂志,2004,27(7):468-474.
[3]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生命的化学,2005,22(1):1-3.
[4]郭晓青,李兆申. DNA甲基化与恶性肿瘤[J].国际消化病杂志,2007,27(1):57-60.
[5] Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past andfuture[J]. J Gastroenterol,2006,41(5):401-407.
[6] Vauhkonen M, Vauhkonen H, Sipponen P. Pathology and molecular biology ofgastric cancer[J]. Best Pract Res Clin Gastroenterol,2006,20(4):651-674.
[7] Shirahata A, Sakuraba K, Kitamura Y, et al. Detection of vimentin methylation in theserum of patients with gastric cancer[J]. Anticancer Res,2012,32(3):791-794.
[8] Joo JK, Kim SH, Kim HG, et al. CpG Methylation of transcription factor4ingastriccarcinoma[J]. Ann Surg Oncol,2010,17(2):3344-3353.
[9] Mikata R, Fukai K, Arai M, et al. BCL2L10is frequently silenced by promoterhypermethylation in gastric cancer[J]. Oncol Rep,2010,23(6):1701-1708.
[10]魏国华,杨春雨,杨静,等. HPV感染与p16基因甲基化在胃癌发生中的作用[J].肿瘤防治研究,2011,38(1):51-54.
[11]Leal MF, Lima EM, Silva PN, et al. Promoter hypermethylation of CDH1, FHIT,MTAP and PLAGL1in gastric adenocarcinoma in individuals from NorthernBrazil[J]. World J Gastroenterol,2007,13(18):2568-2574.
[12]Chen L, Su L, Li J, et al. Hypermethylated FAM5C and MYLK in serum as diagnosisand pre-warning markers for gastric cancer[J]. Dis Markers,2012,32(3):195-202.
[13]Bae JM, Shin SH, Kwon HJ, et al. ALU and LINE-1hypomethylations in multistepgastric carcinogenesis and their prognostic implications[J]. Int J Cancer,2011,28.doi:10.1002/ijc.27369.
[14]Yang Y, Liu J, Li X, et al. PCDH17gene promoter demethylation and cell cyclearrest by genistein in gastric cancer[J]. Histol Histopathol,2012,27(2):217-224.
[15]Oishi Y, Watanabe Y, Yoshida Y,et al. Hypermethylation of Sox17gene is useful as amolecular diagnostic application in early gastric cancer[J]. Tumour Biol,2012,33(2):383-393.
[16]Jemal A, Siegel R, Ward E, et al. Cancer statistics2007. CA Cancer J Clin,2007,57(1):43-66.
[17]Migheli F, Migliore L. Epigenetics of colorectal cancer[J]. Clinical Genetics,2012,81:312–318. doi:10.1111/j.1399-0004.
[18]Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers[J].Nature,1997,386(6625):623-627.
[19]Das PM, Signal R. DNA methylation and cancer[J]. J Clin Oncol,2004,22(22):4632-4642.
[20]Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomichypomethylation[J]. Science,2003,300(5618):489-492.
[21]Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer[J]. NatRev Genet,2002,3(6):415-428.
[22]Kawasaki T, Nosho K, Ohnishi M, et al. IGFBP3promoter methylation in colorectalcancer:relationship with microsatellite instability, CpG island methylator phenotype,and p53[J]. Neoplasia,2007,9(12):1091-1098.
[23]邹继红,吴平平,汤日宁,等.结直肠癌血清中DLC1p16和RUNX3基因甲基化检测的临床意义[J].江苏医药,2011,37(24):2938-2940.
[24]Gómez Del Pulgar T, Valdés-Mora F, Bandrés E, et al. Cdc42is highly expressed incolorectal adenocarcinoma and downregulates ID4through an epigenetic mechanism[J].Int J Oncol,2008,33(1):185-193.
[25]Sameer AS, Abdullah S, Nissar S, et al. The blues of P(16)INK(4a):Aberrantpromoter methylation and association with colorectal cancer in the Kashmir valley[J].Mol Med Report,2012,5(4):1053-1057.
[26]deSousa E, Melo F, Colak S, et al. Methylation of cancer-stem-cell-associated Wnttarget genes predicts poor prognosis in colorectal cancer patients[J]. Cell Stem Cell,2011,9(5):476-485.
[27]Hibi K, Goto T, Shirahata A, et al. Methylation of TFPI2No Longer Detected in theSerum DNA of Colorectal Cancer Patients after Curative Surgery[J]. Anticancer Res,2012,32(3):787-790.
[28]McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer[J]. IntImmunopharmacol,2005,5(7-8):1113-1130
[29]Li JY. Epidemiology of esophageal cancer in China[J]. Natl Cancer Inst Monogr,1982,62:113-120.
[30]Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joinsgenetics[J]. Trends Genet,2000,16(4):168-174.
[31]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA Methylation of p16, MGMT, and hMLH1Genes in Combination with MTH FRC677T Genetic Polymorphism inEsophageal Squamous Cell Carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[32]宋长山,谭家驹,崔金环,等.食管鳞癌中p16基因启动子区甲基化及其表达[J].肿瘤防治研究,2008,35(1):14-17.
[33]Wang JS, Guo M, Montgomery EA, et al. DNA promoter hypermethylation of p16and APC predicts neoplastic progression in Barrett's esophagus[J]. Am J Gastroenterol,2009,104(9):2153-2160.
[34]郭晓青,王士杰,张健慧,等.食管鳞状细胞癌及癌前病变组织中p16基因甲基化的研究[J].肿瘤防治杂志,2005,12(7):495-497.
[35]姚群峰,康新江,郝巧玲,等.巢式甲基化特异性PCR检测食管癌病人血清中p16基因启动子区过甲基化[J].肿瘤防治研究,2005,32(8):463-466.
[36]Hardie LJ, Darnton SJ, Wallis YL, et al. P16expression in Barretts' esophagus andesophageal adenocarcinoma:association with genetic and epigenetic alterations[J].Cancer Lett,2005,217(2):221-230.
[37]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[38]Guo XQ, Wang SJ, Zhang LW, et al. DNA methylation and loss of protein expressionin esophageal squamous cell carcinogenesis of high-risk area[J]. J Exp Clin CancerRes,2007,26(4):587-594.
[39]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of p16, MGMT, andhMLH1genes in combination with MTHFRC677T genetic polymorphism inesophageal squamous cell carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[40]KurokiT, Trapasso F, Yendamuri S, et al. Allele loss and promoter hypermethylationof VHL, RAR-B, RASSF1A, and FHIT tumor suppressor genes on chromosome3pin esophageal squamous cell carcinoma[J]. Cancer Res,2003,63(13):3724-3728.
[41]Lee EJ, Lee BB, Kim JW, et al. Aberrant methylation of Fragile Histidine Triad geneis associated with poor prognosis in early stage esophageal squamous cellcarcinoma[J]. Eur J Cancer,2006,42(7):972-980.
[42]Noguchi T, Takeno S, Kimura Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. Int J MolMed,2003,11(4):441-447.
[43]Schildhaus HU, Krochel I, Lippert H, et al. Promoter hypermethylation of p16IN K4a,E2cadherin, O62MGMT, DAPK and FHIT in adenocarcinomas of the esophagus,esophagogastric junction and proximal stomach[J]. Int J Oncol,2005,26(6):1493-1500.
[44]Tsao I, Atramentova LA. Genetic and epigenetic changes of FHIT gene in patientswith esophageal cancer[J]. Tsitol Genet,2009,43(6):40-44.
[45]Kaz AM, Luo Y, Dzieciatkowski S, et al. Aberrantly methylated PKP1in theprogression of Barrett's esophagus to esophageal adenocarcinoma[J]. GenesChromosomes Cancer,2012,51(4):384-393.
[46]You YJ, Chen YP, Zheng XX, et al. Aberrant methylation of the PTPRO gene inperipheral blood as a potential biomarker in esophageal squamous cell carcinomapatients[J]. Cancer Lett,2012,315(2):138-144.
[47]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[48]Ling ZQ, Li P, Ge MH, et al. Hypermethylation-modulated down-regulation ofCDH1expression contributes to the progression of esophageal cancer[J]. Int J MolMed,2011,27(5):625-635.
[49]Dong SW, Cui YT, Zhong RR, et al. Decreased expression of retinoblastomaprotein-interacting zinc-finger gene1in human esophageal squamous cell cancer byDNA methylation[J]. Clin Lab,2012,58(1-2):41-51.
[50]Liu Z, Zhang L, Ding F, et al.5-Aza-2'-deoxycytidine induces retinoic acidreceptor-beta(2) demethylation and growth inhibition in esophageal squamouscarcinoma cells[J]. Cancer Lett,2005,230(2):271-283.
[51]Biewusch K, Heyne M, Grützmann R. DNA methylation in pancreaticcancer:protocols for the isolation of DNA and bisulfite modification[J]. Methods MolBiol,2012,863(3):273-280.
[52]Chen M, Xue X, Wang F, et al. Expression and promoter methylation analysis ofATP-binding cassette genes in pancreatic cancer[J]. Oncol Rep,2012,27(1):265-269.
[53]Attri J, Srinivasan R, Majumdar S, et al. Alterations of Tumor Suppressor Genep16INK4in Pancreatic Ductal Carcinoma[J]. BMC Gastroenterol,2005,(5):22. doi:10.1186/1471-230X-5-22.
[54]Sato N, Ueki T, Fukushima N, et al. Aberrant Methylation of CpG Islands inIntraductal Papillary Mucinous Neoplasms of the Pancreas[J]. Gastroenterology,2002,123(1):365-372.
[55]House MG, Guo M, Iacobuzio Donahue C, et al. Molecular Progression of PromoterMethylation in Intraductal Papillary Mucinous Neoplasms(IPMN)of the Pancreas[J].Carcinogenesis,2003,24(2):193-198.
[56]Gerdes B, Ramaswamy A, Kersting M, et al. P16(INK4)Alterations in ChronicPancreatitis-indicator for High-risk Lesions for Pancreatic Cancer[J]. Surgery,2001,129(4):490-497.
[57]Dey P, Ponnusamy MP, Deb S, et al. Human RNA polymerase II-association factor1(hPaf1/PD2)regulates histone methylation and chromatin remodeling in pancreaticcancer[J]. PLoS One,2011,6(10):e26926.
[58]Li M, Zhao ZW. Clinical implications of mismatched repair gene promotermethylation in pancreatic cancer[J]. Med Oncol,2011,1:10.doi:10.1007/s12032-011-9968-y.
[59]Nomoto S, Kinoshita T, Mori T, et al. Adverse prognosis of epigenetic inactivation inRUNX3gene at1p36in human pancreatic cancer[J]. Br J Cancer,2008,98(10):1690-1695.
[60]Cai HH, Sun YM, Miao Y, et al. Aberrant methylation frequency of TNFRSF10Cpromoter in pancreatic cancer cell lines[J]. Hepatobiliary Pancreat Dis Int,2011,10(1):95-100.
[61]Abe T, Toyota M, Suzuki H, et al. Upregulation of BNIP3by5-aza-2'-deoxycytidinesensitizes pancreatic cancer cells to hypoxia-mediated cell death[J]. J Gastroenterol,2005,40(5):504-510.
[62]MomParler RL, Bovenzi V. DNA methylation and cancer[J]. J Cell Physiol,2000,183(2):145-154.
[63]Leone G. Voso MT, Teofili L, et al. Inhibitors of DNA methylation in the treatment ofhematological malignancies and MDS[J]. Clin imunol,2003,109(1):89-102.
[64]李卉,刘玲,王洪江,等.高分辨熔解曲线法检测哈萨克族食管癌患者癌组织中FHIT CDKN2A启动子区甲基化水平及临床意义[J].科技导报,2011,29(31):59-63.
[65]Sun M, Uozaki H, Hino R, et al. SOX9expression and its methylation status ingastric cancer[J]. Virchows Arch,2012,460(3):271-279.
[2] Munoz N. Epidemiological aspects of oesophageal cancer[J]. Endoscopy,1993,25:609-612.
[3] Pisani P, Parkin DM, Ferlay J. Estimate of the worldwide mortality from eighteenmajor cancers in1985:implications for prevention and projection of futureburden[J]. Int J Cancer,1993,55:891-903.
[4] Bai SX.原发性食管腺癌-附19例报告[J].中华肿瘤杂志,1989,11(5):383-385.
[5] Sales, Levin. DeMeester TR, Levin B. Cancer of the esophagus[M]. Grune andStratun,1985:8~17.
[6] Sandoval J, Esteller M. Cancer epigenomics: beyond genomics[J]. Curr Opin GenetDev,2012,22(1):50-55.
[7] Wu CT, Morris JR. Genes, genetics and epigenetics:a correspondence[J]. Science,2001,293(5532):1103-1105.
[8]王树人.基因的表达与Epigenetics[J].四川生理科学杂志,2006,28(1):29-33.
[9] Jaenisch R, Bird A. Epigenetic regulation of gene expression:how the genomeintegrates intrinsic and environmental signals[J]. Not Rev Genet,2003,33(3):245-254.
[10]黄庆,郭颖,府伟灵.人类表观基因组计划[J].生命的化学,2004,24(2):101-102.
[11] Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joinsgenetics[J]. Trends Genet,2000,16(4):168-174.
[12] Bird AP. CpG-rich islands and the function of DNA methylation[J]. Nature,1986,321(6067):209-213.
[13] Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer[J]. NatRev Genet,2002,3(6):415-428.
[14] Robertson KD. DNA methylation and human disease[J]. Nat Rev Genet,2005,6(8):597-610.
[15] Narayan A, Ji W, Zhang XY, et al. Hypomethylation of pericent romeric DNA inbreast adenocarcinomas[J]. Int J Cancer,1998,77(6):833-838.
[16] Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human disease[J].Biochim Bio phys Acta,2007,1775(01):138-162.
[17] Wajed SA, Laird PW, DeMeester T R. DNA methylation:An alternative pathway toCancer[J]. Ann Surg,2001,234(1):10-20.
[18] Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of16, MGMT, and hMLH1genes in combination with MTHFRC677T genetic polymorphism in esophagealsquamous cell carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[19] Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[20] Jones PA, Baylin SB. The fundamental role of epigenetic events in carcer[J]. NatRev Genet,2002,3(6):415-428.
[21] Shin CM, Kim N, Park JH, et al. Prediction of the risk for gastric cancer usingcandidate methylation markers in the non-neoplastic gastric mucosa[J]. J Pathol,2012,226(4):654-665.
[22] Sameer AS, Abdullah S, Nissar S, et al. The blues of P(16)INK(4a):Aberrantpromoter methylation and association with colorectal cancer in the Kashmirvalley[J]. Mol Med Report,2012,5(4):1053-1057.
[23] Johanning GL, Heimburger DC, Piyathilake CJ. DNA methylation and diet incancer[J]. J Nutr,2002,132(12):3814S-3818S.
[24]姚群峰.基因启动子异常甲基化及其作为肿瘤生物标志物的研究进展[J].国外医学分子生物学分册,2003,25(3):162-165.
[25]陆嵘,房静远.人消化道肿瘤的表观遗传学研究[J].自然科学进展,2007,17(5):568-572.
[26] Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: whyXIAP is the black sheep of the family[J]. EMBO Rep,2006,7(10):988-994.
[27] Dohi T, Beltrami E, Wall NR, et al. Mitochondrial survivin inhibits apoptosis andpromotes tumorigenesis[J]. J Clin Invest,2004,114(8):1117-1127.
[28]朱红霞,王益华,周翠琦,等.抗凋亡基因survivin在食管癌中的表达及其意义[J].中华肿瘤杂志,2005,27(1):22-24.
[29] Johnson DI. Cdc42: An essential Rho-type GTPase controlling eukaryotic cellpolarity[J]. Microbiol Mol Biol Rev,1999,63(1):54-105.
[30] Cerione RA. Cdc42: new roads to travel[J]. Trends Cell Biol,2004,14(3):127-132.
[31] Chen QY, Jiao DM, Yao QH, et al. Expression analysis of Cdc42in lung cancer andmodulation of its expression by curcumin in lung cancer cell lines[J]. Int J Oncol,2012,40(5):1561-1568.
[32] Yao R, Wang Y, Lubet RA,et al. Differentially Expressed Genes Associated withMouse Lung Tumor Progression[J]. Oncogene,2002,21(37):5814-5821.
[33] Serrano M, Hannon GJ. Beach D. A new regulatory motif in cell cycle controlcausing specific inhibition of cyclinD/CDK4[J]. Nature,1993,366(6456):704-707.
[34] Kamb A, Gruis NA, Weave FJ, et al. A cell cycle regulator potentially involved ingenesis of many tumor types[J]. Science,1994,264((5157):436-440.
[35] Caldas C, Halm SA, Costa D, et al. Frequent somatic mutation and homozygousdeletions of the MTSI gene in pancreatic adenocarcinoma[J]. Nature Geret,1994,8(1):27-32.
[36] Okamoto A, Demetrick DJ, Spillare EA. Mutations and altered expression ofp16INK4in human cancer[J]. Proc Natl Acad Sci USA,1994,91(23):11045-11049.
[37] Lukas J, Parry D, Aagaard L, et al. Retinoblastoma-protein dependent cell-cycleinhibition by the tumour suppressor p16[J]. Nature,1995,75(6531):503-506.
[38] Chen YW, Kao SY, Yang MH. Analysis of p16(INK4A)expression of oral squamouscell carcinomas in Taiwan:Prognostic correlation without relevance to betel quidconsumption[J]. J Surg Oncol,2012,21. doi:10.1002/jso.23067.
[39] Ohta M, Inoue H, Cotticelli MG, et a1. The FHIT gene, spanning the chromosome3P14.2fragile site and renal carcinoma-associated t(3;8)breakpoint is abnormal indigestive tract cancers[J]. Cell,1996,84(4):587-597.
[40] Barnes LD, Garrison PN, Siprashvili Z, et a1. Fhit, a putative tumor suppressor inhumans is a dinucleoside5',5"'-P1, P3-triphosphate hydrolase[J]. Biochemistry,1996,35(36):11529-11535.
[41] Huebner K, Garrison PN, Barnes LD, et al. The role of the FHIT/FRA3B locus incancer[J]. Annu Rev Genet,1998,32:7-31.
[42] Siprashvili Z, Sozzi G, Barnes LD, et al. Replacement of Fhit in cancer cellssuppresses tumorigenicity[J]. Proc Natl Acad Sci USA,1997,94(25):13771-13776.
[43] Chaudhuri AR, Khan IA, Prasad V, et al. The tumor suppressor protein Fhit, A novelinteraction with tubulin[J]. Biol Chem,1999,274(34):24378-24382.
[44] Chava S, Mohan V, Shetty PJ, et al. Immunohistochemical evaluation of p53, FHIT,and IGF2gene expression in esophageal cancer[J]. Dis Esophagus,2012,25(1):81-87.
[45] Keeney S, Bauer TL. Epidemiology of adenocarcinoma of the esophagogastricjunction[J]. Surg Oncol Clin N Am,2006,15(4):687-96.
[46]张月明.新疆哈萨克族食管癌的分布[J].新疆医学院学报,1988,11(2):139-145.
[47] Whelan SL. Cancer Incidence in Five Continents. Coding practices[J]. IARC SciPubl,1992,(120):31-38.
[48] Mu oz N. Epidemiological aspects of oesophageal cancer[J]. Endoscopy,1993,25(9):609-612.
[49]居来提·艾尼瓦尔,李德生,张力为,等.新疆2005~2008年伊犁地区食管癌患病情况调查研究[J].新疆医学,2011,41:112-114.
[50] Yang D, Welm A, Bishop JM. Cell division and cell survival in the absence ofsurvivin[J]. Proc Natl Acad Sci USA,2004,101(42):15100-15105.
[51] Li S, Tian D, Fei P, et al. A cyclooxygase-2inhibitor NS-398-enhanced apoptosis ofesophageal carcinoma cell EC9706by adjusting expression of survivin andcaspase-3[J]. Cancer Invest,2011,29(2):102-106.
[52] Kato J, Kuwabara Y, Mitani M, et al. Expression of Survivin in esophagealcancer:correlation with the prognosis and response to chemotherapy[J]. Int J Cancer,2001,95(2):92-95.
[53] Grabowski P, Kuhnel T, Muhr W, et al. Prognostic value of nuclear survivinexpression in oesophageal squamous cell carcinoma[J]. Br J Cancer,2003,88(1):115.
[54] Ikeguchi M, Yamaguchi K, Kaibara N. Survivin gene expression positivelycorrelates with proliferative activity of cancer cells in esophageal cancer[J]. TumourBiol,2003,24(1):40-45.
[55]钱志英,何流.荧光定量PCR法检测食管癌中survivin基因的临床研究[J].肿瘤研究与临床,2005,17(2):86-88.
[56] Grimminger P, Vallb hmer D, Hoffmann A, et al. Quantitative analysis of survivinRNA expression in blood as a non-invasive predictor of response to neoadjuvantradiochemotherapy in esophageal cancer[J]. J Surg Oncol,2009,100(6):447-451.
[57] Cao M, Yie SM, Wu SM, et al. Detection of survivin-expressing circulating cancercells in the peripheral blood of patients with esophageal squamous cell carcinomaand its clinical significance[J]. Clin Exp Metastasis,2009,26(7):751-758.
[58] Hsu KF, Lin CK, Yu CP, et al. Cortactin, fascin, and survivin expression associatedwith clinicopathological parameters in esophageal squamous cell carcinoma[J]. DisEsophagus,2009,22(5):402-408.
[59] Hoffmann AC, Vallb hmer D, Grimminger P, et al. Preoperative survivin mRNAdetection in peripheral blood is an independent predictor of outcome in esophagealcarcinoma[J]. Pharmacogenomics,2010,11(3):341-347.
[60] Takeno S, Yamashita S, Takahashi Y, et al. Survivin expression in oesophagealsquamous cell carcinoma:its prognostic impact and splice variant expression[J]. EurJ Cardiothorac Surg,2010,37(2):440-445.
[61] Zhu H, Wang Q, Hu C, et al. High expression of survivin predicts poor prognosis inesophageal squamous cell carcinoma following radiotherapy[J]. Tumour Biol,2011,32(6):1147-1153.
[62]王会恩,张霄鹏,王志康.食管鳞状细胞癌中Survivin的表达[J].河北医药,2011,33(22):3413-3414.
[63]杜媛鲲,王雷,李月牛,等.食管鳞癌组织VCAM-1和Survivin的表达及意义[J].山东医药,2008,48(16):1-2.
[64]张砚,陈卫刚,郑勇.哈萨克族食管鳞癌组织中CyclinD1survivin的表达[J].山东医药,2011,51(16):22-24.
[65]李卉,卢晓梅,赵学信,等. Survivin CyclinD1基因在哈萨克族食管癌中表达及其意义的研究[J].新疆医科大学学报,2007,30(6):560-562.
[66] Adams AE, Johnson DI, Longnecker RM, et al. CDC42and CDC43, two additionalgenes involved in budding and the establishment of cell polarity in the yeastSaccharomyces cerevisiae[J]. J Cell Biol,1990,111(1):131-142.
[67] Sinha S, Yang W. Cellular signaling for activation of Rho GTPase Cdc42[J].2008,20(11):1927-1934.
[68] Peterson FC, Penkert RR, Volkman BF, et al. Cdc42regulates the Par-6PDZ domainthrough an allosteric CRIB-PDZ transition[J]. Mol Cell,2004,13(5):665-676.
[69] Tcherkezian J, Lamarche-Vane N. Current knowledge of the large RhoGAP familyof proteins[J]. Biol Cell,2007,99(2):67-86.
[70] Olofsson B. Rho guanine dissociation inhibitors: pivotal molecules in cellularsignalling[J]. Cell Signal,1999,11(8):545-554.
[71] Moon SY, Zheng Y. Rho GTPase-activating proteins in cell regulation[J].Trends CellBiol,2003,13(1):13-22.
[72] Stengel K, Zheng Y. Cdc42in oncogenic transformation, invasion, andtumorigenesis[J]. Cell Signal,2011,23(9):1415-23.
[73]江隆昌,张勇,屈新才.细胞分裂周期蛋白42高表达在雌激素诱导的乳腺细胞耐药性增强过程中的作用[J].中华肿瘤杂志,2011,33(7):489-493.
[74] Melendez J, Grogg M, Zheng Y. Signaling role of Cdc42in regulating mammalianphysiology[J]. J Biol Chem,2011,286(4):2375-2381.
[75] Zhang JY, Zhang D, Wang EH. Overexpression of small GTPases directly correlateswith expression of δ-catenin and their coexpression predicts a poor clinical outcomein nonsmall cell lung cancer[J]. Mol Carcinog,2011,2:27.doi:10.1002/mc.21854.
[76] Chen QY, Jiao DM, Yao QH, et al. Expression analysis of Cdc42in lung cancer andmodulation of its expression by curcumin in lung cancer cell lines[J]. Int J Oncol,2012,40(5):1561-1568.
[77] Yeh YM, Pan YT, Wang TC. Cdc42/Rac1participates in the control of telomeraseactivity in human nasopharyngeal cancer cells[J]. Cancer Lett,2005,218(2):207-213.
[78] Oliver AW, He X, Borthwick K, et al. The HPV16E6binding protein Tip-1interactswith ARHGEF16, which activates Cdc42[J]. Br J Cancer,2011,104(2):324-331.
[79] Marques CA, H hnel PS, W lfel C, et al. An immune escape screen reveals Cdc42as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression[J].Blood,2008,111(3):1413-1419.
[80] Adithi M, Venkatesan N, Kandalam M. Expressions of Rac1, Tiam1and Cdc42inretinoblastoma[J]. Exp Eye Res,2006,83(6):1446-1452.
[81] Kamai T, Yamanishi T, Shirataki H, et al. Overexpression of RhoA, Rac1, and Cdc42GTPases is associated with progression in testiular cancer[J]. Clin Cancer Res,2004,10(14):4799-4805.
[82] Zuo Y, Wu Y, Chakraborty C. Cdc42negatively regulates intrinsic migration ofhighly aggressive breast cancer cells[J]. J Cell Physiol,2012,227(4):1399-1407.
[83] Gómez Del Pulgar T, Valdés-Mora F, Bandrés E, et al. Cdc42is highly expressed incolorectal adenocarcinoma and downregulates ID4through an epigeneticmechanism[J]. Int J Oncol,2008,33(1):185-193.
[84]瓦热斯江﹒衣不拉音,李惠武,王洪江,等. Cdc42基因在维吾尔族食管癌中表达的研究[J].地方病通报,2009,24(6):12-14.
[85]冯国军,卢晓梅. AnnexinAZ Cdc42在食管鳞状细胞癌中的表达及与浸润转移的关系.新疆医科大学硕士学位论文.
[86]刘赞,李卉,马文静,等. Cdc42, Rb基因在哈萨克族食管癌中的表达及其意义的研究[J].地方病通报,2008,23(4):1-3.
[87] Shapiro GI, Edwards CD, Ewen ME. P16INK4A participates in a G1arrestcheckpoint in response to DNA damage[J]. Mol Cell Biol,1998,18(1):378-387.
[88] Lydiatt WM, Murty VV, Davidson BJ, et al. Homozygous deletions and loss ofexpression of the CDKN2gene occur frequently in head and neck squamous cellcarcinoma cell lines but infrequently in primary tumors[J]. Genes ChromosomesCancer,1995,13(2):94-96.
[89] Hayashi K, Metzger R, Sslonga D, et al. High frequency of simultaneous loss of p16and p16beta gene expression in squamous cell carcinoma of the esophagus but notin adenocarcinoma of the esophagus or stomach[J]. Oncogene,1997,15(12):1481-1488.
[90] Takamura H, Fushida S, Hashimoto T, et al. Analysis of the p16INK4, p15INK4Bgenes abnormality and the amplification of cyclin D1gene in esophageal cancer[J].Nippon Rinsho,1996,54(4):1043-1048.
[91] Suzuki H, Zhou X, Yin J, et al. Intragenic mutations of CDKN2B and CDKN2A inprimary human esophageal cancers[J]. Hum Mol Genet,1995,4(10):1883-1887.
[92] Maesawa C, Tamura G, Nishizuka S, et al. Inactivation of the CDKN2gene byhomozygous deletion and de novo methylation is associated with advanced stageesophageal squamous cell carcinoma[J]. Cancer Res,1996,56(17):3875-3877.
[93] Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A)and their relevance to cancer[J]. Biochemistry,2011,50(25):5566-5582.
[94] Kamb A. Cell-cycle regulators and cancer[J]. Trends Genet,1995,11(4):136-140.
[95] Kamb A. Cyclin-dependent kinase inhibitors and human cancer[J]. Curr TopMicrobiol Immunol,1998,227(2):139-148.
[96] Felin IP, Grivicich I, Felin CR, et al. p53, p16E COX-2expression in esophagealsquamous cell carcinoma and histopathological association[J]. Arq Gastroenterol,2008,45(4):308-312.
[97] Sharpless NE. INK4a/ARF:A multifunctional tumor suppressor locus[J]. Mutat Res,2005,576(1-2):22-38.
[98] Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4inhibitorsand cancer[J]. Biochim Biophys Acta,2002,1602(1):73-87.
[99] Forbes S, Clements J, Dawson E, et al. COSMIC2005[J]. Br J Cancer,2006,4(2):318-322.
[100]Li J, Byeon IJ, Ericson K, et al. Tumor suppressor INK4:determination of thesolution structure of p18INK4C and demonstration of the functional significance ofloops in p18INK4C and p16INK4A[J]. Biochemistry,1999,38(10):2930-2940.
[101]Kim SG, Hong SJ, Kwon KW, et al. The expression of p53, p16, cyclin D1inesophageal squamous cell carcinoma and esophageal dysplasia[J]. Korean JGastroenterol,2006,48(4):269-276.
[102]刘海明. p16在食管癌变过程中的表达[J].中国医疗前沿,2011,6(12):14-15.
[103]谢有科,钟雪云,陈少湖. P16, CDK4及cyclin D1在粤东地区食管癌中的表达及意义[J].广东医学,2008,29(2):280-282.
[104]宋长山,谭家驹,赵建亭,等. p16与survivin蛋白在食管癌中的表达及意义[J].中国肿瘤,2007,16(8):625-627.
[105]Liu YS, Yu CH, Li L, et al. Expression of p53, p16and cyclooxygenase-2inesophageal cancer with tissue microarray[J]. J Dig Dis,2007,8(3):133-138.
[106]Jung A, Schrauder M, Oswald U, et al. The invasion front of human colorectaladenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, andp16INK4A and is a region of low proliferation[J]. Am J Pathol,2001,159(5):1613-1617.
[107]Natarajan E, Saeb M, Crum CP, et al. Co-expression of p16(INK4A)and laminin5gamma2by microinvasive and superficial squamous cell carcinomas in vivo and bymigrating wound and senescent keratinocytes in culture[J]. Am JPathol,2003,163(2):477-491.
[108]Svensson S, Nilsson K, Ringberg A, et al. Invade or proliferate? Two contrastingevents in malignant behavior governed by p16(INK4a)and an intact Rb pathwayillustrated by a model system of basal cell carcinoma[J]. Cancer Res,2003,63(8):1737-1742.
[109]Horree N, van Diest PJ, Sie-Go DM, et al. The invasive front in endometrialcarcinoma:higher proliferation and associated derailment of cell cycle regulators[J].Hum Pathol,2007,38(8):1232-1238.
[110]Palmqvist R, Rutegard JN, Bozoky B, et al. Human colorectal cancers with an intactp16/cyclinD1/pRb pathway have up-regulated p16expression and decreased-proliferation in small invasive tumor clusters[J]. Am J Pathol,2000,157(6):1947-1953.
[111]Mulvany NJ, Allen DG, Wilson SM. Diagnostic utility of p16INK4a:a reappraisal ofits use in cervical biopsies[J]. Pathology,2008,40(4):335–344.
[112]Chen JH, Ozanne SE, Hales CN. Heterogeneity in premature senescence byoxidative stress correlates with differential DNA damage during the cell cycle[J].DNA Repair(Amst),2005,4(10):1140–1148.
[113]Guida M, Sanguedolce F, Bufo P, et al. Aberrant DNA hypermethylation of hMLH-1and CDKN2A/p16genes in benign, premalignant and malignant endometriallesions[J]. Eur J Gynaecol Oncol,2009,30(3):267-270.
[114]Carnero A, Lleonart ME. Epigenetic mechanisms in senescence, immortalisationand cancer[J]. Biol Rev Camb Philos Soc,2011,86(2):443-455.
[115]Krishnamurthy J, Torrice C, Ramsey MR. et al. Ink4a/Arf expression is a biomarkerof aging[J]. J Clin Invest,2004,114(9):1299-1307.
[116]Gray-Schopfer VC, Cheong SC, Chong H, et al. Cellular senescence in naevi andimmortalisation in melanoma:a role for p16[J]. Br J Cancer,2006,95(4):496-505.
[117]Di Vinci A, Perdelli, Banelli, et al. p16(INK4a)promoter methylation and proteinexpression in breast fibroadenomaand carcinoma[J]. Int J Cancer,2005,114(3):414-421.
[118]Hilliard NJ, Krahl D, Sellheyer K. p16expression differentiates betweendesmoplastic Spitz nevus and desmoplastic melanoma[J]. J Cutan Pathol,2009,36(7):753-759.
[119]Zhao P, Mao X, Talbot IC. Aberrant cytological localization of p16and CDK4incolorectal epithelia in the normal adenoma carcinoma sequence[J]. World JGastroenterol,2006,12(39):6391-6396.
[120]Dai CY, Furth EE, Mick R, et al. p16(INK4a)expression begins early in humancolon neoplasia and correlates inversely with markers of cell proliferation[J].Gastroenterology,2000,119(4):929-942.
[121]Herschkowitz JI, He X, Fan C, et al. The functional loss of the retinoblastoma tumorsuppressor is a common event in basal-like and luminal B breast carcinomas[J].Breast Cancer Res,2008,10(5):R75.
[122]Kerlikowske K, Molinaro AM, Gauthier ML, et al. Biomarker expression and riskof subsequent tumors after initial ductal carcinoma in situ diagnosis[J]. J NatlCancer Inst,2010,102(9):627-637.
[123]Lam AK, Ong K, Giv MJ, et al. p16expression in colorectal adenocarcinoma:marker of aggressiveness and morphological types[J]. Pathology,2008,40(6):580-585.
[124]杨春梅,陈卫刚,郑义,等.新疆哈萨克族食管鳞癌中p16蛋白的表达及其意义[J].肿瘤防治研究,2012,39(3):289-291.
[125]Ohta M, Inoue H, Cotticelli MG, et al. The FHIT gene, spanning the chromosome3p14.2fragile site and renal cell carcinoma associated translocation breakpoint, isabnormal in digestive tract cancers[J]. Cell,1996,84(4):587-597.
[126]Pekarsky Y, Zanesi N, Palamarchuk A, et al. FHIT:from gene discovery to cancertreatment and prevention[J]. Lancet Oncol,2002,3(12):748-754.
[127]Druck T, Hadaczek P, Fu TB, et al. Structure and expression of the human FHITgene in normal and tumor cells[J]. Cancer Res,1997,57(3):504-512.
[128]Sozzi G, Tornielli S, Tagliabue E, et al. Absence of Fhit protein in primary lungtumors and cell lines with FHIT gene abnormalities[J]. Cancer Res,1997,57(23):5207-5212.
[129]Baffa R, Veronese ML, Santoro R, et al. Loss of FHIT expression in gastriccarcinoma[J]. Cancer Res,1998,58(20):4708-4714.
[130]Sozzi G, Pastorino U, Moiraghi L, et al. Loss of FHIT function in lung cancer andpreinvasive bronchial lesions[J]. Cancer Res,1998,58(22):5032-5037.
[131]Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of currentand former smokers[J]. J Natl Cancer Inst,1997,89(12):857-862.
[132]Hadaczek P, Siprashvili Z, Markiewski M, et al. Absence or reduction of Fhitexpression in most clear cell renal carcinomas[J]. Cancer Res,1998,58(14):2946-2951.
[133]Greenspan DL, Connolly DC, Wu R, et al. Loss of FHIT expression in cervicalcarcinoma cell lines and primary tumors[J]. Cancer Res,1997,57(21):4692-4698.
[134]Simon B, Bartsch D, Barth P, et al. Frequent abnormalities of the putative tumorsuppressor gene FHIT at3p14.2in pancreatic carcinoma cell lines[J]. Cancer Res,1998,58(3):1583-1587.
[135]Negrini M, Monaco C, Vorechovsky I, et al. The FHIT gene at3p14.2is abnormalin breast carcinomas[J]. Cancer Res,1996,56(14):3173-3179.
[136]Ingvarsson S, Agnarsson BA, Sigbjornsdottir BI, et al. Reduced Fhit expression insporadic and BRCA2-linked breast carcinomas[J]. Cancer Res,1999,59(11):2682-2689.
[137]Campiglio M, Pekarsky Y, Menard S, et al. FHIT loss of function in human primarybreast cancer correlates with advanced stage of the disease[J]. Cancer Res,1999,59(16):3866-3869.
[138]Yang QF, Nakamura M, Nakamura Y, et al. Two-hit inactivation of FHIT by loss ofheterozygosity and hypermethylation in breast cancer[J]. Clin Cancer Res,2002,8(9):2890-2893.
[139]Siprashvili Z, Sozzi G, Barnes LD,et al.Replacement of Fhit in cancer cellssuppresses tumorigenicity[J].Proc Natl Acad Sci USA,1997,94(25):13771-13776.
[140]Pace HC, Garrison PN, Robinson AK, et al.Genetic, biochemical, and crystallo-graphic characterization of Fhit-substrate complexes as the active signaling form ofFhit[J]. Proc Natl Acad Sci USA,1998,95(10):5484-5489.
[141]冯艳玲,李冬霞,张红旗.脆性组氨酸三联体(FHIT)基因外显子5,8纯合性缺失及突变与胃癌的关系[J].中国临床医学,2007,14(16):822-824.
[142]Zhao P, Liu W, Lu YL, et al. Clinicopathological significance of FHIT proteinexpression in gastric adenocarcinoma patients[J]. World J Gastroenterol,2005,11(36):5735-5738.
[143]Arun B, Kilic G, Yen C. Loss of FHIT expression in breast cancer is correlated withpoor prognostic marker[J]. Cancer Epidemiol Biomarkers Prev,2005,14(7):1681-1685.
[144]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究[J].癌变畸变突变,2007,1(3):242-245.
[145]Huang Q, Xie F, Tang Z, et al. FHIT promotes the apoptosis of QBC939byreducing the expression of cyclin D1[J]. Hepatogastroenterology,2011,58(107-108):713-718.
[146]Gatalica Z, Lele SM, Rampy BA, et al. The expression of FHIT protein is relatedinversely to disease progression in patients with breast carcinoma[J]. Cancer,2000,88(6):1378-1383.
[147]张德庆,陈东育,宋兆峰. FHIT蛋白及mRNA在食管癌组织中的表达及意义[J].中国诊断实验学,2011,15(1):83-85.
[148]Fang JM, Arlt MF, Burgess AC, et al. Translocation breakpoints in FHIT andFRA3B in both homologs of chromosome3in an esophageal adenocarcinoma[J].Genes Chromosomes Cancer,2001,30(3):292-298.
[149]赵坡,吕亚莉,钟梅.食管癌Fhit蛋白表达丢失的临床病理研究[J].肿瘤防治研究,2002,29(6):463-464.
[150]刘复兴,黄晓平,王明荣.食管鳞癌FHIT基因等位缺失及其表达下调[J].中国癌症杂志,2004,23(9):992-998.
[151]Derek J. Nancarrow, Herlina Y. et al, Genome-Wide Copy Number Analysis inEsophageal Adenocarcinoma Using High-Density Single-Nucleotide PolymorphismArrays[J]. Cancer Res,2008,68(11):4163-4172.
[152]常志伟,王立东,高珊珊.家族性食管癌组织中FHIT, p53蛋白的表达[J].郑州大学学报(医学版),2006,41(1):24-26.
[153]Wierzbicki PM, Adrych K, Kartanowicz D, et al. Fragile histidine triad(FHIT)geneis overexpressed in colorectal cancer[J]. J Physiol Pharmacol,2009,60(4):63-70.
[154]郭向东.食管癌组织中基因蛋白的表达变化及意义[J].山东医药,2007,47(18):44.
[155]杨国涛,闫召华,周玉汀,等. MMP10FHIT基因在食管癌中的表达及临床意义[J].山东大学学报(医学版),2005,43(12):1159-1162.
[156]李吉学,李燕杰,秦艳茹,等.河南食管癌高发区食管癌和癌旁正常组织中FHIT蛋白及其mRNA的表达[J].世界华人消化杂志,2005,13(12):1417-1420.
[157]张松法,叶枫,陈怀增,等.基因组CpG岛甲基化检测技术研究进展[J].国际遗传学杂志,2006,29(3):201-203.
[158]武立鹏,朱卫国. DNA甲基化的生物学应用及检测方法进展[J].中国检验医学杂志,2004,27(7):468-474.
[159]白丽荣,时丽冉.表观遗传学及其相关研究进展[J].安徽农业科学,2007,35(20):6056-6057.
[160]南克俊,魏永长.肿瘤患者血清DNA甲基化的研究进展[J].癌变畸变突变,2003,15(4):249-253.
[161]宋长山,杨光,谭家驹. DNA甲基化与食管癌的关系[J].中华肿瘤防治杂志,2007,14(1):71-74.
[162]McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer[J]. IntImmunopharmacol,2005,5(7-8):1113-1130.
[163]沈望珍,赵学信,王丽蓉,等.食管癌患者染色体3p14-24等位基因杂合缺失的研究[J].中华医学杂志,1995,75(9):560.
[164]赵学信,王丽蓉,沈望珍.哈萨克族食管癌患者3号染色体短臂3p24等位基因杂合缺失的研究[J].新疆医学院学报,1996,19(3):143-145.
[165沈望珍,王丽蓉,赵学信,等.食管癌组织p53抑癌基因等位基因杂合缺失及突变的研究[J].新疆医学院学报,1998,21(1):10-14.
[166]库热西·玉努斯,王丽容,赵学信,等.新疆哈萨克族食管癌APC抑癌基因等位基因杂合缺失和点突变研究[J].新疆医科大学学报,1999,22(2):79-81.
[167]沈望珍,赵学信,王丽容.新疆地区食管癌组织ras基因突变的研究[J].新疆医科大学学报,1999,22(4):233-235.
[168]库热西·玉努斯,王丽容,斯坎德尔·白克力,等.新疆哈萨克族食管癌p16抑癌基因缺失及其表达的研究[J].新疆医科大学学报,2000,23(1):10-12.
[169]陈健,王炳宇,斯坎德尔·白克力,等.食管癌中3p24和11p15.5染色体位点潜在抑癌基因的研究[J].新疆医科大学学报,2000,23(3):213-215.
[170]李涛,吴明拜,赵学信,等.食管癌3p24等位基因LOH及其扩增产物克隆的研究[J].新疆医科大学学报,2003,26(3):224-226.
[171]胡燕荣,吴明拜,赵学信,等.食管癌患者3p25等位基因杂合缺失的初步研究[J].新疆医科大学学报,2003,26(3):238-240.
[172]郭伟鹏,卢晓梅,赵学信,等.新疆哈萨克族食管癌患者HPV16E6基因的克隆及序列分析[J].新疆医科大学学报,2005,28(4):318-320.
[173]伊利亚尔·夏合丁,李卉,霍奇,等.基质金属蛋白酶-7在哈萨克族食管癌中的表达及其意义[J].地方病通报,2008,23(4):7-9.
[174]李卉,陈艳,秦永德,等.新疆哈萨克族食管癌cDNA表达文库的建立[J].地方病通报,2008,23(4):10-13.
[175]李卉,姜孝芳,李惠武.食管癌发生早期相关基因研究进展[J].地方病通报,2008,23(4):14-17.
[176]李海燕,李惠武,陈艳,等. MTA1及nm23H1基因在新疆哈萨克族食管癌组织中的表达及临床意义[J].新疆医科大学学报,2008,31(8):943-945.
[177]王树人.基因的表达与Epigenetics[J].四川生理科学杂志,2006,28(1):29-33.
[178]朱卫国. DNA甲基化,基因调控和癌症[J].世界华人消化杂志,2002,10(6):680-683.
[179]Dahl C, Guldberg P. DNA methylation analysis techniques[J]. Biogerontology,2003,4(4):233-250.
[180]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生命的化学,2005,22(1):1-3.
[181]Cottrell S E. Molecular diagnostic applications of DNA methylation technology[J].Clin Biochem,2004,37(7):595-604.
[182]Jones PA, Baylin SB. The fundamental role of epigenetic events in carcinoma[J].Nat Rev Gene,2002,3(6):415-428.
[183]Esteller M. DNA methylation and cancer therapy:new developments andexpectations[J]. Curr Opin Onco,2005,17(1):55-60.
[184]Das PM, Singal R. DNA methylation and cancer[J]. JClin Oncol,2004,22(22):4632-4642.
[185]Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrientinteractions[J]. Exp Biol Med(Maywood),2004,229(10):988-995.
[186]Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genesoverexpressed in pancreatic ductal adenocarcinoma[J]. Cancer Res,2003,63(14):4158-4166.
[187]Grunau C, Sanchez C, Ehrlich M, et al. Frequent DNA hypomethylation of humanjuxtacentromeric BAGE loci in cancer[J]. Genes Chromosomes Cancer,2005,43(1):11-24.
[188]Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases[J].Biochin Biophys Acta,2007,1775(1):138-162.
[189]Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR:a novel PCRassay for methylation status of CpG islands[J]. Proc Natl Acad Sci USA,1996,93(18):9821-9826.
[190]Liu ZJ, Maekawa M. Polymerase chain reaction-based methods of DNAmethylation analysis[J]. Anal Biochem,2003,317(2):259-265.
[191]Gundry C, Vandersteen J, Reed G, et al. Amplicon melting analysis with labeledprimers:A closed-tube method for differentiating homozygotes and heterozygotes[J].Clinical Chemistry,2003,49(3):396-406.
[192]White HE, Hall VJ, Cross NC. Methylation-sensitive high resolution melting-curveanalysis of the SNRPN gene as a diagnostic screen for Prader-Willi and Angelmansyndromes[J]. Clinical Chemistry,2007,53(11):1960-1962.
[193]Reed GH, Kent JO, Wittwer CT. High-resolution DNA melting analysis for simpleand efficient molecular diagnostics[J]. Pharmacogenomics,2007,8(6):597-608.
[194]Wojdacz TK, Dobrovic A, Algar EM. Rapid detection of methylation change at H19in human imprinting disorders using methylation-sensitive high-resolutionmelting[J]. Human Mutation,2008,29(10):1-6.
[195]Wojdacz TK, Dobrovic A. Methylation-sensitive high resolution melting(MS-HRM): a new approach for sensitive and high-throughput assessment ofmethylation[J]. Nucleic Acids Res,2007,35(6):e41(4-7).
[196]Adams L, Roth MJ, Abnet CC, et al. Promoter methylation in cytology specimensas an early detection marker for esophageal squamous dysplasia and earlyesophageal squamous cell carcinoma[J]. Cancer Prev Res(Phila),2008,1(5):357-361.
[197]Li B, Wang B, Niu LJ, et al. Hypermethylation of multiple tumor-related genesassociated with DNMT3b up-regulation served as a biomarker for early diagnosis ofesophageal squamous cell carcinoma[J]. Epigenetics,2011,6(3):307-316.
[198]Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, survivin, expressedin cancer and lymphoma[J]. Nat Med,1997,3(8):917-921.
[199]Hattori M, Sakamoto H, Satoh K, et al. DNA demethylase is expressed in ovariancancers and the expression correlates with demethylation of CpG sites in thepromoter region of c-erbB-2and survivin genes[J]. Cancer Lett,2001,169(2):155-164.
[200]付文荣,程正江. SYBR GreenⅠ实时荧光PCR检测survivin甲基化状态[J].国际检验医学杂志,2008,29(11):992-994.
[201]胡华梅,杨晓亚,熊刚,等.食管鳞状细胞癌survivin表达与其CpG岛甲基化的研究[J].第三军医大学学报,2010,32(1):13-15.
[202]Osmani N, Peglion F, Chavrier P, et al. Cdc42localization and cell polarity dependon membrane traffic[J]. J Cell Biol,2010,191(7):1261-1269.
[203]Bae JM, Shin SH, Kwon HJ, et al. ALU and LINE-1hypomethylations in multistepgastric carcinogenesis and their prognostic implications[J]. Int J Cancer,2011,28.doi:10.1002/ijc.27369.
[204] Jones PL, Veenstra GJ, Wade PA,et al. Methylated DNA and MeCP2recruit histonedeacetylase to repress transcription[J].Nat Genet,1998,19(2):187-191.
[205]Bird AP, Wolffe AP. Methylation-induced repression-belts, braces, and chromatin[J].Cell,1999,99(5):451-454.
[206]Wade PA, Jones PL, Vermaak D, et al.Histone deacetylase directs the dominantsilencing of transcription in chromatin: association with MeCP2and the Mi-2chromodomain SWI/SNF ATPase[J].Cold Spring Harb Symp QuantBiol,1998,63:435-445.
[207]国丽,王洪江,李卉,等.新疆哈萨克族食管癌中cdc42基因启动子区甲基化与其mRNA表达改变的研究[J].地方病通报,2009,24(2):21-23.
[208]Kamb A, Gruis WA, Weaver-Feldhaus J, et al. A cell cycle regulatory potentiallyinvolved in genesis of many tumor types[J]. Science,1994,264(2):436-440.
[209]Roth MJ, Abnet CC, Hu N, et al. p16, MGMT, RARbeta2, CLDN3, CRBP andMT1G gene methylation in esophageal squamous cell carcinoma and its precursorlesions[J]. Oncol Rep,2006,15(6):1591-1597.
[210]Abbaszadegan MR, Raziee HR, Ghafarzadegan K, et al. Aberrant p16methylation,a possible epigenetic risk factor in familial esophageal squamous cell carcinoma[J].Int J Gastrointest Cancer,2005,36(1):47-54.
[211]Taghavi N, Biramijamal F, Sotoudeh M, et al. p16INK4a hypermethylation and p53,p16and MDM2protein expression in esophageal squamous cell carcinoma[J].BMC Cancer,2010,13(10):138.
[212]Mohammad GS, Miotto E, Callegari E, et al. Associations of risk factors obesityand occupational airborne exposures with CDKN2A/p16aberrant DNA methylationin esophageal cancer patients[J]. Dis Esophagus,2010,23(7):597-602.
[213]Salam I, Hussain S, Mir MM, et al. Aberrant promoter methylation and reducedexpression of p16gene in esophageal squamous cell carcinoma from Kashmirvalley:a high-risk area[J]. Mol Cell Biochem,2009,332(1-2):51-58.
[214]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[215]Guo XQ, Wang SJ, Zhang LW, et al. DNA methylation and loss of proteinexpression in esophageal squamous cell carcinogenesis of high-risk area[J]. J ExpClin Cancer Res,2007,26(4):587-594.
[216]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of16, MGMT, andhMLH1genes in combination with MTHFRC677T genetic polymorphism inesophageal squamous cellar cinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[217]郭晓青,王士杰,张健慧,等.食管癌前病变组织p16及FHIT基因甲基化探讨[J].中国肿瘤临床,2005,32(10):554-557.
[218]余炜伟,王立东,李醒亚.食管鳞癌组织p16基因调控区甲基化及其蛋白表达研究[J].山东医药,2005,45(31):5-7.
[219]宋长山,谭家驹,崔金环,等.食管鳞癌中p16基因启动子区甲基化及其表达[J].肿瘤防治研究,2008,35(1):14-17.
[220]HaoXP, Willis JE, Pretlow TG, et al. Loss of fragile histidine triad expression incolorectal carcinomas and premalignant lesions[J]. Cancer Res,2000,60(1):18-21.
[221]Mori M, Mimori K, Masuda T, et al. Absence of MSH2protein expression isassociated with alteration in the FHIT locus and FHIT protein expression incolorectal carcinoma[J]. Cancer Res,2001,61(20):7379-7382.
[222]Glover TW, Stein CK. Chromosome breakage and recombination at fragile sites[J].Am J Hum Genet,1988,43(3):265-273.
[223]Leal MF, Lima EM, Silva PN. Promoter hypermethylationof CDH1, FH IT, MTAPand PLAGL1in gastric adenocarcinoma in individuals from Northern Brazil[J].World J Gastroenterol,2007,13(18):2568-2574.
[224]Carolina B, Macarena V. DNA methylation profile in diffuse type gastriccancer:evidence for hypermethylation of the BRCA1promoterregion in early-onsetgastric carcinogenesis[J]. Biol Res,2008,41(3):303-315.
[225]Noguchi T, akeno S, Kimnta Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. International Journal of MolecularMedicine,2003,11(4):441-447.
[226]Kuroki T, Trapasso F, Yendamuri S, et al. Allele loss and promoterhypermethylation of VHL, RAR-B, RASSF1A, and FHIT tumor suppressor geneson chromosome3p in esophageal squamous cell carcinoma[J]. Cancer Res,2003,63(13):3724-3728.
[227]Lee EJ, Lee BB, Kim JW, et al. Aberrant methylation of Fragile Histidine Triadgene is associated with poor prognosis in early stage esophageal squamous cellcarcinoma[J]. Eur J Cancer,2006,42(7):972-980.
[228]Noguchi T, Takeno S, Kimura Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. Int J MolMed,2003,11(4):441-447.
[229]Schildhaus HU, Krochel I, Lippert H, et al. Promoter hypermethylation of p16INK4a, E2cadherin, O62MGMT, DAPK and FHIT in adenocarcinomas of theesophagus, esophagogastric junction and proximal stomach[J]. Int J Oncol,2005,26(6):1493-1500.
[230]Tsao I, Atramentova LA. Genetic and epigenetic changes of FHIT gene in patientswith esophageal cancer[J]. Tsitol Genet,2009,43(6):40-44.
[231]Silveira AP, Da Silva Manoel-Caetano F, Aoki S, et al. Gene mutations andpolymorphisms of TP53and FHIT in chronic esophagitis and esophagealcarcinoma[J]. Anticancer Res,2011,31(5):1685-1690.
[232]Worm J, Guldberg P. DNA methylation:an epigenetic pathway to cancer and apromising target for anticancer therapy[J]. J Oral Pathol Med,2002,31(8):443-449.
[233]Zingg JM, Jones PA. Genetic and epigenetic aspects of DNA methylation ongenome expression, evolution, mutation and carcinogenesis[J]. Carcinogenesis,1997,18(5):869-882.
[234]Tao L, Yang S, Xie M, et al. Hypomethylation and overexpression of c-jun andc-myc protooncogenes and increased DNA methyltransferase activity indichloroacetic and trichloroacetic acid-promoted mouse liver tumors[J]. Cancer Let,2000,58(2):185-193.
[235]Greger V, Passarge E, H pping W, et al. Epigenetic changes may contribute to theformation and spontaneous regression of retinoblastoma[J]. Hum Genet,1989,83(2):155-158.
[236]Sakai T. Molecular cancer epidemiology-the present status and futurepossibilities[J]. Nihon Eiseigaku Zasshi,1996,50(6):1036-1046.
[237]Szyf M. The DNA methylation machinery as a target for anticancer therapy[J].Pharmacol Ther,1996,70(1):1-37.
[238]Vachtenheim J, Horakova I, Novotna H. Hypomethylation of CCGG sites in the3'region of H-ras protooncogene is frequent and is associated with H-ras allele lossin non-small cell lung cancer[J]. Cancer Res,1994,54(5):1145-1148.
[239]Cheah MS, Wallace CD, Hoffman RM. Hypomethylation of DNA in human cancercells:a site-specific change in the c-myc oncogene[J]. J Natl Cancer Inst,1984,73(5):1057-1065.
[240]吴莺,王世宣,马丁. FHIT基因在宫颈癌细胞中的表达及其甲基化调控[J].医药导报,2007,26(6):600-603.
[241]吴燕飞,张乐鸣. CDH13基因在乳腺癌细胞株MCF-7中表达及甲基化调控[J].现代实用医学,2010,22(8):855-858.
[242]司徒镇强,吴军正.细胞培养[M].世界图书出版社,2004:78-88.
[243]张耀洲,物相甫,李载平.氯霉素乙酰基转移酶基因在家蚕核型多角体病毒P10基因启动子控制下得表达[J].病毒学报,1998,9(4):361-366.
[244]武建秋,秦松,邓田,等.氯霉素乙酰转移酶(CAT)基因在海带中的表达[J].海洋与湖沼,1999,30(1):28-32.
[245]Alam J, Cook JL. Reporter genes: application to the study of mammalian genetranscription[J]. Anal Biochem,1990,188(2):245-254.
[246]Bronstein I, Fortin J, Stanley PE, et al. Chemiluminescent and bioluminescentreporter gene assays[J]. Anal Biochem,1994,219(2):169-181.
[247]Schwartz O, Virelizier JL, Montagnier L, et al. A microtransfection method usingthe luciferase-encoding reporter gene for the assay of human immunodeficiencyvirus LTR promoter activity[J]. Gene,1990,88(2):197-205.
[248]Gorman G. DNA Cloning: A Practical Approach[M].2nd ed, IRL Press at OxfordUniversity Press,1995:143-l90.
[249]Shaw WV. Chloramphenicol acetyltrasferase from chloramphenicol-resistantbacteria. Methods enzymol[M]. Methods Enzymol,1975,43:737-755.
[250]Schenborn E, Titus D. Detection of eukaryotic transcription DNA regulatorysequences with the CAT reporter gene assay. Promega Notes21,1989:1-3.
[251]Wu H, Tao J, Sun YE. Regulation and function of mammalian DNA methylationpatterns:a genomic perspective[J]. Brief Funct Genomics,2012,3:7.doi:10.1093/bfgp/els011.
[252]Okano M, Bell DW, Haber DA, et al. DNA methyltransferases Dnmt3a and Dnmt3bare essential for de novo methylation and mammalian development[J]. Cell,1999,99(3):247-257.
[253]Lyko F, Ramsahoye BH, Kashevsky H, et al. Mammalian (cytosine-5)methyltransferases cause genomic DNA methylation and lethality in Drosophila[J].Nat Genet,1999,23(3):363-366.
[254]Kawai J, Hirose K, Fushiki S, et al. Comparison of DNA methylation patternsamong mouse cell lines by restriction landmark genomic scanning[J]. Mol Cell Biol,1994,14(11):7421-7427.
[255]Yamagata Y, Szabó P, Szüts D, et al. Rapid turnover of DNA methylation in humancells[J]. Epigenetics,2012,7(2):141-145.
[256]白坚石,王萍,马晴,等. S-腺苷酰-L-甲硫氨酸(SAM)对HL-60细胞生长与分化的影响[J].北京师范大学学报(自然科学版),2000,36(6):826-829.
[257]Pascale RM, Marras V, Simile MM, et al. Chemprevention of rat livercarcinogenesis by S-adenosyl-L-methionine:a long-term study[J]. Cancer Res,1992,52(18):4979-4986.
[258]Luo J, Li YN, Wang F, et al. S-adenosylmethionine inhibits the growth of cancercells by reversing the hypomethylation status of c-myc and H-ras in human gastriccancer and colon cancer[J]. Int J Biol Sci,2010,6(7):784-795.
[259]Wang BX, Yin BL, He B, et al. Overexpression of DNA damage-induced45alphagene contributes to esophageal squamous cell cancer by promoterhypomethylation[J]. J Exp Clin Cancer Res,2012,31(1):11.
[260]Tokizane T, Shiina H, Igawa M, et al. Cytochrome P4501B1is overexpressed andregulated by hypomethylation in prostate cancer[J]. Clin Cancer Res,2005,11(16):5793-5801.
[261]Kinzler KW, Vogelstein B. Landscaping the cancer terrain[J]. Science,1998,280(5366):1036-1037.
[262]Jones PA, Laird PW. Cancer epigenetics comes of age[J]. Nat Genet,1999,21(2):163-167.
[263]Paredes J, Albergaria A, Oliveira JT, et al. P-cadherin overexpression is an indicatorof clinical outcome in invasive breast carcinomas and is associated with CDH3promoter hypomethylation[J]. Clin Cancer Res,2005,11(16):5869-5877.
[264] Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genesoverexpressed in pancreatic ductal adenocarcinoma[J]. Cancer Res,2003,63(14):4158-4166.
[265] Litkouhi B, Kwong J, Lo CM, et al. Claudin-4overexpression in epithelial ovariancancer is associated with hypomethylation and is a potential target for modulationof tight junction barrier function using a C-terminal fragment of Clostridiumperfringens enterotoxin[J]. Neoplasia,2007,9(4):304-314.
[266]Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics[J].Science,2001,293(5532):1068-1070.
[1]张松法,叶枫,陈怀增,等.基因组CpG岛甲基化检测技术研究进展[J].国际遗传学杂志,2006,29(3):201-203.
[2]武立鹏,朱卫国. DNA甲基化的生物学应用及检测方法进展[J].中国检验医学杂志,2004,27(7):468-474.
[3]董玉玮,侯进慧,朱必才,等.表观遗传学的相关概念和研究进展[J].生命的化学,2005,22(1):1-3.
[4]郭晓青,李兆申. DNA甲基化与恶性肿瘤[J].国际消化病杂志,2007,27(1):57-60.
[5] Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past andfuture[J]. J Gastroenterol,2006,41(5):401-407.
[6] Vauhkonen M, Vauhkonen H, Sipponen P. Pathology and molecular biology ofgastric cancer[J]. Best Pract Res Clin Gastroenterol,2006,20(4):651-674.
[7] Shirahata A, Sakuraba K, Kitamura Y, et al. Detection of vimentin methylation in theserum of patients with gastric cancer[J]. Anticancer Res,2012,32(3):791-794.
[8] Joo JK, Kim SH, Kim HG, et al. CpG Methylation of transcription factor4ingastriccarcinoma[J]. Ann Surg Oncol,2010,17(2):3344-3353.
[9] Mikata R, Fukai K, Arai M, et al. BCL2L10is frequently silenced by promoterhypermethylation in gastric cancer[J]. Oncol Rep,2010,23(6):1701-1708.
[10]魏国华,杨春雨,杨静,等. HPV感染与p16基因甲基化在胃癌发生中的作用[J].肿瘤防治研究,2011,38(1):51-54.
[11]Leal MF, Lima EM, Silva PN, et al. Promoter hypermethylation of CDH1, FHIT,MTAP and PLAGL1in gastric adenocarcinoma in individuals from NorthernBrazil[J]. World J Gastroenterol,2007,13(18):2568-2574.
[12]Chen L, Su L, Li J, et al. Hypermethylated FAM5C and MYLK in serum as diagnosisand pre-warning markers for gastric cancer[J]. Dis Markers,2012,32(3):195-202.
[13]Bae JM, Shin SH, Kwon HJ, et al. ALU and LINE-1hypomethylations in multistepgastric carcinogenesis and their prognostic implications[J]. Int J Cancer,2011,28.doi:10.1002/ijc.27369.
[14]Yang Y, Liu J, Li X, et al. PCDH17gene promoter demethylation and cell cyclearrest by genistein in gastric cancer[J]. Histol Histopathol,2012,27(2):217-224.
[15]Oishi Y, Watanabe Y, Yoshida Y,et al. Hypermethylation of Sox17gene is useful as amolecular diagnostic application in early gastric cancer[J]. Tumour Biol,2012,33(2):383-393.
[16]Jemal A, Siegel R, Ward E, et al. Cancer statistics2007. CA Cancer J Clin,2007,57(1):43-66.
[17]Migheli F, Migliore L. Epigenetics of colorectal cancer[J]. Clinical Genetics,2012,81:312–318. doi:10.1111/j.1399-0004.
[18]Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers[J].Nature,1997,386(6625):623-627.
[19]Das PM, Signal R. DNA methylation and cancer[J]. J Clin Oncol,2004,22(22):4632-4642.
[20]Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomichypomethylation[J]. Science,2003,300(5618):489-492.
[21]Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer[J]. NatRev Genet,2002,3(6):415-428.
[22]Kawasaki T, Nosho K, Ohnishi M, et al. IGFBP3promoter methylation in colorectalcancer:relationship with microsatellite instability, CpG island methylator phenotype,and p53[J]. Neoplasia,2007,9(12):1091-1098.
[23]邹继红,吴平平,汤日宁,等.结直肠癌血清中DLC1p16和RUNX3基因甲基化检测的临床意义[J].江苏医药,2011,37(24):2938-2940.
[24]Gómez Del Pulgar T, Valdés-Mora F, Bandrés E, et al. Cdc42is highly expressed incolorectal adenocarcinoma and downregulates ID4through an epigenetic mechanism[J].Int J Oncol,2008,33(1):185-193.
[25]Sameer AS, Abdullah S, Nissar S, et al. The blues of P(16)INK(4a):Aberrantpromoter methylation and association with colorectal cancer in the Kashmir valley[J].Mol Med Report,2012,5(4):1053-1057.
[26]deSousa E, Melo F, Colak S, et al. Methylation of cancer-stem-cell-associated Wnttarget genes predicts poor prognosis in colorectal cancer patients[J]. Cell Stem Cell,2011,9(5):476-485.
[27]Hibi K, Goto T, Shirahata A, et al. Methylation of TFPI2No Longer Detected in theSerum DNA of Colorectal Cancer Patients after Curative Surgery[J]. Anticancer Res,2012,32(3):787-790.
[28]McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer[J]. IntImmunopharmacol,2005,5(7-8):1113-1130
[29]Li JY. Epidemiology of esophageal cancer in China[J]. Natl Cancer Inst Monogr,1982,62:113-120.
[30]Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joinsgenetics[J]. Trends Genet,2000,16(4):168-174.
[31]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA Methylation of p16, MGMT, and hMLH1Genes in Combination with MTH FRC677T Genetic Polymorphism inEsophageal Squamous Cell Carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[32]宋长山,谭家驹,崔金环,等.食管鳞癌中p16基因启动子区甲基化及其表达[J].肿瘤防治研究,2008,35(1):14-17.
[33]Wang JS, Guo M, Montgomery EA, et al. DNA promoter hypermethylation of p16and APC predicts neoplastic progression in Barrett's esophagus[J]. Am J Gastroenterol,2009,104(9):2153-2160.
[34]郭晓青,王士杰,张健慧,等.食管鳞状细胞癌及癌前病变组织中p16基因甲基化的研究[J].肿瘤防治杂志,2005,12(7):495-497.
[35]姚群峰,康新江,郝巧玲,等.巢式甲基化特异性PCR检测食管癌病人血清中p16基因启动子区过甲基化[J].肿瘤防治研究,2005,32(8):463-466.
[36]Hardie LJ, Darnton SJ, Wallis YL, et al. P16expression in Barretts' esophagus andesophageal adenocarcinoma:association with genetic and epigenetic alterations[J].Cancer Lett,2005,217(2):221-230.
[37]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[38]Guo XQ, Wang SJ, Zhang LW, et al. DNA methylation and loss of protein expressionin esophageal squamous cell carcinogenesis of high-risk area[J]. J Exp Clin CancerRes,2007,26(4):587-594.
[39]Wang J, Sasco AJ, Fu C, et al. Aberrant DNA methylation of p16, MGMT, andhMLH1genes in combination with MTHFRC677T genetic polymorphism inesophageal squamous cell carcinoma[J]. Cancer Epidemiol Biomarkers Prev,2008,17(1):118-125.
[40]KurokiT, Trapasso F, Yendamuri S, et al. Allele loss and promoter hypermethylationof VHL, RAR-B, RASSF1A, and FHIT tumor suppressor genes on chromosome3pin esophageal squamous cell carcinoma[J]. Cancer Res,2003,63(13):3724-3728.
[41]Lee EJ, Lee BB, Kim JW, et al. Aberrant methylation of Fragile Histidine Triad geneis associated with poor prognosis in early stage esophageal squamous cellcarcinoma[J]. Eur J Cancer,2006,42(7):972-980.
[42]Noguchi T, Takeno S, Kimura Y, et al. FHIT expression and hypermethylation inesophageal squamous cell carcinoma[J]. Int J MolMed,2003,11(4):441-447.
[43]Schildhaus HU, Krochel I, Lippert H, et al. Promoter hypermethylation of p16IN K4a,E2cadherin, O62MGMT, DAPK and FHIT in adenocarcinomas of the esophagus,esophagogastric junction and proximal stomach[J]. Int J Oncol,2005,26(6):1493-1500.
[44]Tsao I, Atramentova LA. Genetic and epigenetic changes of FHIT gene in patientswith esophageal cancer[J]. Tsitol Genet,2009,43(6):40-44.
[45]Kaz AM, Luo Y, Dzieciatkowski S, et al. Aberrantly methylated PKP1in theprogression of Barrett's esophagus to esophageal adenocarcinoma[J]. GenesChromosomes Cancer,2012,51(4):384-393.
[46]You YJ, Chen YP, Zheng XX, et al. Aberrant methylation of the PTPRO gene inperipheral blood as a potential biomarker in esophageal squamous cell carcinomapatients[J]. Cancer Lett,2012,315(2):138-144.
[47]Fujiwara S, Noguchi T, Takeno S, et al. Hypermethylation of p16gene promotercorrelates with loss of p16expression that results in poorer prognosis in esophagealsquamous cell carcinomas[J]. Dis Esophagus,2008,21(2):125-131.
[48]Ling ZQ, Li P, Ge MH, et al. Hypermethylation-modulated down-regulation ofCDH1expression contributes to the progression of esophageal cancer[J]. Int J MolMed,2011,27(5):625-635.
[49]Dong SW, Cui YT, Zhong RR, et al. Decreased expression of retinoblastomaprotein-interacting zinc-finger gene1in human esophageal squamous cell cancer byDNA methylation[J]. Clin Lab,2012,58(1-2):41-51.
[50]Liu Z, Zhang L, Ding F, et al.5-Aza-2'-deoxycytidine induces retinoic acidreceptor-beta(2) demethylation and growth inhibition in esophageal squamouscarcinoma cells[J]. Cancer Lett,2005,230(2):271-283.
[51]Biewusch K, Heyne M, Grützmann R. DNA methylation in pancreaticcancer:protocols for the isolation of DNA and bisulfite modification[J]. Methods MolBiol,2012,863(3):273-280.
[52]Chen M, Xue X, Wang F, et al. Expression and promoter methylation analysis ofATP-binding cassette genes in pancreatic cancer[J]. Oncol Rep,2012,27(1):265-269.
[53]Attri J, Srinivasan R, Majumdar S, et al. Alterations of Tumor Suppressor Genep16INK4in Pancreatic Ductal Carcinoma[J]. BMC Gastroenterol,2005,(5):22. doi:10.1186/1471-230X-5-22.
[54]Sato N, Ueki T, Fukushima N, et al. Aberrant Methylation of CpG Islands inIntraductal Papillary Mucinous Neoplasms of the Pancreas[J]. Gastroenterology,2002,123(1):365-372.
[55]House MG, Guo M, Iacobuzio Donahue C, et al. Molecular Progression of PromoterMethylation in Intraductal Papillary Mucinous Neoplasms(IPMN)of the Pancreas[J].Carcinogenesis,2003,24(2):193-198.
[56]Gerdes B, Ramaswamy A, Kersting M, et al. P16(INK4)Alterations in ChronicPancreatitis-indicator for High-risk Lesions for Pancreatic Cancer[J]. Surgery,2001,129(4):490-497.
[57]Dey P, Ponnusamy MP, Deb S, et al. Human RNA polymerase II-association factor1(hPaf1/PD2)regulates histone methylation and chromatin remodeling in pancreaticcancer[J]. PLoS One,2011,6(10):e26926.
[58]Li M, Zhao ZW. Clinical implications of mismatched repair gene promotermethylation in pancreatic cancer[J]. Med Oncol,2011,1:10.doi:10.1007/s12032-011-9968-y.
[59]Nomoto S, Kinoshita T, Mori T, et al. Adverse prognosis of epigenetic inactivation inRUNX3gene at1p36in human pancreatic cancer[J]. Br J Cancer,2008,98(10):1690-1695.
[60]Cai HH, Sun YM, Miao Y, et al. Aberrant methylation frequency of TNFRSF10Cpromoter in pancreatic cancer cell lines[J]. Hepatobiliary Pancreat Dis Int,2011,10(1):95-100.
[61]Abe T, Toyota M, Suzuki H, et al. Upregulation of BNIP3by5-aza-2'-deoxycytidinesensitizes pancreatic cancer cells to hypoxia-mediated cell death[J]. J Gastroenterol,2005,40(5):504-510.
[62]MomParler RL, Bovenzi V. DNA methylation and cancer[J]. J Cell Physiol,2000,183(2):145-154.
[63]Leone G. Voso MT, Teofili L, et al. Inhibitors of DNA methylation in the treatment ofhematological malignancies and MDS[J]. Clin imunol,2003,109(1):89-102.
[64]李卉,刘玲,王洪江,等.高分辨熔解曲线法检测哈萨克族食管癌患者癌组织中FHIT CDKN2A启动子区甲基化水平及临床意义[J].科技导报,2011,29(31):59-63.
[65]Sun M, Uozaki H, Hino R, et al. SOX9expression and its methylation status ingastric cancer[J]. Virchows Arch,2012,460(3):271-279.