特发性肺纤维化中CDH1及RUNX3启动子甲基化状态的检测及其意义
摘要
[背景]特发性肺纤维化(IPF)是一类原因未明的慢性进展性间质性肺疾病,以成纤维细胞的异常增殖和分化以及细胞外基质的堆积为特点,目前缺乏有效的治疗手段。近年来逐渐发现IPF与肺癌无论是在临床还是发病机制方面均存在许多相关性,有学者提出从肿瘤学的角度出发研究IPF,可能会对IPF有更全面认识。表观遗传学尤其是DNA甲基化引起的抑癌基因失活参与肿瘤的发生发展,DNA甲基化在IPF中的研究正逐步展开。肌成纤维母细胞是IPF发病中重要的效应细胞,肺泡上皮间充质转化是形成肌成纤维母细胞的一个重要来源。已知CDHl以及RUNX3缺失促进上皮间充质转化过程,同时CDH1及RUNX3也是重要的肿瘤抑制基因,多种肿瘤中存在CDHl及RUNX3甲基化现象。但是IPF中CDH1及RUNX3是否也存在甲基化现象目前尚无相关报道。
[目的]本研究拟检测IPF组织学标本中CDHl及RUNX3甲基化状态,并分析与临床指标相关性。
[方法]本实验应用甲基化特异性PCR(Methylation specific PCR, MSP)方法检测10株细胞系、16例IPF患者和17对肺癌及切缘正常组织中CDH1及RUNX3启动子的甲基化状态。利用real-time qPCR技术检测10株细胞系中CDH1及RUNX3mRNA表达水平。利用Western Blot方法检测10株细胞系中CDH1蛋白(E-cadherin)表达并利用免疫组织化学方法检测17对肺癌及切缘正常组织以及16例IPF组织E-cadherin表达。回顾16例IPF患者临床资料,分析CDH1及RUNX3甲基化状态与其临床指标相关性；分析17例肺癌患者E-cadherin表达与CDH1甲基化相关性。
[结果]
1、发生CDH1甲基化细胞系(293T, BGC823, RKO, MGC803, Hela, MKN45)比未发生甲基化细胞系(MKN74, MCF7, HCT116, AGS)其mRNA表达水平明显降低。
2、发生CDH1完全甲基化细胞系(RKO, Hela, MGC803)无CDH1蛋白(E-cadherin)表达。
3、发生RUNX3甲基化细胞系(RKO,293T, MCF7, MKN74, AGS, MGC803, Hela)比未发生甲基化细胞系(BGC823, HCT116, MKN45)其mRNA表达水平明显降低。
4、11例(68.75%)IPF组织有CDHl启动子甲基化,7例(41.18%)肺癌组织中有CDHl启动子甲基化,切缘正常组织无CDHl甲基化。IPF中CDHl启动子甲基化与病人年龄、性别、吸烟、病程无关。
5、9例(52.94%)肺癌组织E-cadherin表达异常,CDHl甲基化患者中E-cadherin异常表达的比例(71.4%)比正常表达比例(28.6%)高。2例CDHl甲基化的IPF患者,其成纤维细胞灶表面被覆的上皮细胞中E-cadherin表达减弱或缺失。
6、7例(43.75%)IPF组织中有RUNX3启动子甲基化,9例(52.94%)肺癌组织中有RUNX3启动子甲基化,3例(17.65%)切缘正常组织有RUNX3启动子甲基化。IPF中RUNX3启动子甲基化与病人年龄、性别、吸烟、病程无关。
[结论]
1、细胞系试验表明CDHl及RUNX3启动子区域高甲基化在转录水平上抑制目的基因表达。
2、IPF同肺癌一样,存在CDH1及RUNX3启动子区域甲基化现象,其中CDHl甲基化发生率显著高于切缘正常组织。IPF发生抑癌基因甲基化可能是IPF容易合并肺癌的原因之一。
3、IPF组织成纤维细胞灶表面被覆的肺泡上皮细胞E-cadherin表达缺失或减弱可能与CDHl甲基化有关。CDHl甲基化引起蛋白表达缺失,促进EMT进程,参与IPF发病。
Backgroud
Idiopathic pulmonary fibrosis(IPF)is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, without effective therapy. Its pathological character is the fibroblastic foci which comprises of aggregates of mesenchymal cells and extra cellular matrix(ECM). More and more evidences from clinic and basic research show that IPF is a diseae with similarities and links to cancer. Further research on IPF from an oncologist's view will help us get a more comprehensive understanding of IPF. Epigenetic alterations, espeically DNA methylation, participate in the pathogenesis of cancer. DNA methylation research in IPF is gradually conducted. Myofibroblasts are key effector cells in pulmonary fibrosis and one of their cellular origins is considered to be pulmonary epithelial cell which go under epithelial mesenchymal transition(EMT). The loss of CDH1and RUNX3promotes EMT process. CDH1and RUNX3are thought to be function as tumor suppressor genes and are inactivated or downregulated by promoter hypermethylation in a variety of tumors. However, the promoter hypermethylation of CDH1and RUNX3in IPF have not been reported.
Objective
To detect the methylation status of CDH1and RUNX3promoter region CpG islands in IPF and analyse the relationship between genes'methylation frequency and clinic parameters.
Methods
In the present study, we examined the methylation status of CDH1and RUNX3promoter region CpG islands in10cell lines,16cases of IPF,17cases of lung cancer and17cases of matching non-neoplastic tissue by methylation-specific PCR. CDH1and RUNX3gene expression were examined in10cell lines by real-time quantitative PCR. The protein expression of CDH1(E-cadherin) was examined in10cell lines by Western Blot and in17cases of lung cancer,17cases of matching non-neoplastic tissues and16cases of IPF tissues which have CDH1promoter hypermethylation by immunohistochemistry. We also reviewed the clinic data of IPF patients and analysed the correlations between the two genes'methylation frequency and clinic parameters. We also analysed the correlations between E-cadherin expression and CDH1promoter methylation status in17cases of lung cancer.
Results
1. The expression of CDH1mRNA were lower in those cell lines which were promoter hypermethylation, including293T, BGC823, RKO,MGC803, Hela, MKN45than in those cell lines which were promoter unmethylaion, including MKN74, MCF7, HCT116,AGS.
2. Those cell lines which were completely methylated, including RKO, Hela, MGC803, were not detected in expression of CDH1protein level(E-cadherin).
3. The expression of RUNX3mRNA were lower in those cell lines which were promoter hypermethylation, including RKO,293T, MCF7, MKN74, AGS, MGC803, Hela than in those cell lines which were promoter unmethylaion, including BGC823, HCT116,MKN45.
4. Aberrant hypermethylation of CDH1was detected in11of16(68.75%) IPF tissues,7of17(41.18%) lung cancer tissues. Whereas none of the matched normal lung tissues presented hypermethylation of CDH1. Statistical analyses of the correlation between CDH1promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
5. Aberrant CDH1protein(E-cadherin) expression was detected in9/17(52.94%) lung cancer tissues. In CDH1methylated lung cacer patients, aberrant E-cadherin expression(71.4%)is higher than normal expression(28.6%). Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in two cases of IPF tissues which are CDH1promoter hypermethylation.
6. Aberrant hypermethylation of RUNX3was detected in7of16(43.75%) IPF tissues,9of17(52.94%) lung cancer tissues and3of17(17.65%) matched normal lung tissues. Statistical analyses of the correlation between RUNX3promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
Conclusions
1. The cell lines experiments show that the transcription of CDH1and RUNX3may be downregulated by promoter hypermethylation.
2. Promoter hypermethylation of CDH1and RUNX3are observed in IPF, similar to lung cancer.The gene CDH1methylation incidence shows significantly higher when it compares to matching normal lung tissues. Tumor suppressor genes'promoter hypermethylation in IPF tissues is one of the reasons that IPF patients are susceptible to tumor.
3. Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in IPF tissues may be related with CDH1promoter hypermethylation. The loss of E-cadherin due to CDH1methylation may take part in EMT process of IPF.
[目的]本研究拟检测IPF组织学标本中CDHl及RUNX3甲基化状态,并分析与临床指标相关性。
[方法]本实验应用甲基化特异性PCR(Methylation specific PCR, MSP)方法检测10株细胞系、16例IPF患者和17对肺癌及切缘正常组织中CDH1及RUNX3启动子的甲基化状态。利用real-time qPCR技术检测10株细胞系中CDH1及RUNX3mRNA表达水平。利用Western Blot方法检测10株细胞系中CDH1蛋白(E-cadherin)表达并利用免疫组织化学方法检测17对肺癌及切缘正常组织以及16例IPF组织E-cadherin表达。回顾16例IPF患者临床资料,分析CDH1及RUNX3甲基化状态与其临床指标相关性；分析17例肺癌患者E-cadherin表达与CDH1甲基化相关性。
[结果]
1、发生CDH1甲基化细胞系(293T, BGC823, RKO, MGC803, Hela, MKN45)比未发生甲基化细胞系(MKN74, MCF7, HCT116, AGS)其mRNA表达水平明显降低。
2、发生CDH1完全甲基化细胞系(RKO, Hela, MGC803)无CDH1蛋白(E-cadherin)表达。
3、发生RUNX3甲基化细胞系(RKO,293T, MCF7, MKN74, AGS, MGC803, Hela)比未发生甲基化细胞系(BGC823, HCT116, MKN45)其mRNA表达水平明显降低。
4、11例(68.75%)IPF组织有CDHl启动子甲基化,7例(41.18%)肺癌组织中有CDHl启动子甲基化,切缘正常组织无CDHl甲基化。IPF中CDHl启动子甲基化与病人年龄、性别、吸烟、病程无关。
5、9例(52.94%)肺癌组织E-cadherin表达异常,CDHl甲基化患者中E-cadherin异常表达的比例(71.4%)比正常表达比例(28.6%)高。2例CDHl甲基化的IPF患者,其成纤维细胞灶表面被覆的上皮细胞中E-cadherin表达减弱或缺失。
6、7例(43.75%)IPF组织中有RUNX3启动子甲基化,9例(52.94%)肺癌组织中有RUNX3启动子甲基化,3例(17.65%)切缘正常组织有RUNX3启动子甲基化。IPF中RUNX3启动子甲基化与病人年龄、性别、吸烟、病程无关。
[结论]
1、细胞系试验表明CDHl及RUNX3启动子区域高甲基化在转录水平上抑制目的基因表达。
2、IPF同肺癌一样,存在CDH1及RUNX3启动子区域甲基化现象,其中CDHl甲基化发生率显著高于切缘正常组织。IPF发生抑癌基因甲基化可能是IPF容易合并肺癌的原因之一。
3、IPF组织成纤维细胞灶表面被覆的肺泡上皮细胞E-cadherin表达缺失或减弱可能与CDHl甲基化有关。CDHl甲基化引起蛋白表达缺失,促进EMT进程,参与IPF发病。
Backgroud
Idiopathic pulmonary fibrosis(IPF)is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, without effective therapy. Its pathological character is the fibroblastic foci which comprises of aggregates of mesenchymal cells and extra cellular matrix(ECM). More and more evidences from clinic and basic research show that IPF is a diseae with similarities and links to cancer. Further research on IPF from an oncologist's view will help us get a more comprehensive understanding of IPF. Epigenetic alterations, espeically DNA methylation, participate in the pathogenesis of cancer. DNA methylation research in IPF is gradually conducted. Myofibroblasts are key effector cells in pulmonary fibrosis and one of their cellular origins is considered to be pulmonary epithelial cell which go under epithelial mesenchymal transition(EMT). The loss of CDH1and RUNX3promotes EMT process. CDH1and RUNX3are thought to be function as tumor suppressor genes and are inactivated or downregulated by promoter hypermethylation in a variety of tumors. However, the promoter hypermethylation of CDH1and RUNX3in IPF have not been reported.
Objective
To detect the methylation status of CDH1and RUNX3promoter region CpG islands in IPF and analyse the relationship between genes'methylation frequency and clinic parameters.
Methods
In the present study, we examined the methylation status of CDH1and RUNX3promoter region CpG islands in10cell lines,16cases of IPF,17cases of lung cancer and17cases of matching non-neoplastic tissue by methylation-specific PCR. CDH1and RUNX3gene expression were examined in10cell lines by real-time quantitative PCR. The protein expression of CDH1(E-cadherin) was examined in10cell lines by Western Blot and in17cases of lung cancer,17cases of matching non-neoplastic tissues and16cases of IPF tissues which have CDH1promoter hypermethylation by immunohistochemistry. We also reviewed the clinic data of IPF patients and analysed the correlations between the two genes'methylation frequency and clinic parameters. We also analysed the correlations between E-cadherin expression and CDH1promoter methylation status in17cases of lung cancer.
Results
1. The expression of CDH1mRNA were lower in those cell lines which were promoter hypermethylation, including293T, BGC823, RKO,MGC803, Hela, MKN45than in those cell lines which were promoter unmethylaion, including MKN74, MCF7, HCT116,AGS.
2. Those cell lines which were completely methylated, including RKO, Hela, MGC803, were not detected in expression of CDH1protein level(E-cadherin).
3. The expression of RUNX3mRNA were lower in those cell lines which were promoter hypermethylation, including RKO,293T, MCF7, MKN74, AGS, MGC803, Hela than in those cell lines which were promoter unmethylaion, including BGC823, HCT116,MKN45.
4. Aberrant hypermethylation of CDH1was detected in11of16(68.75%) IPF tissues,7of17(41.18%) lung cancer tissues. Whereas none of the matched normal lung tissues presented hypermethylation of CDH1. Statistical analyses of the correlation between CDH1promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
5. Aberrant CDH1protein(E-cadherin) expression was detected in9/17(52.94%) lung cancer tissues. In CDH1methylated lung cacer patients, aberrant E-cadherin expression(71.4%)is higher than normal expression(28.6%). Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in two cases of IPF tissues which are CDH1promoter hypermethylation.
6. Aberrant hypermethylation of RUNX3was detected in7of16(43.75%) IPF tissues,9of17(52.94%) lung cancer tissues and3of17(17.65%) matched normal lung tissues. Statistical analyses of the correlation between RUNX3promoter hypermethylation and clinic parameters demonstrated that there was no significant difference between methylated and unmethylated patients with regard to age, gender, smoke history and duration of disease.
Conclusions
1. The cell lines experiments show that the transcription of CDH1and RUNX3may be downregulated by promoter hypermethylation.
2. Promoter hypermethylation of CDH1and RUNX3are observed in IPF, similar to lung cancer.The gene CDH1methylation incidence shows significantly higher when it compares to matching normal lung tissues. Tumor suppressor genes'promoter hypermethylation in IPF tissues is one of the reasons that IPF patients are susceptible to tumor.
3. Alveolar epithelial cells covering fibroblastic foci showed negative or slight positive immunoreactivity to E-cadherin in IPF tissues may be related with CDH1promoter hypermethylation. The loss of E-cadherin due to CDH1methylation may take part in EMT process of IPF.
引文
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