食管鳞癌预后相关的DNA甲基化分子标志物及其功能研究
发布时间：2018-08-17 10:56
【摘要】：目的:利用TCGA公共数据库的资源,筛选出预测食管鳞癌预后的DNA甲基化位点,并在已建立的食管鳞癌随访队列中进行验证;分析甲基化水平与病理参数、随访数据之间的关系,揭示DNA甲基化在食管鳞癌中的作用;将分子标志物检测与临床信息相结合,构建用以有效评价肿瘤预后风险的预测模型;对食管鳞癌相关的新候选基因FAM178B进行细胞水平的功能研究,观察去甲基化药物对基因表达的影响及FAM178B过表达对食管鳞癌细胞生物学行为的影响,初步探讨FAM178B在食管鳞癌中的作用机制。方法:1、从TCGA网站和UCSC Cancer Browser网站下载68例食管鳞癌男性患者的Human Methylation 450K BeadChip甲基化芯片、Illumina HiSeq_RNA-Seq Version 2转录组测序数据和临床信息。用R软件读入数据并构建数据集。根据注释筛选甲基化位点,用Spearman法分析不同位点甲基化水平与对应基因表达的相关性,Cox多因素回归模型调整年龄和临床分期后,分析每个位点甲基化值的风险比(HR)和95%可信区间(CI)。2、在135例食管鳞癌患者的癌组织石蜡切片中,采用荧光定量甲基化特异性PCR检测10个候选基因的甲基化水平,用甲基化百分比参数(PMR)表示。用Pearsonχ2检验或Fisher确切概率法分析每个基因甲基化程度与临床参数之间的关系,用Kaplan-Meier法绘制生存曲线并用Log-rank进行检验,单因素和多因素Cox风险比例模型计算HR值及95%CI。3、体外培养TE-1和Eca-109食管鳞癌细胞株,加入10μmol/L含5-氮杂-2’-脱氧胞苷(5-Aza-CdR)的培养液,并设立等体积的二甲基亚砜溶剂作为阴性对照组。分别收集各组培养0h、48h、72h的细胞,采用逆转录PCR法检测FAM178B基因表达水平的变化。4、构建GV358-FAM178B过表达慢病毒载体,用Western blot检测目的基因表达。转染HK293T细胞并对其进行包装,获得高滴度的慢病毒颗粒。慢病毒质粒感染TE-1和Eca-109细胞,分为实验组(加FAM178B基因过表达慢病毒感染的食管癌细胞组)和对照组(加阴性对照病毒的食管癌细胞组)。分别用克隆形成实验、Transwell实验和细胞凋亡实验评价FAM178B过表达对肿瘤细胞的增殖、侵袭和凋亡的影响。结果:1、TCGA数据中与基因表达有相关性且与预后相关的位于CpG岛的甲基化位点867个,其中具有潜在的抑癌生物学意义和临床应用价值的位点(相关系数-0.5,风险比2.0)48个。32个位点位于启动子区,对应15个基因,用于后续样本验证;其余16个位点位于基因体区。2、以PMR为4%作为截断值,将各基因甲基化水平分为高甲基化和低甲基化。FAM178B、FAM83C、PDLIM4、PRSS27、KLHDC7B、CALML5、MT1L、HOXC11、EVC2和OTOP3的高甲基化频率分别为94.81%、85.19%、42.22%、85.93%、82.96%、94.07%、83.70%、57.04%、44.44%和84.44%。低分化癌患者发生FAM83C基因高甲基化的风险比中分化和高分化癌患者降低了63.1%(OR=0.369,95%CI=0.140-0.972,P=0.039)。低分化癌患者发生PRSS27基因高甲基化的风险比中分化和高分化患者增加了3.305倍(OR=4.305,95%CI=0.946-19.585,P=0.042)。无淋巴结转移患者发生PDLIM4基因高甲基化的风险比有淋巴结转移患者降低了51.1%(OR=0.488,95%CI=0.242-0.985,P=0.044)。无脉管神经浸润患者发生PDLIM4基因高甲基化的风险比有脉管神经浸润患者降低了62.3%(OR=0.377,95%CI=0.156-0.909,P=0.026)。3、135例食管鳞癌患者的5年总体生存率为18.3%。单因素Cox预后分析显示,FAM178B(HR=1.881,95%CI=1.334-2.652,P0.001)、PRSS27(HR=4.789,95%CI=1.195-19.184,P=0.027)、PDLIM4(HR=7.646,95%CI=1.595-36.662,P=0.011)、EVC2(HR=2.313,95%CI=1.364-3.924,P=0.002)、OTOP3(HR=1.379,95%CI=1.045-1.822,P=0.023)、CALML5(HR=3.416,95%CI=1.426-8.181,P=0.006)和MT1L(HR=1.559,95%CI=1.086-2.240,P=0.016)基因高甲基化均会影响食管鳞癌患者的总体生存率,是危险因素。进一步分层分析发现,多项临床参数考虑为引起基因甲基化与预后之间发生相关性的混杂因素。通过Cox多因素回归模型控制混杂因素,FAM178B(HR=1.684,95%CI=1.160-2.445,P=0.006)、PRSS27(HR=5.116,95%CI=1.320-19.826,P=0.018)、PDLIM4(HR=10.264,95%CI=2.297-45.857,P=0.002)、EVC2(HR=2.412,95%CI=1.396-4.169,P=0.002)、CALML5(HR=3.173,95%CI=1.327-7.586,P=0.009)基因高甲基化可独立预测食管鳞癌患者的不良预后。逐步向前法得到预后指数(PI)方程式:PI=1.109×X5+0.557×X9+0.650×FAM178B+1.440×CALML5+0.701×EVC2,其中X5为浸润深度,X9为有无脉管神经浸润。以PI的上下四分位数为界,将观察对象分为低危组(PI2.474),中危组(2.474≤PI3.197)和高危组(PI≥3.197),三组的生存率具有统计学差异(χ2=29.716,P0.001)。4、在使用5-Aza-CdR分别处理48小时和72小时后,Eca-109细胞中FAM178B基因表达变化无统计学意义(F=2.987,P=0.126),而TE-1细胞中FAM178B基因表达下调,组间差异有统计学意义(F=576.460,P0.001)。5、克隆形成实验显示,Eca-109细胞中实验组的克隆形成数高于对照组(268±4个vs.212±3个,P0.001);TE-1细胞中实验组的克隆形成数高于对照组(67±2个vs.58±2个,P=0.005)。Transwell实验结果显示,Eca-109细胞中实验组的穿膜细胞数高于对照组(77±1.52个vs.66±1.49个,P=0.048);TE-1细胞无阳性结果。细胞凋亡实验结果显示,Eca-109细胞中实验组的细胞凋亡率高于对照组((6.56±0.04)%vs.(5.18±0.08)%,P0.001);TE-1细胞无阳性结果。结论:1、甲基化芯片和转录组测序数据的整合分析,有助于从海量的甲基化位点中筛选出潜在的预后相关标志物。2、食管鳞癌中存在多基因同时甲基化的现象,多因素Cox回归分析显示,FAM178B、PRSS27、PDLIM4、EVC2和CALML5基因甲基化是食管鳞癌术后生存时间的独立危险因素。3、由浸润深度、有无脉管神经浸润、FAM178B甲基化、CALML5甲基化和EVC2甲基化五项影响因素构建的预后指数公式可有效地预测食管鳞癌患者的长期生存状况。4、不同食管鳞癌细胞中去甲基化药物对FAM178B基因表达的影响不一致,提示启动子区CpG岛的甲基化对基因表达的调控具有肿瘤异质性,癌变过程中可能存在其他分子机制参与了基因表达。5、过表达FAM178B可促进食管鳞癌细胞的克隆形成,增强侵袭能力,同时又加速了肿瘤细胞的凋亡,提示FAM178B基因在食管鳞癌发病中具有致癌作用,其在食管鳞癌患者预后中的具体机制值得进一步研究。
[Abstract]:Objective: To screen DNA methylation sites for predicting the prognosis of esophageal squamous cell carcinoma (ESCC) using TCGA public database and validate them in the established follow-up cohort of ESCC. The function of FAM178B, a novel candidate gene related to esophageal squamous cell carcinoma, was studied at cell level to observe the effect of demethylation drugs on gene expression and the effect of FAM178B overexpression on the biological behavior of esophageal squamous cell carcinoma cells. Methods: 1. Human Methylation 450K BeadChip methylation chip, Illumina HiSeq_RNA-Seq Version 2 transcriptome sequencing data and clinical information were downloaded from TCGA website and UCSC Cancer Browser website from 68 male patients with esophageal squamous cell carcinoma. Spearman method was used to analyze the correlation between methylation levels at different sites and corresponding gene expression. Cox multivariate regression model adjusted the age and clinical stage. The risk ratio (HR) and 95% confidence interval (CI) of methylation values at each site were analyzed. Fluorescence quantitative methylation specificity was used in paraffin sections of 135 esophageal squamous cell carcinoma patients. The methylation levels of 10 candidate genes were detected by sex PCR and expressed by methylation percentage parameter (PMR). The relationship between methylation degree of each gene and clinical parameters was analyzed by Pearson_2 test or Fisher exact probability method. Survival curves were drawn by Kaplan-Meier method and tested by Log-rank. Single-factor and multifactor Cox risk ratio models were used. HR value and 95% CI.3 were calculated. TE-1 and Eca-109 esophageal squamous cell lines were cultured in vitro. The expression of FAM178B gene was detected by reverse transcription polymerase chain reaction (RT-PCR). 4. The lentiviral vector GV358-FAM178B was constructed and the target gene expression was detected by Western blot. The lentiviral particles with high titer were obtained by transfecting HK293T cells and packaging them. The lentiviral plasmids infected TE-1 and Eca-109 cells were divided into experimental group (esophageal cancer cells infected with lentiviral overexpression of FAM178B gene) and control group (esophageal cancer cells infected with lentiviral overexpression of FAM178B gene). The effects of FAM178B overexpression on proliferation, invasion and apoptosis of tumor cells were evaluated by clone formation assay, Transwell assay and apoptosis assay. Results: 1. There were 867 methylation sites on CpG island in TCGA data which were correlated with gene expression and prognosis. 48 loci (correlation coefficient-0.5, risk ratio 2.0) with potential biological significance and clinical application value were located in the promoter region, corresponding to 15 genes for subsequent sample validation; the remaining 16 loci were located in the genome region.2, with 4% PMR as the cut-off value, the methylation levels of each gene were divided into hypermethylation and hypomethylation. The hypermethylation frequencies of FAM178B, FAM83C, PDLIM4, PRSS27, KLHDC7B, CALML5, MT1L, HOXC11, EVC2 and OTOP3 were 94.81%, 85.19%, 42.22%, 85.93%, 82.96%, 94.07%, 83.70%, 57.04%, 44.44% and 84.44% respectively. The risk of hypermethylation of FAM83C gene in poorly differentiated cancer patients was 63.1% lower than that in moderately differentiated and highly differentiated cancer patients (OR = 0.369, 95% CI = 0.140%). The risk of PRSS27 hypermethylation in poorly differentiated cancer patients was 3.305 times higher than that in moderately differentiated and well differentiated patients (OR = 4.305, 95% CI = 0.946-19.585, P = 0.042). The risk of PDLIM4 hypermethylation in patients without lymph node metastasis was 51.1% lower than that in patients with lymph node metastasis (OR = 0.488, 95% CI = 0.242-0.985, P = 0.044). The risk of PDLIM4 hypermethylation in patients without vascular nerve invasion was 62.3% (OR = 0.377, 95% CI = 0.156-0.909, P = 0.026). 3, 135 patients with esophageal squamous cell carcinoma had a 5-year overall survival rate of 18.3%. Univariate Cox prognostic analysis showed that FAM178B (HR = 1.881, 95% CI = 1.334-2.652, P 0.001), PRSS27 (HR = 4.789, 95% CI = 4.652, P 0.001). 1.195-19.184, P = 0.027, P = 0.027, PDLIM4 (HR = 7.646, 95% CI = 7.646, 95% CI = 1.595-36.662, P = 0.011), EVC2 (HR = 2.313, 95% CI = 1.364-3.924, P = 0.002, P = 0.002), OTOP3 (HR = 1.379, 95% CI = 1.379, 95% CI = 1.045-1.045-1.822, P = 0.023), CALM5 (HR = CALM5 (HR = 3.416, 95% CI = 3.416, 95% CI = 3.95% CI = 1.95% CI = 1.416, 95% 006) and MTL (HR = 1.559, 95% CI = 1.086-2.240, P = 0.016) gene hypermethylation may affect the overall survival of esophageal squamous cell carcinoma patients. Further stratified analysis revealed that multiple clinical parameters were confounding factors associated with genetic methylation and prognosis. Cox multivariate regression model was used to control confounding factors, including FAM178B (HR = 1.684, 95% CI = 1.160-2.445, P = 0.006), PRSS27 (HR = 5.116, 95% CI = 1.320-19.826, P = 0.018), PDLIM4 (HR = 10.264, 95% CI = 1.160-2.445, P = 0.006). CI = 2.297-45.857, P = 0.002, P = 0.002, EVC2 (HR = 2.412, 95% CI = 2.412, 95% CI = 1.396-4.169, P = 0.002), EVC2 (HR = 2.412, 95% CI = 1.396-4.169, P = 0.169, P = 0.002), CALML5 (HR = 3.173, 95% CI = 3.173, 95% CI = 1.327-7-7.586, P = 0.327-7-7.586, P = 0.009) gene hypermethylation independently predictpoor prognosis in esophagsquamous cell carcinoma patients. Prognostic index (PI) equation was obtained by stepL5 + 0.701 * EVC2, where X5 is The patients were divided into low-risk group (PI2.474), middle-risk group (2.474 < PI3.197) and high-risk group (PI < 3.197). The survival rates of the three groups were statistically different (2 = 29.716, P 0.001). After treatment with 5-Aza-CdR for 48 hours and 72 hours, the survival rates of FA in Eca-109 cells were significantly different (2 = 29.716, P 0.001). There was no significant difference in the expression of M178B gene (F = 2.987, P = 0.126), but the expression of FAM178B gene in TE-1 cells was down-regulated. There was a significant difference between the two groups (F = 576.460, P 0.001). Cloning formation assay showed that the number of clones in the experimental group was higher than that in the control group (268 + 4 vs. 212 + 3, P 0.001). The number of penetrating cells in Eca-109 cells was higher than that in the control group (67 + 2 vs. 58 + 2, P = 0.005). CONCLUSIONS: 1. Integration of methylation chip and transcriptome sequencing data is helpful to screen out potential prognostic markers from a large number of methylation sites. 2. Simultaneous methylation of multiple genes exists in esophageal squamous cell carcinoma. Multivariate Cox regression analysis shows that FAM178B and PRS are associated with multiple gene methylation. Methylation of S27, PDLIM4, EVC2 and CAML5 genes is an independent risk factor for survival time after esophageal squamous cell carcinoma surgery. 3 Prognostic index formula constructed by five factors including depth of invasion, presence or absence of vascular nerve invasion, FAM178B methylation, CALML5 methylation and EVC2 methylation can effectively predict the long-term survival of patients with esophageal squamous cell carcinoma. The effect of demethylation drugs on the expression of FAM178B gene was inconsistent, suggesting that the methylation of CpG island in promoter region has tumor heterogeneity in the regulation of gene expression. Other molecular mechanisms may be involved in gene expression during carcinogenesis. 5. Overexpression of FAM178B can promote the cloning and invasion of esophageal squamous cell carcinoma cells. It is suggested that FAM178B gene has carcinogenic effect in the pathogenesis of esophageal squamous cell carcinoma, and its specific mechanism in the prognosis of patients with esophageal squamous cell carcinoma deserves further study.
【学位授予单位】：宁波大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.1
本文编号：2187382
[Abstract]:Objective: To screen DNA methylation sites for predicting the prognosis of esophageal squamous cell carcinoma (ESCC) using TCGA public database and validate them in the established follow-up cohort of ESCC. The function of FAM178B, a novel candidate gene related to esophageal squamous cell carcinoma, was studied at cell level to observe the effect of demethylation drugs on gene expression and the effect of FAM178B overexpression on the biological behavior of esophageal squamous cell carcinoma cells. Methods: 1. Human Methylation 450K BeadChip methylation chip, Illumina HiSeq_RNA-Seq Version 2 transcriptome sequencing data and clinical information were downloaded from TCGA website and UCSC Cancer Browser website from 68 male patients with esophageal squamous cell carcinoma. Spearman method was used to analyze the correlation between methylation levels at different sites and corresponding gene expression. Cox multivariate regression model adjusted the age and clinical stage. The risk ratio (HR) and 95% confidence interval (CI) of methylation values at each site were analyzed. Fluorescence quantitative methylation specificity was used in paraffin sections of 135 esophageal squamous cell carcinoma patients. The methylation levels of 10 candidate genes were detected by sex PCR and expressed by methylation percentage parameter (PMR). The relationship between methylation degree of each gene and clinical parameters was analyzed by Pearson_2 test or Fisher exact probability method. Survival curves were drawn by Kaplan-Meier method and tested by Log-rank. Single-factor and multifactor Cox risk ratio models were used. HR value and 95% CI.3 were calculated. TE-1 and Eca-109 esophageal squamous cell lines were cultured in vitro. The expression of FAM178B gene was detected by reverse transcription polymerase chain reaction (RT-PCR). 4. The lentiviral vector GV358-FAM178B was constructed and the target gene expression was detected by Western blot. The lentiviral particles with high titer were obtained by transfecting HK293T cells and packaging them. The lentiviral plasmids infected TE-1 and Eca-109 cells were divided into experimental group (esophageal cancer cells infected with lentiviral overexpression of FAM178B gene) and control group (esophageal cancer cells infected with lentiviral overexpression of FAM178B gene). The effects of FAM178B overexpression on proliferation, invasion and apoptosis of tumor cells were evaluated by clone formation assay, Transwell assay and apoptosis assay. Results: 1. There were 867 methylation sites on CpG island in TCGA data which were correlated with gene expression and prognosis. 48 loci (correlation coefficient-0.5, risk ratio 2.0) with potential biological significance and clinical application value were located in the promoter region, corresponding to 15 genes for subsequent sample validation; the remaining 16 loci were located in the genome region.2, with 4% PMR as the cut-off value, the methylation levels of each gene were divided into hypermethylation and hypomethylation. The hypermethylation frequencies of FAM178B, FAM83C, PDLIM4, PRSS27, KLHDC7B, CALML5, MT1L, HOXC11, EVC2 and OTOP3 were 94.81%, 85.19%, 42.22%, 85.93%, 82.96%, 94.07%, 83.70%, 57.04%, 44.44% and 84.44% respectively. The risk of hypermethylation of FAM83C gene in poorly differentiated cancer patients was 63.1% lower than that in moderately differentiated and highly differentiated cancer patients (OR = 0.369, 95% CI = 0.140%). The risk of PRSS27 hypermethylation in poorly differentiated cancer patients was 3.305 times higher than that in moderately differentiated and well differentiated patients (OR = 4.305, 95% CI = 0.946-19.585, P = 0.042). The risk of PDLIM4 hypermethylation in patients without lymph node metastasis was 51.1% lower than that in patients with lymph node metastasis (OR = 0.488, 95% CI = 0.242-0.985, P = 0.044). The risk of PDLIM4 hypermethylation in patients without vascular nerve invasion was 62.3% (OR = 0.377, 95% CI = 0.156-0.909, P = 0.026). 3, 135 patients with esophageal squamous cell carcinoma had a 5-year overall survival rate of 18.3%. Univariate Cox prognostic analysis showed that FAM178B (HR = 1.881, 95% CI = 1.334-2.652, P 0.001), PRSS27 (HR = 4.789, 95% CI = 4.652, P 0.001). 1.195-19.184, P = 0.027, P = 0.027, PDLIM4 (HR = 7.646, 95% CI = 7.646, 95% CI = 1.595-36.662, P = 0.011), EVC2 (HR = 2.313, 95% CI = 1.364-3.924, P = 0.002, P = 0.002), OTOP3 (HR = 1.379, 95% CI = 1.379, 95% CI = 1.045-1.045-1.822, P = 0.023), CALM5 (HR = CALM5 (HR = 3.416, 95% CI = 3.416, 95% CI = 3.95% CI = 1.95% CI = 1.416, 95% 006) and MTL (HR = 1.559, 95% CI = 1.086-2.240, P = 0.016) gene hypermethylation may affect the overall survival of esophageal squamous cell carcinoma patients. Further stratified analysis revealed that multiple clinical parameters were confounding factors associated with genetic methylation and prognosis. Cox multivariate regression model was used to control confounding factors, including FAM178B (HR = 1.684, 95% CI = 1.160-2.445, P = 0.006), PRSS27 (HR = 5.116, 95% CI = 1.320-19.826, P = 0.018), PDLIM4 (HR = 10.264, 95% CI = 1.160-2.445, P = 0.006). CI = 2.297-45.857, P = 0.002, P = 0.002, EVC2 (HR = 2.412, 95% CI = 2.412, 95% CI = 1.396-4.169, P = 0.002), EVC2 (HR = 2.412, 95% CI = 1.396-4.169, P = 0.169, P = 0.002), CALML5 (HR = 3.173, 95% CI = 3.173, 95% CI = 1.327-7-7.586, P = 0.327-7-7.586, P = 0.009) gene hypermethylation independently predictpoor prognosis in esophagsquamous cell carcinoma patients. Prognostic index (PI) equation was obtained by stepL5 + 0.701 * EVC2, where X5 is The patients were divided into low-risk group (PI2.474), middle-risk group (2.474 < PI3.197) and high-risk group (PI < 3.197). The survival rates of the three groups were statistically different (2 = 29.716, P 0.001). After treatment with 5-Aza-CdR for 48 hours and 72 hours, the survival rates of FA in Eca-109 cells were significantly different (2 = 29.716, P 0.001). There was no significant difference in the expression of M178B gene (F = 2.987, P = 0.126), but the expression of FAM178B gene in TE-1 cells was down-regulated. There was a significant difference between the two groups (F = 576.460, P 0.001). Cloning formation assay showed that the number of clones in the experimental group was higher than that in the control group (268 + 4 vs. 212 + 3, P 0.001). The number of penetrating cells in Eca-109 cells was higher than that in the control group (67 + 2 vs. 58 + 2, P = 0.005). CONCLUSIONS: 1. Integration of methylation chip and transcriptome sequencing data is helpful to screen out potential prognostic markers from a large number of methylation sites. 2. Simultaneous methylation of multiple genes exists in esophageal squamous cell carcinoma. Multivariate Cox regression analysis shows that FAM178B and PRS are associated with multiple gene methylation. Methylation of S27, PDLIM4, EVC2 and CAML5 genes is an independent risk factor for survival time after esophageal squamous cell carcinoma surgery. 3 Prognostic index formula constructed by five factors including depth of invasion, presence or absence of vascular nerve invasion, FAM178B methylation, CALML5 methylation and EVC2 methylation can effectively predict the long-term survival of patients with esophageal squamous cell carcinoma. The effect of demethylation drugs on the expression of FAM178B gene was inconsistent, suggesting that the methylation of CpG island in promoter region has tumor heterogeneity in the regulation of gene expression. Other molecular mechanisms may be involved in gene expression during carcinogenesis. 5. Overexpression of FAM178B can promote the cloning and invasion of esophageal squamous cell carcinoma cells. It is suggested that FAM178B gene has carcinogenic effect in the pathogenesis of esophageal squamous cell carcinoma, and its specific mechanism in the prognosis of patients with esophageal squamous cell carcinoma deserves further study.
【学位授予单位】：宁波大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.1
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