【摘要】：目的:利用TCGA公共數(shù)據(jù)庫的資源,篩選出預(yù)測食管鱗癌預(yù)后的DNA甲基化位點(diǎn),并在已建立的食管鱗癌隨訪隊(duì)列中進(jìn)行驗(yàn)證;分析甲基化水平與病理參數(shù)、隨訪數(shù)據(jù)之間的關(guān)系,揭示DNA甲基化在食管鱗癌中的作用;將分子標(biāo)志物檢測與臨床信息相結(jié)合,構(gòu)建用以有效評價(jià)腫瘤預(yù)后風(fēng)險(xiǎn)的預(yù)測模型;對食管鱗癌相關(guān)的新候選基因FAM178B進(jìn)行細(xì)胞水平的功能研究,觀察去甲基化藥物對基因表達(dá)的影響及FAM178B過表達(dá)對食管鱗癌細(xì)胞生物學(xué)行為的影響,初步探討FAM178B在食管鱗癌中的作用機(jī)制。方法:1、從TCGA網(wǎng)站和UCSC Cancer Browser網(wǎng)站下載68例食管鱗癌男性患者的Human Methylation 450K BeadChip甲基化芯片、Illumina HiSeq_RNA-Seq Version 2轉(zhuǎn)錄組測序數(shù)據(jù)和臨床信息。用R軟件讀入數(shù)據(jù)并構(gòu)建數(shù)據(jù)集。根據(jù)注釋篩選甲基化位點(diǎn),用Spearman法分析不同位點(diǎn)甲基化水平與對應(yīng)基因表達(dá)的相關(guān)性,Cox多因素回歸模型調(diào)整年齡和臨床分期后,分析每個(gè)位點(diǎn)甲基化值的風(fēng)險(xiǎn)比(HR)和95%可信區(qū)間(CI)。2、在135例食管鱗癌患者的癌組織石蠟切片中,采用熒光定量甲基化特異性PCR檢測10個(gè)候選基因的甲基化水平,用甲基化百分比參數(shù)(PMR)表示。用Pearsonχ2檢驗(yàn)或Fisher確切概率法分析每個(gè)基因甲基化程度與臨床參數(shù)之間的關(guān)系,用Kaplan-Meier法繪制生存曲線并用Log-rank進(jìn)行檢驗(yàn),單因素和多因素Cox風(fēng)險(xiǎn)比例模型計(jì)算HR值及95%CI。3、體外培養(yǎng)TE-1和Eca-109食管鱗癌細(xì)胞株,加入10μmol/L含5-氮雜-2’-脫氧胞苷(5-Aza-CdR)的培養(yǎng)液,并設(shè)立等體積的二甲基亞砜溶劑作為陰性對照組。分別收集各組培養(yǎng)0h、48h、72h的細(xì)胞,采用逆轉(zhuǎn)錄PCR法檢測FAM178B基因表達(dá)水平的變化。4、構(gòu)建GV358-FAM178B過表達(dá)慢病毒載體,用Western blot檢測目的基因表達(dá)。轉(zhuǎn)染HK293T細(xì)胞并對其進(jìn)行包裝,獲得高滴度的慢病毒顆粒。慢病毒質(zhì)粒感染TE-1和Eca-109細(xì)胞,分為實(shí)驗(yàn)組(加FAM178B基因過表達(dá)慢病毒感染的食管癌細(xì)胞組)和對照組(加陰性對照病毒的食管癌細(xì)胞組)。分別用克隆形成實(shí)驗(yàn)、Transwell實(shí)驗(yàn)和細(xì)胞凋亡實(shí)驗(yàn)評價(jià)FAM178B過表達(dá)對腫瘤細(xì)胞的增殖、侵襲和凋亡的影響。結(jié)果:1、TCGA數(shù)據(jù)中與基因表達(dá)有相關(guān)性且與預(yù)后相關(guān)的位于CpG島的甲基化位點(diǎn)867個(gè),其中具有潛在的抑癌生物學(xué)意義和臨床應(yīng)用價(jià)值的位點(diǎn)(相關(guān)系數(shù)-0.5,風(fēng)險(xiǎn)比2.0)48個(gè)。32個(gè)位點(diǎn)位于啟動(dòng)子區(qū),對應(yīng)15個(gè)基因,用于后續(xù)樣本驗(yàn)證;其余16個(gè)位點(diǎn)位于基因體區(qū)。2、以PMR為4%作為截?cái)嘀?將各基因甲基化水平分為高甲基化和低甲基化。FAM178B、FAM83C、PDLIM4、PRSS27、KLHDC7B、CALML5、MT1L、HOXC11、EVC2和OTOP3的高甲基化頻率分別為94.81%、85.19%、42.22%、85.93%、82.96%、94.07%、83.70%、57.04%、44.44%和84.44%。低分化癌患者發(fā)生FAM83C基因高甲基化的風(fēng)險(xiǎn)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)。低分化癌患者發(fā)生PRSS27基因高甲基化的風(fēng)險(xiǎn)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)。無淋巴結(jié)轉(zhuǎn)移患者發(fā)生PDLIM4基因高甲基化的風(fēng)險(xiǎn)比有淋巴結(jié)轉(zhuǎn)移患者降低了51.1%(OR=0.488,95%CI=0.242-0.985,P=0.044)。無脈管神經(jīng)浸潤患者發(fā)生PDLIM4基因高甲基化的風(fēng)險(xiǎn)比有脈管神經(jīng)浸潤患者降低了62.3%(OR=0.377,95%CI=0.156-0.909,P=0.026)。3、135例食管鱗癌患者的5年總體生存率為18.3%。單因素Cox預(yù)后分析顯示,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)基因高甲基化均會影響食管鱗癌患者的總體生存率,是危險(xiǎn)因素。進(jìn)一步分層分析發(fā)現(xiàn),多項(xiàng)臨床參數(shù)考慮為引起基因甲基化與預(yù)后之間發(fā)生相關(guān)性的混雜因素。通過Cox多因素回歸模型控制混雜因素,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)基因高甲基化可獨(dú)立預(yù)測食管鱗癌患者的不良預(yù)后。逐步向前法得到預(yù)后指數(shù)(PI)方程式:PI=1.109×X5+0.557×X9+0.650×FAM178B+1.440×CALML5+0.701×EVC2,其中X5為浸潤深度,X9為有無脈管神經(jīng)浸潤。以PI的上下四分位數(shù)為界,將觀察對象分為低危組(PI2.474),中危組(2.474≤PI3.197)和高危組(PI≥3.197),三組的生存率具有統(tǒng)計(jì)學(xué)差異(χ2=29.716,P0.001)。4、在使用5-Aza-CdR分別處理48小時(shí)和72小時(shí)后,Eca-109細(xì)胞中FAM178B基因表達(dá)變化無統(tǒng)計(jì)學(xué)意義(F=2.987,P=0.126),而TE-1細(xì)胞中FAM178B基因表達(dá)下調(diào),組間差異有統(tǒng)計(jì)學(xué)意義(F=576.460,P0.001)。5、克隆形成實(shí)驗(yàn)顯示,Eca-109細(xì)胞中實(shí)驗(yàn)組的克隆形成數(shù)高于對照組(268±4個(gè)vs.212±3個(gè),P0.001);TE-1細(xì)胞中實(shí)驗(yàn)組的克隆形成數(shù)高于對照組(67±2個(gè)vs.58±2個(gè),P=0.005)。Transwell實(shí)驗(yàn)結(jié)果顯示,Eca-109細(xì)胞中實(shí)驗(yàn)組的穿膜細(xì)胞數(shù)高于對照組(77±1.52個(gè)vs.66±1.49個(gè),P=0.048);TE-1細(xì)胞無陽性結(jié)果。細(xì)胞凋亡實(shí)驗(yàn)結(jié)果顯示,Eca-109細(xì)胞中實(shí)驗(yàn)組的細(xì)胞凋亡率高于對照組((6.56±0.04)%vs.(5.18±0.08)%,P0.001);TE-1細(xì)胞無陽性結(jié)果。結(jié)論:1、甲基化芯片和轉(zhuǎn)錄組測序數(shù)據(jù)的整合分析,有助于從海量的甲基化位點(diǎn)中篩選出潛在的預(yù)后相關(guān)標(biāo)志物。2、食管鱗癌中存在多基因同時(shí)甲基化的現(xiàn)象,多因素Cox回歸分析顯示,FAM178B、PRSS27、PDLIM4、EVC2和CALML5基因甲基化是食管鱗癌術(shù)后生存時(shí)間的獨(dú)立危險(xiǎn)因素。3、由浸潤深度、有無脈管神經(jīng)浸潤、FAM178B甲基化、CALML5甲基化和EVC2甲基化五項(xiàng)影響因素構(gòu)建的預(yù)后指數(shù)公式可有效地預(yù)測食管鱗癌患者的長期生存狀況。4、不同食管鱗癌細(xì)胞中去甲基化藥物對FAM178B基因表達(dá)的影響不一致,提示啟動(dòng)子區(qū)CpG島的甲基化對基因表達(dá)的調(diào)控具有腫瘤異質(zhì)性,癌變過程中可能存在其他分子機(jī)制參與了基因表達(dá)。5、過表達(dá)FAM178B可促進(jìn)食管鱗癌細(xì)胞的克隆形成,增強(qiáng)侵襲能力,同時(shí)又加速了腫瘤細(xì)胞的凋亡,提示FAM178B基因在食管鱗癌發(fā)病中具有致癌作用,其在食管鱗癌患者預(yù)后中的具體機(jī)制值得進(jìn)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.
【學(xué)位授予單位】：寧波大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.1

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