基于生物信息学分析CHDH基因在结肠腺癌中的表达及其与预后的关系
Analysis of CHDH Gene Expression in COAD and Its Relationship with Prognosis Based on Bioinformatics
DOI: 10.12677/ACM.2023.13122618, PDF, HTML, XML, 下载: 121  浏览: 168 
作者: 王倚天, 厉运凤, 张继东*:青岛大学附属医院心血管内科,山东 青岛
关键词: 胆碱脱氢酶结肠腺癌蛋白互作网络TCGA数据库CHDH COAD PPI TCGA Database
摘要: 目的:评估CHDH在结肠腺癌中的表达,及其与结肠腺癌患者临床病理特征、预后的关系。方法:在本研究中,我们通过分析源自TCGA数据库的478例结肠腺癌组织和60例正常组织的转录组数据样本,分析CHDH基因在结肠腺癌及癌旁组织中的表达以及与结肠腺癌患者临床特征、预后的关系,随后使用q-PCR验证CHDH在细胞系中的表达,紧接着我们构建蛋白质互作网络,并使用TIMER数据库分析CHDH在不同肿瘤中的表达。结果:CHDH在结肠腺癌肿瘤组织中的表达显著增加(P < 0.001),并且CHDH的高表达与结肠腺癌的临床特征(病理分期、T分期)显著相关(P < 0.05)。CHDH的低表达提示患者预后不佳(Log rank P = 0.0086)。结论:CHDH的表达与结肠腺癌的进展有关,可能成为改善结肠腺癌预后的潜在靶点,为结肠腺癌的治疗提供了新的理论依据。
Abstract: Objective: To evaluate the expression of CHDH in colorectal adenocarcinoma and its relationship with clinicopathological features and prognosis of colorectal adenocarcinoma patients. Methods: In this study, we analyzed the transcriptome data samples of 478 colorectal adenocarcinoma tissues and 60 normal tissues from the TCGA database to analyze the expression of CHDH gene in colorectal adenocarcinoma and adjacent tissues as well as its relationship with clinical characteristics and prognosis of colorectal adenocarcinoma patients. Then q-PCR was used to verify the expression of CHDH in cell lines. Then we constructed a protein interaction network and analyzed the expression of CHDH in different tumors using the TIMER database. Results: The expression of CHDH in colorec-tal adenocarcinoma was significantly increased (P < 0.001), and the high expression of CHDH was significantly correlated with the clinical features (pathological stage, T stage) of colorectal adeno-carcinoma (P < 0.05). Low expression of CHDH suggested poor prognosis (Log rank P = 0.0086). Con-clusion: The expression of CHDH is related to the progression of colorectal adenocarcinoma, which may be a potential target to improve the prognosis of colorectal adenocarcinoma, providing a new theoretical basis for the treatment of colorectal adenocarcinoma.
文章引用:王倚天, 厉运凤, 张继东. 基于生物信息学分析CHDH基因在结肠腺癌中的表达及其与预后的关系[J]. 临床医学进展, 2023, 13(12): 18623-18631. https://doi.org/10.12677/ACM.2023.13122618

1. 引言

结直肠癌(CRC, colorectal cancer)是最常见的消化系统肿瘤,其发病率位居全球第三,死亡率位居第二 [1] [2] 。每年新增超过185万结直肠癌确诊病例,其中约85,000例死亡病例 [3] 。结直肠癌最常见的病理类型是起源于结直肠黏膜上皮细胞的结肠腺癌(COAD) [4] 。结直肠癌的传统治疗干预措施包括手术、化疗和放疗。近年来,靶向治疗和免疫治疗等新兴疗法取得了重大进展。治疗方法的进步提高了结直肠癌患者的生存率。然而,结直肠癌的预后仍然较差。患者预后不良可能是因为许多患者在诊断时已处于晚期,并且更容易发生远处转移 [5] [6] 。研究表明,结直肠癌患者的5年生存率为65%,I期结肠癌和直肠癌的5年生存率为90%,而IV期结肠癌和直肠癌的5年生存率则分别降至11%和15% [7] 。因此,迫切需要寻找新的生物标志物来改善结直肠癌的诊断和预后。

CHDH (胆碱脱氢酶,Choline dehydrogenase)基因是一种蛋白质编码相关基因,位于人类3号染色体2区1带1亚带(3p21.1),能够编码分子量为65KD的蛋白质 [8] 。CHDH是一种与线粒体自噬相关的线粒体酶,分布在线粒体膜上,同时也是胆碱代谢的关键酶之一 [9] 。近年来,越来越多的研究开始探索CHDH与不同疾病的关系。研究发现,CHDH与多种疾病密切相关 [8] ,包括精神疾病 [10] 、代谢综合征以及肿瘤等 [11] 。CHDH与乳腺癌 [12] 、头颈鳞状细胞癌 [13] 、胰腺癌 [14] 、肝癌 [15] 、胃癌 [16] 、肾透明细胞癌 [17] 发病密切相关。有研究表明,胃癌组织中CHDH低表达提示具有较差的预后,其潜在调控机制可能与NF-κB通路调控的肿瘤代谢有关 [16] 。

基于以上的研究,我们发现CHDH与多种恶性肿瘤进展有关,很可能成为结肠腺癌的潜在生物标志物。然而,CHDH在结肠腺癌发生、发展和转移中的潜在作用尚未被揭示。因此,本研究旨在通过对公共数据库的转录组数据进行生物信息学分析,探究CHDH在结肠腺癌中的表达及其与结肠腺癌患者临床病理特征、预后的联系,为结肠腺癌的早期诊断和治疗寻找新的靶点。

2. 方法

2.1. 数据来源

我们从TCGA公共数据库下载了478例结肠腺癌样本和60例正常样本组织的转录组数据 [18] 。然后,我们对转录组数据进行均一化处理以便于进一步分析。

2.2. 分析CHDH基因在结肠腺癌组织中的表达

Wilcoxon秩和检验和Wilcoxon符号秩检验用来分析CHDH基因在结肠腺癌组织中的表达。

2.3. 分析CHDH基因与结肠腺癌患者临床特征、预后关系

通过Kruskal-Wallis检验,Wilcoxon符号秩检验,logistic回归分析CHDH基因与临床病理特征的关系。紧接着,通过Kaplan-Meier plotter (http://kmplot.com/analysis) [19] 进行生存分析,制作生存曲线,分析CHDH在结肠腺癌中的预后价值。

2.4. 细胞系和细胞培养

NCM、SW480细胞系均使用含有10% FBS及1%青链霉素混合液的RPMI 1640培养基去培养,并且应该放置在环境温度为37℃、CO2浓度为5%的培养箱中培养。

2.5. RT-qPCR法检测CHDH mRNA表达水平

收集并提取各组细胞的总mRNA,利用分光光度计测定相应的浓度和纯度,进一步合成cDNA,以cDNA为模板进行PCR扩增。随后以95℃预变性30 s;95℃ 10 s,60℃ 30 s,循环40次;溶解曲线为95℃ 15 s,60℃ 60 s,95℃ 15 s。使用GAPDH作为内参,采用2-ΔΔCt法计算各基因相对表达量。引物:GAPDH-F,5'-TGACTTCAACAGCGACACCCA-3'和GAPDH-R,5'-CACCCTGTTGCTGTAGCCAAA-3';CHDH-F,5'-GCATCGGGAATGCTGATGA-3',CHDH-R,5'-GGCCAACCCCAGGTAGGT-3'。

2.6. TIMER数据库分析

应用TIMER数据库(https://cistrome.shinyapps.io/timer/)分析CHDH在不同肿瘤组织中的表达 [20] 。

2.7. 蛋白–蛋白互作网络(Protein-Protein Interaction Network, PPI)

使用STRING (http://string-db.org)数据库 [21] 探索目标基因与相关基因的交互关系,随后将确定下来的10个关键基因导入Cytoscape构建PPI蛋白互作网络。

2.8. 数据分析

使用R包(版本4.2.0)进行统计分析和绘图。本实验采用GraphPad Software Prism 9软件进行数据分析。所有数据均表示为标准差(SEM) ± 平均值(Mean)。两组数据使用t检验进行分析。所有研究均以P值 < 0.05为有统计学意义。

3. 结果

3.1. CHDH在结肠腺癌组织中高表达

为了研究CHDH在结肠腺癌和正常组织中的表达水平差异,我们分别比较了两组未配对样本和配对样本。结果显示,在结肠腺癌患者中,未配对样本中CHDH的表达显着增加(P < 0.001) (图1(A))。配对样品的结果与未配对样品的结果相同(P < 0.001) (图1(B))。

*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 1. Expression of CHDH in normal and COAD tissues. (A) The expression of CHDH in unpaired samples. (B) The expression of CHDH in paired samples

图1. CHDH在正常和结肠腺癌组织中的表达。(A) 未配对样品中CHDH的表达。(B) 配对样品中CHDH的表达

3.2. CHDH的表达与结肠腺癌的临床相关性

为了探究CHDH的表达与结肠腺癌是否具有临床相关性,我们对结肠腺癌的临床特征进行了研究,结果如图2所示。结果显示,CHDH高表达与病理分期、T分期具有显著的临床相关性,其差异具有统计学意义(P < 0.05) (图2)。

*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 2. Clinical correlation of CHDH expression in COAD. (A) T stage; (B) Pathologic stage

图2. CHDH的表达与结肠腺癌的临床相关性。(A) T分期;(B) 病理分期

3.3. CHDH的表达与结肠腺癌的预后关系

为了进一步明确CHDH表达与结肠腺癌患者临床结局之间的关系,我们利用Kaplan-Meier plotter绘制生存曲线,展开预后分析,结果显示,CHDH低表达组患者的总生存期(OS)低于高表达组(Log-rank P = 0.0086,图3)。

*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 3. Survival curves of patients with COAD with high CHDH expression and low CHDH expression

图3. 结肠腺癌患者CHDH高表达组与低表达组生存曲线

3.4. CHDH在结肠腺癌细胞系中高表达

为了进一步验证CHDH在结肠腺癌细胞系中的表达,我们从人正常的结肠上皮细胞和结肠腺癌细胞中提取总RNA并进行实时定量荧光PCR的检测。q-PCR检测结果显示,与人正常的结肠上皮细胞NCM组相比,SW480组CHDH的mRNA表达明显提高,差异具有统计学意义(P < 0.001,图4)。

*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 4. Expression of CHDH in NCM and SW480

图4. CHDH在NCM、SW480中的表达

3.5. CHDH在不同肿瘤中的表达

紧接着,为了进一步探究CHDH的表达在不同肿瘤类型中是否具有差异性,我们使用TIMER数据库对RNA测序数据进行分析。结果显示,与正常组织相比,CHDH在结肠腺癌组织中高表达;在膀胱癌、弥漫性大B细胞淋巴瘤、食管癌、低级别脑胶质瘤、前列腺癌、直肠腺癌、胸腺瘤等肿瘤中,CHDH呈现高表达;在肾上腺皮质癌、宫颈癌、头颈鳞状细胞癌、肾嫌色细胞癌、肾透明细胞癌、急性髓系白血病、肺鳞状细胞癌、胰腺癌、嗜铬细胞瘤和副神经节瘤、皮肤黑色素瘤、睾丸生殖细胞瘤、甲状腺癌、子宫癌肉瘤等肿瘤中,CHDH呈现低表达;而胆管癌、星形胶质瘤、肾乳头状细胞癌、肝细胞癌、肺腺癌、卵巢浆液性囊腺癌、子宫内膜癌等肿瘤中,CHDH表达并无统计学差异(图5)。

*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 5. Using TIMER database to analyze the expression of CHDH in different tumors

图5. 通过TIMER数据库分析CHDH在不同肿瘤中的表达

3.6. 蛋白互作网络分析

使用STRING工具进行蛋白互作网络构建,筛选出排名前十的基因,分别是:RGN、IL17RB、EIF3D、IFT52、ALDH7A1、MBOA、PLD2、 PEMT、SELENOI、CEPT1 (图6)。这些基因与CHDH具有较强的相关性,在结肠腺癌的进程中可能起到重要的作用。

Figure 6. Protein-protein interactions network results

图6. 蛋白–蛋白互作网络结果

4. 讨论

尽管结直肠癌的诊断和治疗取得了重大进展,但结直肠癌的早期诊断一直困扰着临床医生,因为结直肠癌的早期症状不是明显,通常没有特殊症状。结直肠癌的诊断主要依靠内窥镜检查 [22] 。内镜检查具有侵入性,病人依从性差,因此不能成为早期筛查的有效诊断方法 [23] 。目前临床上通常采用CEA或CA19-9作为CRC的生物标志物 [24] 。但上述两种生物标志物特异性和敏感性较差,对早期结直肠癌缺乏诊断价值,早期筛查能力欠佳。它们常用于评估肿瘤负荷和监测术后复发。研究表明结直肠癌患者CEA的敏感性水平为65%~74%,而CA19-9的敏感性水平仅为26%~48% [24] [25] 。血清CA19-9和CEA的水平在恶性和一些良性病变中均可升高。比如,在结直肠癌、乳腺癌、胃癌、肺癌、卵巢癌和胰腺癌等恶性肿瘤中发现了高水平的血清CEA [26] [27] 。CA19-9是临床上常用的胰腺癌生物标志物,可用于胰腺癌早期诊断、评估预后以及胰腺癌糖基化水平的异常改变 [28] 。此外,肺纤维化 [29] 、肝硬化 [30] 、肝炎 [31] 、胰腺炎 [32] 等非肿瘤疾病中血清CA199水平也可能会升高。因此,迫切需要新的肿瘤生物标志物来改善结直肠癌(CRC)的早期诊疗水平。

CHDH是一种蛋白质编码相关基因。CHDH编码的胆碱脱氢酶是胆碱代谢的关键酶,能够调控细胞内胆碱浓度,参与细胞代谢进程。先前的各项研究表明,CHDH在肿瘤发生发展中起到重要作用 [8] 。有研究指出,CHDH的表达与雌激素受体相关,乳腺癌CHDH的低表达可能会增加乳腺癌的复发风险 [33] 。

在本研究中,通过对TGCA结肠腺癌公共数据库进行分析,我们发现CHDH在结肠腺癌组织中表达增加,同时通过实时荧光定量PCR进一步验证这一结果,与结肠上皮细胞相比,结肠腺癌细胞系SW480中CHDH mRNA呈现高表达。此外,CHDH的高表达与结肠腺癌临床特征中的病理分期、T分期显著相关。这可能与结肠腺癌的增殖侵袭的改变有关,表明CHDH可能参与了结肠腺癌的发生发展。紧接着,通过绘制K-M曲线,我们发现CHDH低表达组患者的总生存期(OS)低于高表达组,因此,我们推测CHDH 的高表达与结肠腺癌的较好预后显著相关。通过STRING数据库对构建与CHDH相关的蛋白互作网络,我们发现RGN、IL17RB、EIF3D、IFT52、ALDH7A1、MBOA、PLD2、PEMT、SELENOI、CEPT1等10个核心基因。其中,EIF3D能够通过调控结直肠癌对5-氟尿嘧啶的耐药性影响肿瘤侵袭能力 [34] 。ALDH7A1也被证实与胰腺癌 [35] 、肾透明细胞癌 [36] 、肺小细胞癌 [37] 、前列腺癌 [38] 增殖迁移相关,可能成为肿瘤逃逸的潜在靶点。这也为CHDH在结肠腺癌中的可能存在的调控机制提供了一个新的切入点。

5. 结论

综上所述,本研究首次分析了CHDH在结肠腺癌中的作用。结果表明,CHDH在结肠腺癌的表达增加,表达量增高与肿瘤患者较好预后相关。CHDH有望成为结肠腺癌早期诊断的潜在生物标志物,这也为进一步研究CHDH在结肠腺癌的作用打下基础。本研究的不足之处在于,CHDH在结肠腺癌中的生物学机制仍有待进一步研究。此外,还需要进一步的实验、更多的临床数据来评估CHDH表达与临床特征、分期和预后的关系,这可能有助于发现新的肿瘤分期评估标志物,帮助药物开发,提高治疗效率。

NOTES

*通讯作者。

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