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World Journal of Cancer Research
Vol. 13  No. 02 ( 2023 ), Article ID: 64483 , 10 pages
10.12677/WJCR.2023.132011

MMP11基因对肺腺癌诊断和预后的影响

赵强1*，李兴广2,3#

1天津市肿瘤医院空港医院肿瘤精准检测与转化中心，天津

2中国科学院大学宁波华美医院，浙江 宁波

3中国科学院大学宁波生命与健康产业研究院，浙江 宁波

收稿日期：2023年3月24日；录用日期：2023年4月14日；发布日期：2023年4月25日

摘要

目的：分析MMP11基因在肺腺癌中的表达特征，并评估其对肺腺癌诊断和预后的影响。方法：从TCGA数据库中下载肺腺癌转录组数据，利用生物信息学方法对MMP11在肺腺癌中的表达特征进行分析、并将该基因的表达特征与临床信息进行关联分析，进而对肺腺癌诊断及预后的影响进行系统分析。结果：MMP11基因在肺癌中高表达，对肺腺癌的诊断具有重要价值，但对肺腺癌预后的影响还有待于进一步研究。结论：MMP11基因有可能成为肺腺癌诊断相关的重要生物标记物。

关键词

MMP11，肺腺癌，诊断，预后

Effect of MMP11 Gene on Diagnosis and Prognosis of Lung Adenocarcinoma

Qiang Zhao1*, Xingguang Li2,3#

1Center for Precion Medicine and Translational Research, Tianjin Cancer Hospital Airport Hospital, Tianjin

2Ningbo Huamei Hospital, University of Chinese Academy of Sciences, Ningbo Zhejiang

3Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo Zhejiang

Received: Mar. 24th, 2023; accepted: Apr. 14th, 2023; published: Apr. 25th, 2023

ABSTRACT

Objective: To analyze the characteristics of MMP11 expression in lung adenocarcinoma and evaluate the impact on diagnosis and prognosis of lung adenocarcinoma. Method: The transcriptomic data of lung adenocarcinoma were downloaded from the TCGA database, and the expression characteristics of MMP11 in lung adenocarcinoma were analyzed by bioinformatic method, and then the expression characteristics of MMP11 were correlated with clinical information, so as to systematically analyze its influence on lung adenocarcinoma’ diagnosis and prognosis. Result: MMP11 gene is highly expressed in lung cancer and plays a significant role in the diagnosis of lung adenocarcinoma, but its effect on the prognosis of lung adenocarcinoma remains to be further elucidated. Conclusion: MMP11 gene may be an important biomarker in the diagnosis of lung adenocarcinoma.

Keywords:MMP11, Lung Adenocarcinoma, Diagnosis, Prognosis

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

肺癌是造成癌症相关死亡的主要原因，其病理分型大致可以分为两类：非小细胞肺癌(Non-small cell lung cancer, NSCLC)和小细胞肺癌，其中非小细胞肺癌占肺癌总数的85%左右。非小细胞肺癌又可以分为：腺癌、鳞癌和大细胞癌，其中以肺腺癌(Lung adenocarcinoma, LUAD)最为常见，占肺癌总数的一半左右。手术、放疗和化疗是肺癌治疗的三种常用方法，然而，局部治疗方法，包括手术和放射治疗，对晚期转移患者效果较差。目前，化疗是晚期转移性肺癌的主要治疗方法，但化疗药物对肿瘤细胞的靶向性不强，在杀伤肿瘤细胞的同时，对人体正常组织细胞的损害很大，导致其副作用过大，如恶心、呕吐、腹泻、便秘、心肺损伤等 [1] [2] [3] [4] [5] 。同时，多次用药会导致肿瘤细胞耐药 [6] 。

最近几年，随着“精准医学”概念的兴起，越来越多的针对特定基因的靶向药物被应用于临床，且取得了较好的临床效果，为很多肿瘤尤其是肺癌的治疗带来了革命性的变化 [7] [8] 。同时，很多对肿瘤起到驱动作用的基因被陆续开发为肿瘤治疗的靶点，如EGFR、VEGF、ALK、MET、KRAS、ROS1和HER2等，靶向药物通过特异性杀伤肿瘤细胞或者改变肿瘤微环境对肿瘤的发生发展起到明显的抑制作用 [9] - [15] 。在肺癌的治疗领域，针对肺癌相关特定基因的靶向治疗药物已被陆续开发出来，包括细胞生长因子受体抑制剂、血管生成抑制剂、信号转导抑制剂等 [16] [17] [18] 。虽然这些靶向药物取得了较好的临床效果，极大地延长了病人的生存期，但随着肿瘤细胞耐药性的出现，肺癌的治疗仍面临较大挑战，临床上对新型靶向治疗药物的需求仍然较大 [19] [20] [21] 。

基因组学和生物信息学的发展为肿瘤致病机理研究提供了有效的方法，被证明是一种寻找肿瘤相关基因靶点的可靠方法 [21] [22] 。此外，国内外很多公共数据库中存储了大量的肿瘤相关基因的表达数据，也为破译肿瘤发生发展的分子机制提供了较为方便和有效的方法，如TCGA (The Cancer Gene Atlas, https://gdc.cancer.gov/)数据库包含了大量由微阵列或高通量测序产生的转录组数据。胶原和纤维组织代谢过程被很多研究证明与肿瘤的侵袭转移密切相关，基质金属蛋白酶(MMPs)被认为是参与胶原和纤维组织代谢过程的重要基因，现在，在人类基因组中已经发现了24种MMPs基因，研究较多的主要有MMP2、MMP3、MMP7、MMP9、MMP10、MMP12、MMP23等，MMPs不仅对肿瘤微环境发挥调节作用，对肿瘤的侵袭和转移过程也同样发挥重要调控作用 [23] [24] [25] 。MMP11，也被称为基质溶血素-3，是基质金属蛋白酶家族的一个重要成员，通常分泌到细胞外发挥其酶活性作用，可在患者血清中检测到 [26] [27] 。在本研究中，我们从TCGA数据库中下载肺腺癌相关基因表达数据，通过生物信息学方法对MMP11在肺腺癌中的表达特征、及在肿瘤的诊断和预后评估过程中的作用进行了分析，系统评估了MMP11作为肺腺癌在诊断和预后评估中的价值。

2. 材料和方法

2.1. 肺腺癌相关转录组数据的下载和获取

从TCGA公共数据库中下载594例肺腺癌RNAseq转录组数据(TCGA-LUAD)，将FPKM (fregments per kilobase per million)格式的RNAseq数据转换成TPM (transcripts per million reads)格式并进行log2转化。

2.2. 统计分析

R语言(3.6.3版本)用于数据的统计分析，ggplot2包(3.3.3版本)用于数据的可视化，pROC包用于ROC曲线的绘制，卡方检验(Chi-square test)用于MMP11表达量和临床病理特征之间的关联分析。Kaplan-Meier 分析和Cox多因素分析用于MMP11表达量和预后之间的关联分析。

3. 结果

3.1. 肺腺癌患者的临床特征分析

从TCGA公共数据库中下载肺腺癌患者的临床特征相关信息，临床特征包括病人的年龄、性别、总生存期、病理分期、远端转移情况、生存状况等。我们利用卡方检验(Chi-square test)对肺腺癌中MMP11基因表达与临床特征进行了关联分析，以MMP11的表达中位数作为分界线，将入组的肺腺癌患者分为MMP11高表达组和低表达组，结果显示MMP11基因与肺腺癌中不同的T分期、N分期、M分期、病理组织学分期、性别、年龄、人种、肿瘤部位等临床特征在统计学上无明显差异(p > 0.05) (表1)。

Table 1. Correlation analysis between MMP11 gene and clinical features of lung adenocarcinoma

表1. MMP11基因与肺腺癌临床特征的关联分析

3.2. MMP11基因在肺腺癌中高表达

我们对TCGA数据库中MMP11基因在肺腺癌的表达水平进行了分析，发现MMP11基因在肺腺癌组织中的表达水平明显高于正常组织(p < 0.001) (图1)。此外，对不同亚组中MMP11基因的表达情况进行统计分析，发现不同性别(图2(A))、年龄(图2(B))、病理分期(图2(C))、T分期(图2(D))和M分期(图2(E))等中MMP11基因的表达情况无显著性差异(p > 0.05)，但与患者是否吸烟相关(图2(F))，MMP11基因在非吸烟患者中的表达高于吸烟患者，两者的差值中位数为0.624 (95%CI, 0.058~1.178)，差异具有统计学意义(p < 0.05)。但根据不同吸烟年限对吸烟患者的MMP11基因进行进一步统计分析发现，吸烟年限 < 40组的表达中位数(上下四分位数)为4.294 (95%CI, 3.112~5.631)，≥40组的中位数(上下四分位数)为4.294 (95%CI, 3.128~5.755)进行分组，在统计学上无显著性差异(p > 0.05)。

Figure 1. Expression levels of MMP11 gene in lung adenocarcinoma. (A) Expression levels of MMP11 gene in lung adenocarcinoma and normal tissues; (B) Expression levels of MMP11 gene in lung adenocarcinoma and paired adjacent normal tissues

图1. MMP11基因在肺腺癌中的表达水平。(A) MMP11基因在肺腺癌组织和正常组织中的表达水平；(B) MMP11基因在肺腺癌组织和配对的临近正常组织中的表达水平

Figure 2. Correlation analysis between the expression level of MMP11 and clinicopathologic features of lung adenocarcinoma. Correlation analysis of MMP11 expression level with sex (A), age (B), pathological stage (C), T stage (D), M stage (E), smoking (F) and smoking years (G). ns, p ≥ 0.05; *, p < 0.05

图2. MMP11表达水平和肺腺癌临床病理特征的关联分析。MMP11表达水平和性别(A)、年龄(B)、病理分期(C)、T分期(D)、M分期(E)、吸烟(F)和吸烟年限(G)的关联分析。ns，p ≥ 0.05；*，p < 0.05

3.3. MMP11基因的表达有助于肺腺癌中的诊断

在本研究中，我们利用受试者工作特征曲线(ROC)对MMP11在肺腺癌中的诊断价值进行了评估，结果表明，MMP11的曲线下面积(Area Under The Curve, AUC)为0.970 (图3)。此外，我们还对MMP11在肺腺癌不同病理分期中的ROC进行了进一步的分析，发现其在I期、II期、III期和IV期肺腺癌中的AUC分别为0.964、0.981、0.979和0.965 (图3)。

Figure 3. Receiver Operating characteristic curve (ROC) to assess the role of MMP11 gene in the diagnosis of lung adenocarcinoma. ROC analysis of MMP11 gene in normal and tumor tissue (A), stage I (B), stage II (C), stage III (D), stage IV (E) of lung adenocarcinoma

图3. 受试者工作特征曲线(ROC)评估MMP11基因在肺腺癌诊断中的作用。MMP11基因在正常组织和肿瘤组织(A)、I期(B)、II期(C)、III期(D)、IV期(E)肺腺癌中的ROC分析

3.4. MMP11基因对肺腺癌预后的影响

KM生存曲线分析结果显示，MMP11的表达对肺腺癌病人的总生存期(OS)没有显著影响(p > 0.05)，为了能够更充分的研究MMP11的表达对肺腺癌OS的影响，我们依据不同的病理分期进行分组，分别研究了其对不同分组肺腺癌OS的影响，发现MMP11的表达对I/II、III/IV、T1/T2、T3/T4、N0/N1、N2/N3、M0/M1分期的OS均没有显著的影响(p > 0.05) (图4)。单因素Cox回归分析显示，虽然不同的病理组织分期(II/IIIIV)、T分期(T2/T3)、M分期(M1)能够影响肺腺癌病人的OS，但MMP11的表达对OS没有影响。多因素Cox回归分析显示MMP11的表达是一个影响OS的非独立因素(表2)。

Table 2. Univariate and multivariate Cox regression analysis of clinical features and overall survival (OS) of lung adenocarcinoma

表2. 肺腺癌临床特征与总生存期(OS)的单因素和多因素Cox回归分析

Figure 4. KM curve analysis of MMP11 gene expression and overall survival of lung adenocarcinoma (OS). KM curve analysis of MMP11 gene expression and overall survival (OS) of lung adenocarcinoma (A), I/II stage (B), III/IV stage (C), T1/T2 (D), T3/T4 (E), N0/N1 (F), N2 and N3 (G), M0/M1 (H)

图4. MMP11基因表达与肺腺癌总体生存期(OS)的KM曲线分析。MMP11基因表达与肺腺癌(A)、I/II期(B)、III/IV期(C)、T1/T2 (D)、T3/T4 (E)、N0/N1 (F)、N2/N3 (G)、M0/M1 (H)总体生存期(OS)的KM曲线分析

4. 讨论

生物信息学分析显示，相对于正常组织，MMP11基因在肺腺癌组织中高表达，对不同亚组中MMP11基因的表达与性别、年龄、病理分期、T分期和M分期无关，但吸烟是一个能够影响MMP11表达的重要因素，MMP11基因在非吸烟患者中的表达高于吸烟患者。ROC分析显示，MMP11的高表达有助于肺腺癌的诊断，其在I期、II期、III期和IV期肺腺癌中的AUC分别为0.964、0.981、0.979和0.965。为了进一步研究MMP11基因对肺腺癌预后的影响，我们利用KM生存曲线分析和单/多因素Cox回归分析系统论证了MMP11基因的表达对肺腺癌OS的影响，KM生存曲线分析显示，MMP11基因的表达对肺腺癌I/II、III/IV、T1/T2、T3/T4、N0/N1、N2/N3、M0/M1分期的OS均没有显著的影响，但单因素Cox回归分析显示，不同的病理组织分期(II/III/IV)、T分期(T2/T3)、M分期(M1)能够影响肺腺癌病人的OS，MMP11的表达对OS没有影响，多因素Cox回归分析显示MMP11的表达是一个影响OS的非独立因素。

文章引用

赵 强,李兴广. MMP11基因对肺腺癌诊断和预后的影响
Effect of MMP11 Gene on Diagnosis and Prognosis of Lung Adenocarcinoma[J]. 世界肿瘤研究, 2023, 13(02): 69-78. https://doi.org/10.12677/WJCR.2023.132011

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    28. NOTES

    *第一作者。

    #通讯作者。

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