ACM Advances in Clinical Medicine 2161-8712 Scientific Research Publishing 10.12677/ACM.2021.1111720 ACM-46287 ACM20211100000_66625221.pdf 医药卫生 MMP9蛋白与甲状腺恶性肿瘤关系的Meta分析 Meta-Analysis of the Relationship between MMP9 Protein and Thyroid Cancer 王 松 2 1 尹 方旭 2 1 张 湘生 2 1 王 晓红 3 1 杨 振林 3 1 滨州医学院附属医院甲状腺乳腺外科，山东 滨州 滨州医学院附属医院甲状腺乳腺外科，山东 滨州；滨州医学院第一临床医学院，山东 滨州 null 02 11 2021 11 11 4901 4911 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

目的：探究MMP9蛋白在良性甲状腺结节与甲状腺恶性肿瘤的表达差异。方法：通过检索2020年12月31日之前PubMed、Web of Science、CNKI和万方数据库关于MMP9蛋白水平与甲状腺恶性肿瘤关系的病例对照研究。根据相应标准选择文献并提取相关的数据，采用纽卡斯尔–渥太华量表评价其方法学质量，提取的资料通过Stata12.0软件进行统计学分析，I2检验评价文章的异质性。结果：共纳入10篇符合要求的文献，其中包括554名诊断为甲状腺恶性肿瘤患者和337名良性甲状腺结节患者。甲状腺恶性肿瘤患者组织中MMP9蛋白水平明显高于良性甲状腺结节组，差异有统计学意义(OR = 9.80, 95% CI: 5.77~16.62, P < 0.05)。根据不同临床特征将甲状腺恶性肿瘤分为多个亚组进行Meta分析，结果显示MMP9的高表达与更大的肿瘤直径(OR = 3.37, 95% CI: 1.36~8.34, P < 0.05)，存在包膜侵犯(OR = 13.95, 95% CI: 4.13~47.09)，淋巴结转移(OR = 6.05, 95% CI: 3.28~11.15, P < 0.05)以及更高的TNM分期(OR = 5.03, 95% CI: 2.40~10.56, P < 0.05)密切相关。结论：MMP9蛋白在甲状腺恶性肿瘤中高表达，且与肿瘤直径大小、包膜侵犯、淋巴结转移、临床分期密切相关，有望成为甲状腺癌的一个新的治疗靶点。 Objective: To investigate the difference of MMP9 protein expression in benign thyroid nodules and thyroid cancer. Methods: Case-control studies on the relationship between MMP9 protein levels and thyroid cancer by searching PubMed, Web of Science, CNKI and Wanfang databases before December 31, 2020. The literature was selected and relevant data were extracted according to the inclusion and exclusion criteria, and the methodological quality was evaluated using the Newcastle-Ottawa scale, and the extracted data were statistically analyzed by Stata 12.0 software, and the I2 test was used to evaluate the heterogeneity of the articles. Results: A total of 10 eligible articles, including 554 patients diagnosed with thyroid cancer and 337 patients with benign thyroid nodules were included. MMP9 protein levels were significantly higher in the samples from patients with thyroid cancer than in the group with benign thyroid nodules, with a statistically significant difference (OR = 9.80, 95% CI: 5.77~16.62, P < 0.05). Meta-analysis by dividing thyroid cancer into multiple subgroups by different clinical features showed that high expression of MMP9 was associated with larger tumor diameter (OR = 3.37, 95% CI: 1.36~8.34, P < 0.05), the presence of envelope invasion (OR = 13.95, 95% CI: 4.13~47.09), lymph node metastasis (OR = 6.05, 95% CI: 3.28~11.15, P < 0.05) and higher TNM stage (OR = 5.03, 95% CI: 2.40~10.56, P < 0.05) were closely associated. Conclusion: MMP9 protein is highly expressed in thyroid cancer tissues, closely correlated with tumor diameter size, envelope invasion, lymph node metastasis, and clinical stage, and is expected to be a new therapeutic target for thyroid cancer.

 甲状腺癌，甲状腺良性结节，基质金属蛋白酶9，Meta分析, Thyroid Cancer Benign Thyroid Nodules Matrix Metalloproteinase 9 Meta-Analysis 摘要

目的：探究MMP9蛋白在良性甲状腺结节与甲状腺恶性肿瘤的表达差异。方法：通过检索2020年12月31日之前PubMed、Web of Science、CNKI和万方数据库关于MMP9蛋白水平与甲状腺恶性肿瘤关系的病例对照研究。根据相应标准选择文献并提取相关的数据，采用纽卡斯尔–渥太华量表评价其方法学质量，提取的资料通过Stata12.0软件进行统计学分析，I2检验评价文章的异质性。结果：共纳入10篇符合要求的文献，其中包括554名诊断为甲状腺恶性肿瘤患者和337名良性甲状腺结节患者。甲状腺恶性肿瘤患者组织中MMP9蛋白水平明显高于良性甲状腺结节组，差异有统计学意义(OR = 9.80, 95% CI: 5.77~16.62, P < 0.05)。根据不同临床特征将甲状腺恶性肿瘤分为多个亚组进行Meta分析，结果显示MMP9的高表达与更大的肿瘤直径(OR = 3.37, 95% CI: 1.36~8.34, P < 0.05)，存在包膜侵犯(OR = 13.95, 95% CI: 4.13~47.09)，淋巴结转移(OR = 6.05, 95% CI: 3.28~11.15, P < 0.05)以及更高的TNM分期(OR = 5.03, 95% CI: 2.40~10.56, P < 0.05)密切相关。结论：MMP9蛋白在甲状腺恶性肿瘤中高表达，且与肿瘤直径大小、包膜侵犯、淋巴结转移、临床分期密切相关，有望成为甲状腺癌的一个新的治疗靶点。

 关键词

甲状腺癌，甲状腺良性结节，基质金属蛋白酶9，Meta分析

 Meta-Analysis of the Relationship between MMP9 Protein and Thyroid Cancer<sup> </sup>

Song Wang1,2*, Fangxu Yin1,2, Xiangsheng Zhang1,2, Xiaohong Wang1, Zhenlin Yang1#

1Department of Thyroid and Breast Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou Shandong

2The First School of Clincal Medicine of Binzhou Medical University, Binzhou Shandong

Received: Oct. 2nd, 2021; accepted: Oct. 29th, 2021; published: Nov. 5th, 2021

 ABSTRACT

Objective: To investigate the difference of MMP9 protein expression in benign thyroid nodules and thyroid cancer. Methods: Case-control studies on the relationship between MMP9 protein levels and thyroid cancer by searching PubMed, Web of Science, CNKI and Wanfang databases before December 31, 2020. The literature was selected and relevant data were extracted according to the inclusion and exclusion criteria, and the methodological quality was evaluated using the Newcastle-Ottawa scale, and the extracted data were statistically analyzed by Stata 12.0 software, and the I2test was used to evaluate the heterogeneity of the articles. Results: A total of 10 eligible articles, including 554 patients diagnosed with thyroid cancer and 337 patients with benign thyroid nodules were included. MMP9 protein levels were significantly higher in the samples from patients with thyroid cancer than in the group with benign thyroid nodules, with a statistically significant difference (OR = 9.80, 95% CI: 5.77~16.62, P < 0.05). Meta-analysis by dividing thyroid cancer into multiple subgroups by different clinical features showed that high expression of MMP9 was associated with larger tumor diameter (OR = 3.37, 95% CI: 1.36~8.34, P < 0.05), the presence of envelope invasion (OR = 13.95, 95% CI: 4.13~47.09), lymph node metastasis (OR = 6.05, 95% CI: 3.28~11.15, P < 0.05) and higher TNM stage (OR = 5.03, 95% CI: 2.40~10.56, P < 0.05) were closely associated. Conclusion: MMP9 protein is highly expressed in thyroid cancer tissues, closely correlated with tumor diameter size, envelope invasion, lymph node metastasis, and clinical stage, and is expected to be a new therapeutic target for thyroid cancer.

Keywords:Thyroid Cancer, Benign Thyroid Nodules, Matrix Metalloproteinase 9, Meta-Analysis

Copyright © 2021 by author(s) and beplay安卓登录

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

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 1. 引言

甲状腺癌(TC)是最常见的恶性肿瘤之一 [ 1 ]。由于人口年龄和饮食结构的变化，全球甲状腺癌发病率逐年上升 [ 2 ] [ 3 ]。甲状腺癌的发病机理有待充分阐明。因此，识别与甲状腺癌的发生和发展高度相关的标志对于甲状腺癌的早期诊断和治疗非常重要 [ 4 ]。基质金属蛋白酶(Matrix Metalloproteinase, MMPs)是一系列蛋白质水解，与肿瘤生长、侵袭和转移等密切相关 [ 5 ] [ 6 ]。基质金属蛋白酶不仅可以降解细胞外基质(Extracellular Mtrix, ECM)，还可以控制肿瘤血管的形成 [ 7 ]。它们有许多亚型，MMP-9是研究最多的亚型之一。国内外研究表明，组织MMP-9蛋白水平在癌症中的表达增加 [ 8 ] [ 9 ] [ 10 ]。同时大量文献支持MMP-9在甲状腺癌中具有较高的表达水平 [ 11 ] [ 12 ]。然而，这些研究的样本量很小，或者它们与对照组没有进一步的对比。因此，进行了目前的Meta分析，以探索MMP-9蛋白的表达在甲状腺恶性肿瘤与良性甲状腺结节中的差异及联系。

 2. 资料和方法 2.1. 文献检索

两名作者分别检索PubMed、Web of science、CNKI和万方数据库。收集所有国内外公开发表的有关MMP9蛋白表达与甲状腺相关的研究，遇到分歧时由第三位作者决定。检索时间：自数据库建库以来至2020年12月30日。中文检索词为：MMP9、基质金属蛋白酶9、甲状腺恶性肿瘤、甲状腺癌，检索策略为：((MMP9) or (基质金属蛋白酶9)) and ((甲状腺恶性肿瘤) and (甲状腺癌))；英文检索词为：MMP9 [Mesh], Matrix Metalloproteinase 9, Thyroid Neoplasms [Mesh], ThyroidCancer*, Thyroid Carcinoma*, Thyroid Adenoma*, Thyroid tumor*，检索策略为：((Matrix Metalloproteinase 9) or (MMP9)) and ((Thyroid Neoplasm) or (Thyroid Carcinoma) or (Thyroid Adenoma) or (Thyroid Cancer))。最后，手动检索相关参考文献列表上的文章。

 2.2. 纳入、排除标准 2.2.1. 纳入标准

1) 研究对象为甲状腺肿瘤患者MMP9蛋白相关表达的研究；2) 行甲状腺术后病理诊断为甲状腺恶性肿瘤或良性甲状腺结节以及甲状腺腺瘤组织；3) 采用免疫组织化学方法检测组织中MMP9蛋白的表达水平。

 2.2.2. 排除标准

1) 研究对象病理未确诊或者术前接受其他治疗的研究；2) 数据缺乏或者样本量不足20例的研究；3) 非免疫组化法检测组织中MMP9蛋白的表达水平；4) 细胞实验、动物实验以及重复发表的研究。

 2.3. 文献筛选及资料提取

两名作者通过筛选文章的标题、摘要和全文后提取文章数据，若文章数据不一致将由第三名作者最终决定。对纳入的文献进行资料及数据提取。提取内容包括：① 文章发表时间、第一作者、病人年龄、病人性别、所属国家；② 患者样本量、MMP9表达水平、肿瘤大小、是否肿瘤包膜侵犯、是否淋巴结转移、TNM分期及研究类型等。最终共纳入10篇文献 [ 13 ] - [ 22 ]。

 2.4. 质量评价

采取纽卡斯尔–渥太华量表(Newcastle-Ottawa scale, NOS)评价纳入的文献质量 [ 23 ]。由两名作者分别独立完成，结果不一致由第三位作者决定。评价的内容主要包括病例选择方法、两组患者可比性、接触暴露评估方法。评价标准共计9分。评分低于6分为低质量文章，高于或等于6分则为高质量文章。

 2.5. 统计学处理

所有的统计分析均采用Stata12.0软件。P值和I2分析纳入研究的异质性评价，若各研究间不存在统计学异质性(P > 0.05, I2< 50%)，固定效应模式进行Meta分析；若各研究间存在统计学异质性(P < 0.05, I2> 50%)，随机效应模式进行Meta分析，并对纳入文献进行敏感性分析以及漏斗图分析。最后，Egger’s检验判断是否存在发表偏倚。

 3. 结果 3.1. 纳入文献的来源及基本特征

根据文献的筛选流程(图1)，纳入的10篇文献均为病例对照研究，包括1篇英文文献和9篇中文文献。纳入的10篇文献均报道了MMP9在良性甲状腺结节与甲状腺恶性肿瘤组织中的表达差异，其中关于MMP9与甲状腺恶性肿瘤直径大小关系的文献3篇，MMP9蛋白表达与甲状腺恶性肿瘤肿瘤包膜侵犯关系的文献4篇，MMP9蛋白与甲状腺恶性肿瘤淋巴结转移关系的文献8篇，MMP9蛋白与甲状腺恶性肿瘤TNM分期关系的文献6篇(表1)。

 3.2. Meta分析结果 3.2.1. MMP9在甲状腺恶性肿瘤组织及甲状腺良性结节组织中的表达

纳入的10篇文献包括甲状腺恶性肿瘤554例，良性甲状腺结节组织337例。由于各研究间存在统计学异质性(P = 0.011, I2= 58.1%)，故采用随机效应模型进行Meta分析(图2)。结果显示，与良性甲状腺结节相比，MMP9的在甲状腺恶性肿瘤中的表达是甲状腺良性结节组的9.80倍，差异有统计学意义(OR = 9.80, 95% CI: 5.77~16.62, P < 0.05)。

图1. Meta分析文献筛选和纳入流程图

Basic information about the included literatur
第一作者 发表时间 MMP9 (阳性/总数) 年龄 性别(男/女) 治疗评分
甲状腺癌 甲状腺良性结节 甲状腺癌 甲状腺良性结节 甲状腺癌 甲状腺良性结节
张金军 2007 24/32 8/30 39 22-60 9/23 10/20 6
张金江 2008 32/50 17/45 57.6 27.4 20/30 12/33 6
许力 2009 29/48 2/18 18~64 17~78 12/36 5/13 7
李艳萍 2010 52/60 10/40 48.5 NA 27/33 NA 6
周少飞 2012 40/56 12/40 54 51 24/32 17/23 7
李良毅 2012 51/53 11/20 37.53 NA 10/43 NA 6
王朝辉 2012 46/56 11/30 53 NA 18/38 NA 6
Xian ying meng 2014 61/66 8/40 45.8 42.1 31/35 13/27 7
刘咏 2015 72/85 14/26 44 43 30/55 9/17 7
郜静 2018 37/48 9/48 44 43.15 16/32 18/30 7

表1. 纳入文献的基本情况

图2. MMP9在甲状腺癌组织及良性甲状腺结节中表达的Meta分析

 3.2.2. MMP9在甲状腺恶性肿瘤中的表达与不同临床特征的关系

我们进一步分析MMP9在甲状腺恶性肿瘤中的表达与不同临床特征的关系，根据肿瘤直径大小、包膜侵犯、淋巴结转移、TNM分期分为四个亚组。关于MMP9蛋白的表达与甲状腺恶性肿瘤直径的关系文献中，包括95例甲状腺恶性肿瘤直径大于1 cm以及53例甲状腺恶性肿瘤直径小于1 cm的患者。各研究间不存在异质性(P = 0.285, I2= 20.4%)，Meta分析采用固定效应模型(图3)。结果显示，MMP9蛋白高表达与直径大于1 cm的甲状腺恶性肿瘤密切相关(OR = 3.37, 95% CI: 1.36~8.34, P < 0.05)。关于MMP9的表达与甲状腺恶性肿瘤包膜侵犯的关系文献中，包括119例甲状腺包膜侵犯的患者以及106例无甲状腺包膜侵犯的患者。各研究间无异质性(P = 0.922, I2= 0.0%)，同样运用固定效应模型(图4)。结果显示，MMP9蛋白高表达患者容易发生包膜侵犯(OR = 13.95, 95% CI: 4.13~47.09, P < 0.05)。关于甲状腺恶性肿瘤组织中MMP9的表达与淋巴结转移关系的文献报道中，包括有淋巴结转移患者202例，无淋巴结转移患者243例。根据各研究间不存在异质性(P = 0.227, I2= 25.3%)，采用固定效应模型进行Meta分析(图5)的结果显示，MMP9在有淋巴结转移的甲状腺恶性肿瘤组织中的表达更高(OR = 6.05, 95% CI: 3.28~11.15, P < 0.05)。最后，甲状腺恶性肿瘤组织中MMP9的表达与TNM分期的关系文献中，包括TNM分期I~II期的患者218例，III~IV期的患者147例。各研究间不存在异质性(P = 0.957, I2= 0.0%)，采用固定效应模型进行Meta分析(图6)。Meta分析结果显示，MMP9蛋白高表达与更高的肿瘤分期密切相关，差异有统计学意义(OR = 5.03, 95% CI: 2.40~10.56, P < 0.05)。

 3.3. 敏感性分析

我们逐一剔除每一篇纳入的文献进行敏感性分析。异质性检验结果相差不大，这说明Meta分析结果可靠(图7)。

图3. MMP9在甲状腺癌中的表达与肿瘤直径大小关系的Meta分析

图4. MMP9在甲状腺癌中的表达与肿瘤包膜侵犯关系的Meta分析

图5. MMP9在甲状腺癌中的表达与淋巴结转移关系的Meta分析

图6. MMP9在甲状腺癌中的表达与肿瘤TNM分期关系的Meta分析

图7. MMP9在甲状腺癌组织及良性甲状腺结节组织中表达的敏感性分析

 3.4. 发表性偏倚分析

对纳入文献进行漏斗图的绘制，结果显示漏斗图中文献大部分在可信区间内均匀且对称分布(图8)，同时Egger’s检验结果为P = 0.070。说明我们纳入研究不存在发表偏倚。

图8. MMP9在甲状腺癌组织及良性甲状腺结节组织中表达的漏斗图分析

 4. 讨论

随着人们自我健康意识的增加以及各种精密检查设备的广泛使用，甲状腺结节的发现率呈现逐年增高趋势。这些甲状腺结节大约有10%~15%可以诊断为甲状腺癌 [ 24 ]。目前，通过临床触诊、超声、放射性核素显像、细针穿刺活检等综合评价，可在一定程度上提高甲状腺癌诊断的准确性，但仍有约10%~30%的患者不能明确诊断 [ 25 ]。国内外甲状腺癌指南均建议，甲状腺结节经甲状腺细针穿刺细胞学活检检测尚不能确诊的可利用分子标志物检测以提高诊断准确性，如BRAF、PTC、TPO等 [ 26 ] [ 27 ]。因此寻求新的潜在的甲状腺癌分子标志物，对于甲状腺癌检测准确度的提高，预测甲状腺癌生物学行为，以及寻求甲状腺癌的新的治疗靶点显得尤为重要。MMP家族是一个包含20多个不同成员的锌依赖性内肽酶家族。基质金属蛋白酶家族成员可分为明胶酶、胶原酶、基质溶解素、基质分解素和膜型基质金属蛋白酶等 [ 28 ]。尤其是在癌细胞侵袭和肿瘤转移中起重要作用的MMP-9，是研究最广泛的基质金属蛋白酶之一，有研究结果表明MMP9穿透基底膜、穿透血管的全过程均需要基质金属蛋白酶参与，并通过打破基质金属蛋白酶与其抑制因子之间的平衡关系发挥作用 [ 29 ]。此外，MMP9基因主要通过p38/MAPK [ 30 ]、PI3K/AKT [ 31 ] [ 32 ]、ERK/MMP [ 33 ] 等信号影响肿瘤细胞的增殖、上皮间质转化、凋亡及侵袭迁移等过程，是抗肿瘤治疗研究的理想靶点。国内外大量研究表明，MMP9的增加会促进癌症的发生，通过抑制MMP9蛋白或MMP9信号通路会抑制肿瘤的进展。Yu等人发现SDF-1/CXCR7可诱导p38/MAPK通路的磷酸化，而p38/MAPK抑制剂SB203580预处理可明显降低MMP-9的表达。这表明SDF-1/CXCR7通过p38/MAPK途径通过MMP-9表达增强卵巢癌细胞的侵袭 [ 34 ]。Min等人发现FITM3基因敲除显著降低MMP9的表达，抑制肝癌的侵袭和转移。发现IFITM3通过p38/MAPK途径调节MMP9的表达，其功能失调驱动了肝癌的侵袭性和转移性 [ 35 ]。Liu等人发现TAMs通过分泌MMP-9诱导远处转移，MMP-9通过PI3K-AKT-Snail通路诱导上皮–间充质转化(EMT)过程。应用MMP-9原酶抑制剂可显著提高化疗药物的杀伤效率，减少肺转移 [ 36 ]。Lin等人发现CRKL的过度表达通过上调MMP9的表达和激活ERK途径促进肺癌细胞侵袭 [ 37 ]。我们的研究发现，MMP9蛋白在甲状腺恶性肿瘤的组织中的表达明显高于良性结节组，且随着甲状腺恶性肿瘤淋巴结的转移、薄膜的侵犯、肿瘤直径的增大、TNM分期的增加而在甲状腺恶性肿瘤组织中表达增加。结合结果分析，我们初步认为通过抑制甲状腺癌细胞中MMP9蛋白的表达受多种信号通路的调节，靶向MMP9蛋白会抑制甲状腺癌的进展，这为以后甲状腺癌的治疗提供了一个的方向。本研究共纳入的10篇文献不存在异质性，通过绘制漏斗图及Egger’s检验证明不存在发表偏倚。但是本研究在客观上仍存在一些的局限性：检索文献的语言限于中英文且纳入英文文献较少，可能存在一定的偏倚。综上所述，MMP9蛋白在甲状腺恶性肿瘤组织中高表达，且与甲状腺恶性肿瘤的发展密切相关，有望成为治疗甲状腺恶性肿瘤的新靶点。未来需要提高纳入文献的质量及数量，从而更好地指导临床实践。

 基金项目

国家青年自然科学基金项目(编号：81902702)；山东省临床重点专科项目建设基金项目(编号：20110731250)。

 文章引用

王 松,尹方旭,张湘生,王晓红,杨振林. MMP9蛋白与甲状腺恶性肿瘤关系的Meta分析Meta-Analysis of the Relationship between MMP9 Protein and Thyroid Cancer[J]. 临床医学进展, 2021, 11(11): 4901-4911. https://doi.org/10.12677/ACM.2021.1111720

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