MMP-1、MMP-13和TIMP-4在喉癌中的表达及其意义
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摘要
目的:基质金属蛋白酶(matrix metalloproteinase,MMPs)及其内源性抑制剂(tissue inhibitor of metalloproteinases,TIMPs)是调节基底膜(basement membranes,BM)和细胞外基质(extracellular matrix,ECM)合成与降解动态平衡过程中最重要的蛋白水解酶类。BM和ECM的降解是癌细胞侵袭与转移过程中的一个关键步骤。MMP-1和MMP-13属于MMPs家族中的间质胶原酶,可降解BM和ECM的多种成分,TIMP-4是TIMPs家族中的最新成员,可与MMPs形成1:1的复合体,从而抑制其活性。本研究的目的在于了解MMP-1、MMP-13和TIMP-4在喉癌中的表达情况,探讨三者与喉癌的侵袭和转移的关系,寻找可能预测喉癌侵袭和转移的肿瘤标志物,用于指导临床。
方法:运用组织芯片免疫组化的方法检测50例配对喉癌组织和癌旁组织中MMP-1、MMP-13及TIMP-4的蛋白表达水平;运用荧光定量RT-PCR的方法检测22例配对喉癌组织和癌旁组织中MMP-1、MMP-13及TIMP-4 mRNA的表达水平。根据2002年UICC制定的TNM分期标准将喉癌组织分为T_1+T_2组与T_3+T_4组、根据有无淋巴结转移分为非淋巴结转移组(LN-)和淋巴结转移组(LN+),比较各组之间MMP-1、MMP-13及TIMP-4表达情况。
结果:(1)喉癌组织中MMP-1蛋白高表达率(75.5%)高于癌旁组织(2.2%)、T_1+T_2组低于T_3+T_4组、LN-组低于LN+组(P＜0.05)。喉癌组织中MMP-1mRNA相对表达量(2.005±0.758)高于癌旁组织(0.476±0.350)(P＜0.05);T_1+T_2组和T_3+T_4组之间、LN-组和LN+组之间差异均无统计学意义(P＞0.05)。(2)喉癌组织中MMP-13蛋白高表达率(40.8%)高于癌旁组织(2.4%)、T_1+T_2组低于T_3+T_4组、LN-组低于LN+组(P＜0.05)。喉癌组织中MMP-13mRNA相对表达量(0.604±0.389)高于癌旁组织(0.160±0.101)(P＜0.05);T_1+T_2组和T_3+T_4组之间、LN-组和LN+组之间差异均无统计学意义(P＞0.05)。(3)喉癌组织中TIMP-4蛋白高表达率(16.0%)低于癌旁组织(51.6%)、T_1+T_2组高于T_3+T_4组、LN-组高于LN+组(P＜0.05)。喉癌组织中TIMP-4mRNA相对表达量(0.342±0.243)低于癌旁组织(0.814±0.459)、T_1+T_2组高于T_3+T_4组、LN-组高于LN+组(P＜0.05)。
结论:(1)成功的制作了100点阵的喉癌组织芯片,芯片质量好,平均有效率达93%。(2)喉癌组织中MMP-1和MMP-13的表达增高、TIMP-4的表达降低,对喉癌的诊断有一定的参考价值。(3)MMP-1和MMP-13蛋白在T_3+T_4组和LN+组高表达,这两种蛋白酶可能促进喉癌的的侵袭和淋巴结转移,对临床选择治疗方案和评估预后有一定的参考价值。(4)TIMP-4蛋白及mRNA在T_1+T_2组和LN-组高表达,提示TIMP-4可能起到抑制喉癌侵袭和淋巴结转移的作用,为临床开发抗肿瘤药物提供了新思路。
Objective:Matrix metalloproteinase(MMPs)and tissue inhibitor of metalloproteinases(TIMPs)are two of the most important proteolytic enzymes involving in the regulative process of the synthesis and degradation of the basement membranes(BM)and extracellular matrix (ECM).The degradation of BM and ECM is a key step related to the invasion and metastasis carcinoma.MMP-1 and MMP-13 which belong to collagenase can degrade BM and ECM,TIMP-4 which is a new member of TIMPs family can integrate with MMPs to form a 1:1 complex thus inhibit the activity of the latter.So the objective is to study the expression of MMP-1,MMP-13 and TIMP-4 in laryngeal carcinoma, to discuss the relationship between the three enzymes and the invasion and metastasis of laryngocarcinoma,and then to look for some tumor markers which might prognose the invasion and metastasis of laryngeal carcinoma to be used in clinical.
Method:The technique of tissue microarray and immunohistochemistry was applied to detect the expressions of MMP-1, MMP-13 and TIMP-4 in 50 pairs of laryngeal carcinoma tissues and adjacent tissues;the technique of fluorescent quantitation RT-PCR was applied to detect the expressions of MMP-1,MMP-13 and TIMP-4 in 22 paires of laryngeal carcinoma tissues and adjacent tissues.According to 2002 TNM staging made by UICC,the tissues of laryngeal carcinoma were divided into T_1+T_2 group and T_3+T_4 group,as well as non metastasis group(LN-)and metastasis group(LN+)to compare.
Results:(1)The expression rate of MMP-1 protein(75.5%)was higher than that of adjacent tissues(2.2%)、Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).The relative expressions of MMP-1 mRNA of laryngeal carcinoma tissues (2.005±0.758)was higher than that of adjacent tissues(0.476±0.350) (P＜0.05);the differences between Group T_1+T_2 and Group T_3+T_4、Group LN- and Group LN+ had no statistically significance, respectively.(P＞0.05).(2)The expression rate of MMP-13 protein(40.8%) was higher than that of adjacent tissues(2.4%),Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).The relative expressions of MMP-13 mRNA of laryngeal carcinoma tissues(0.604±0.389)was higher than that of adjacent tissues (0.160±0.101)(P＜0.05);the differences between Group T_1+T_2 and Group T_3+T_4,Group LN- and Group LN+ had no statistically significance,respectively(P＞0.05).(3)The expression rate of TIMP-4 protein of laryngeal carcinoma tissues(16.0%)was lower than that of adjacent tissues(51.6%),Group T_1+T_2 was higher than that of T_3+T_4, Group LN- was higher than that of LN+(P＜0.05).The relative expressions of TIMP-4 mRNA of laryngeal carcinoma tissues (0.342±0.243)was lower than that of adjacent tissues(0.814±0.459); Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).
Conclusions:(1)100-spots laryngeal carcinoma tissue microarrays was successfully constructed,the mean effectivity of them was 93%.(2) The expression of MMP-1 and MMP-13 in laryngeal carcinoma tissues upregulate,and the expression of TIMP-4 downragulate,which might be of great value in the diagnosis of laryngeal carcinoma.(3)The MMP-1 and MMP-13 were highly expressed in Group T_3+T_4 and Group LN+, these two proteases might promote the invasion and metastasis of laryngeal carcinoma,which might be of great value in the determination of therapeutic regimens and prognosis of laryngeal carcinoma.(4)The expression of TIMP-4 and its mRNA were high in Group T1+T2 and Group LN-,which suggest that TIMP-4 might play a role in the suppression of the invasion and metastasis of laryngeal carcinoma,and then pave a way for finding a new antitumor drug.
方法:运用组织芯片免疫组化的方法检测50例配对喉癌组织和癌旁组织中MMP-1、MMP-13及TIMP-4的蛋白表达水平;运用荧光定量RT-PCR的方法检测22例配对喉癌组织和癌旁组织中MMP-1、MMP-13及TIMP-4 mRNA的表达水平。根据2002年UICC制定的TNM分期标准将喉癌组织分为T_1+T_2组与T_3+T_4组、根据有无淋巴结转移分为非淋巴结转移组(LN-)和淋巴结转移组(LN+),比较各组之间MMP-1、MMP-13及TIMP-4表达情况。
结果:(1)喉癌组织中MMP-1蛋白高表达率(75.5%)高于癌旁组织(2.2%)、T_1+T_2组低于T_3+T_4组、LN-组低于LN+组(P＜0.05)。喉癌组织中MMP-1mRNA相对表达量(2.005±0.758)高于癌旁组织(0.476±0.350)(P＜0.05);T_1+T_2组和T_3+T_4组之间、LN-组和LN+组之间差异均无统计学意义(P＞0.05)。(2)喉癌组织中MMP-13蛋白高表达率(40.8%)高于癌旁组织(2.4%)、T_1+T_2组低于T_3+T_4组、LN-组低于LN+组(P＜0.05)。喉癌组织中MMP-13mRNA相对表达量(0.604±0.389)高于癌旁组织(0.160±0.101)(P＜0.05);T_1+T_2组和T_3+T_4组之间、LN-组和LN+组之间差异均无统计学意义(P＞0.05)。(3)喉癌组织中TIMP-4蛋白高表达率(16.0%)低于癌旁组织(51.6%)、T_1+T_2组高于T_3+T_4组、LN-组高于LN+组(P＜0.05)。喉癌组织中TIMP-4mRNA相对表达量(0.342±0.243)低于癌旁组织(0.814±0.459)、T_1+T_2组高于T_3+T_4组、LN-组高于LN+组(P＜0.05)。
结论:(1)成功的制作了100点阵的喉癌组织芯片,芯片质量好,平均有效率达93%。(2)喉癌组织中MMP-1和MMP-13的表达增高、TIMP-4的表达降低,对喉癌的诊断有一定的参考价值。(3)MMP-1和MMP-13蛋白在T_3+T_4组和LN+组高表达,这两种蛋白酶可能促进喉癌的的侵袭和淋巴结转移,对临床选择治疗方案和评估预后有一定的参考价值。(4)TIMP-4蛋白及mRNA在T_1+T_2组和LN-组高表达,提示TIMP-4可能起到抑制喉癌侵袭和淋巴结转移的作用,为临床开发抗肿瘤药物提供了新思路。
Objective:Matrix metalloproteinase(MMPs)and tissue inhibitor of metalloproteinases(TIMPs)are two of the most important proteolytic enzymes involving in the regulative process of the synthesis and degradation of the basement membranes(BM)and extracellular matrix (ECM).The degradation of BM and ECM is a key step related to the invasion and metastasis carcinoma.MMP-1 and MMP-13 which belong to collagenase can degrade BM and ECM,TIMP-4 which is a new member of TIMPs family can integrate with MMPs to form a 1:1 complex thus inhibit the activity of the latter.So the objective is to study the expression of MMP-1,MMP-13 and TIMP-4 in laryngeal carcinoma, to discuss the relationship between the three enzymes and the invasion and metastasis of laryngocarcinoma,and then to look for some tumor markers which might prognose the invasion and metastasis of laryngeal carcinoma to be used in clinical.
Method:The technique of tissue microarray and immunohistochemistry was applied to detect the expressions of MMP-1, MMP-13 and TIMP-4 in 50 pairs of laryngeal carcinoma tissues and adjacent tissues;the technique of fluorescent quantitation RT-PCR was applied to detect the expressions of MMP-1,MMP-13 and TIMP-4 in 22 paires of laryngeal carcinoma tissues and adjacent tissues.According to 2002 TNM staging made by UICC,the tissues of laryngeal carcinoma were divided into T_1+T_2 group and T_3+T_4 group,as well as non metastasis group(LN-)and metastasis group(LN+)to compare.
Results:(1)The expression rate of MMP-1 protein(75.5%)was higher than that of adjacent tissues(2.2%)、Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).The relative expressions of MMP-1 mRNA of laryngeal carcinoma tissues (2.005±0.758)was higher than that of adjacent tissues(0.476±0.350) (P＜0.05);the differences between Group T_1+T_2 and Group T_3+T_4、Group LN- and Group LN+ had no statistically significance, respectively.(P＞0.05).(2)The expression rate of MMP-13 protein(40.8%) was higher than that of adjacent tissues(2.4%),Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).The relative expressions of MMP-13 mRNA of laryngeal carcinoma tissues(0.604±0.389)was higher than that of adjacent tissues (0.160±0.101)(P＜0.05);the differences between Group T_1+T_2 and Group T_3+T_4,Group LN- and Group LN+ had no statistically significance,respectively(P＞0.05).(3)The expression rate of TIMP-4 protein of laryngeal carcinoma tissues(16.0%)was lower than that of adjacent tissues(51.6%),Group T_1+T_2 was higher than that of T_3+T_4, Group LN- was higher than that of LN+(P＜0.05).The relative expressions of TIMP-4 mRNA of laryngeal carcinoma tissues (0.342±0.243)was lower than that of adjacent tissues(0.814±0.459); Group T_1+T_2 was lower than that of T_3+T_4,Group LN- was lower than that of LN+(P＜0.05).
Conclusions:(1)100-spots laryngeal carcinoma tissue microarrays was successfully constructed,the mean effectivity of them was 93%.(2) The expression of MMP-1 and MMP-13 in laryngeal carcinoma tissues upregulate,and the expression of TIMP-4 downragulate,which might be of great value in the diagnosis of laryngeal carcinoma.(3)The MMP-1 and MMP-13 were highly expressed in Group T_3+T_4 and Group LN+, these two proteases might promote the invasion and metastasis of laryngeal carcinoma,which might be of great value in the determination of therapeutic regimens and prognosis of laryngeal carcinoma.(4)The expression of TIMP-4 and its mRNA were high in Group T1+T2 and Group LN-,which suggest that TIMP-4 might play a role in the suppression of the invasion and metastasis of laryngeal carcinoma,and then pave a way for finding a new antitumor drug.
引文
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[15]Huo N,Ichikawa Y,Kamiyama M,et al.MMP-7(matrilysin)accelerated growth of human umbilical vein endothelial cells.Cancer Lett,2002,177(1):95-100
[16]Deryugina EI,Bourdon MA,Jungwirth K,et al.Fuctional activation of integrin alpha V beta in tumor cells expressing membrane-type 1 matrix metalloproteinase.Int J Cancer,2000,86(1):15-23
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[1]Chambers AF,Groom AC,MacDonald IC.Dissemination and growth of cancer cells in metastatic sites.Nature Rev Cancer,2002,2:563-572
[2]Stelter-Stevenson WG,Azanvoorian S,Liotta LA.Tumor cell interactions with the extracellular matrix during invasion and metastasis.Ann Rev cell Biol,1993,9:541-573
[3]Massova I,Kotra L P,Fridman R,et al.Matrix metalloproteinases:structure,evolution,and diversification.FASEB J,1998,12(12):1075-95
[4]Das S,Mandal M,Chakraborti T,Mandal A,et al.Structure and evolutionary aspects of matrix metalloproteinases:a brief overview.Mol Cell Biochem.2003,253(1-2):31-40
[5]Sato H,Seiki M.Membrane-type matrix metalloproteinases(MT-MMPs)in tumor metastasis.J Biochem,1996,119(2):209-215
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[7]Magary SP,RyanMW,Tarnuzzer RW,et al.Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in laryngeal and pharyngeal squamous cell carcinoma:A quantitative analysis.Otolaryngol Head Neck Surg,2000,122(5):712-716
[8]Christopoulos TA,Papageorgakopoulou N,Ravazoula P,et al.Expression of metalloproteinases,and their tissue inhibitors in squamous cell laryngeal carcinoma.Oncol Rep,2007 Oct,18(4):855-860
[9]Xie M,Sun Y,Li Y.Expression of Matrix Metalloproteinases in Supraglottic Carcinoma and Its Clinical Implication for Estimating Lymph Node Metastases.Laryngoscope,2004,114(12):2243-2248
[10]Culhaci N,Metin K,Copcu E,Dikicioglu E.Elevated expression of MMP-13and TIMP-1 in head and neck squamous cell carcinomas may reflect increased tumor invasiveness,BMC Cancer,2004,3(4):42
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[12]孙亚男,李源,姚鸿超,等.喉癌中MT_1、MT_2和MT_3-MMP的mRNA表达及 意义.种瘤,2005,25(3):254-256
[13]Curran S,Murray GI.Matrix metalloproteinases:molecular aspects of their roles in tumor invasion and metastasis.Eur J Cancer,2000,36:1621-1630
[14]Forsyth PA,Wong H,Laing TD,et al.Gelatinase-A(MMP-2),gelatinase-B(MMP-9)and membrane type matrix metalloproteinase-1(MT1-MMP)are involved in different aspects of the pathophysiology of malignantgliomas.Br J Cancer,1999,79(11-12):1828-1835
[15]Huo N,Ichikawa Y,Kamiyama M,et al.MMP-7(matrilysin)accelerated growth of human umbilical vein endothelial cells.Cancer Lett,2002,177(1):95-100
[16]Deryugina EI,Bourdon MA,Jungwirth K,et al.Fuctional activation of integrin alpha V beta in tumor cells expressing membrane-type 1 matrix metalloproteinase.Int J Cancer,2000,86(1):15-23
[17]刘业海,刘之花,唐平章.基质金属蛋白酶MMP20与喉癌的浸润和转移.中国耳鼻咽喉头颈外科,2006,13(7):471-474
[18]Ruokolainen H,Paakko P,Turpeenniemi-Hujanen T.Tissue inhibitor of matrix metalloproteinase-1 is prognostic in head and neck squamous cell carcinoma:comparison of the circulating and tissue immunoreactive protein.Clin Cancer Res,2005,11:3257-264
[19]孙亚男,李源,谢民强,等.基质溶素(MMP-7)与喉癌浸润转移及预后相关性的研究.癌症,2004,23(5):589-592
[20]Charous SJ,Stricklin GP,Narmey LB,et al.Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in head and neck squamous cell carcinoma.Ann Otol Rhinol Laryngol,1997,106:271-278
[21]Gomez D F,Alonso D F,Yoshiji H,et al.Tissue inhibitor of metalloprpteinase:structure regulation and biological fubctions.Eur J Cell Biol,1997,74(2):111-122
[22]Cox G,O 'byrne KJ.Matrix metalloproteinase and cencer.Anticancer Res,2001,21(6B):4207-4219
[23]Gorogh T,Beier UH,Baumken J,et al.Metalloproteinases and their inhibitors:influence on tumor invasiveness and metastasis formation in head and neck squamous cell carcinomas.Head Neck,2006:28(1):31-39
[24]李为,田凤艳,白文中.TIMP-1在喉癌中的表达及其临床意义.华北煤炭医学院院报,2008,01,7-8
[25]Brand K,Baker AH,Perez-Canto A,et al.Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue.Cancer Res,2000,60(20):5723-5730
[26]Ritter LM,Garfield SH,Thorgeirsson UP.Tissue inhibitor of metalloproteinases-1(TIMP-1)binds to the cell surface and translocates to the nucleus of human MCF-7 breast carcinoma cells.Biochem Biophys Res Commun,1999,257(2):494-499
[27]高东梅.基质金属蛋白酶及抑制剂的研究进展.实用肿瘤杂志,2004,19(1):83-87
[28]Lara PN Jr,Stadler WM,Longmate J,et al.A randomized phase Ⅱ trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases.Clin Cancer Res,2006,12(5):1556-1563