MMP-2/9和Ⅳ型胶原蛋白与胃癌患者胃液芳香族氨基酸浓度变化的关系
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摘要
目的探讨基质金属蛋白酶2/9(MMP-2/9)和Ⅳ型胶原(ColⅣ)蛋白在胃癌组织中的表达及其与胃癌患者胃液芳香族氨基酸(aromatic amino acids,AAAs)浓度异常升高之间的关系。方法收集2015年12月~2016年8月胃镜检查120例符合入排标准患者的胃黏膜组织和胃液标本。根据病理诊断结果分为胃癌组(GC,n=29)和胃良性病变组(NGD,n=91)。应用免疫组织化学法和液相色谱串联质谱法对胃黏膜组织中MMP-2/9和ColⅣ蛋白的表达情况及胃液中3种AAAs(酪氨酸、苯丙氨酸、色氨酸)进行检测。比较MMP-2/9和ColⅣ蛋白在GC和NGD组间表达的差异,并与胃液中3种AAAs的浓度进行相关性分析。结果 (1)GC组MMP-2/9蛋白的表达水平均显著高于NGD组,ColⅣ蛋白的表达水平显著低于NGD组(P均=0.000);MMP-2和MMP-9蛋白的表达水平呈正相关关系(ρ=0.418,P=0.000),二者均与ColⅣ蛋白的表达水平呈负相关关系(MMP-2:ρ=-0.454,P=0.000;MMP-9:ρ=-0.383,P=0.000)。(2)GC组胃液3种AAAs浓度均显著高于NGD组(P均=0.000)。(3)胃黏膜组织中MMP-2/9蛋白的表达水平与胃液中3种AAAs浓度均呈正相关关系(MMP-2:ρ=0.262、0.295、0.293,P=0.004、0.001、0.001;MMP-9:ρ=0.442、0.437、0.400,P均=0.000),ColⅣ蛋白的表达水平与胃液中3种AAAs浓度呈负相关关系(ρ=-0.283、-0.280、-0.273,P=0.002、0.002、0.003)。结论胃癌组织通过上调MMP-2/9蛋白的表达,降解基底膜和细胞外基质中ColⅣ蛋白,可能是引起胃癌患者胃液AAAs浓度异常升高的原因之一。
Objective To investigate the expression of matrix metalloproteinase-2/9( MMP-2/9) and type Ⅳ collagen( ColⅣ) in gastric tissues and their relations with abnormal elevation of aromatic amino acids'( AAAs) concentrations in gastric juice in gastric cancer( GC) patients.Methods Gastric mucosal specimens and gastric juice samples were simultaneously collected from 29 GC patients and 91 non-neoplastic gastric disease( NGD) patients.The expression levels of MMP-2/9 and Col Ⅳ in gastric tissues were examined by immunohistochemical staining while the levels of AAAs( tyrosine,phenylalanine and tryptophan) in gastric juice were determined by liquid chromatography-tandem mass spectrometry.The expression of MMP-2/9 and Col Ⅳ was compared between GC group and NGD group,and relation with levels of AAAs was evaluated by the Spearman correlation analysis.Results The expression intensity of MMP-2/9 in the GC group was significantly higher than that in the NGD group,while the expression of ColⅣ was markedly lower than that in the NGD group( P = 0.000).Moreover,there was a positive correlation between the expression level of MMP-2 and MMP-9( ρ = 0.418,P = 0.000),but they were both negatively correlated with Col Ⅳ( ρ =-0.454,P = 0.000;ρ =-0.383,P = 0.000).The levels of AAAs in gastric juice were significantly higher in GC patients than those in NGD individuals( P = 0.000).The expression levels of MMP-2/9 in gastric tissues were both positively correlated with the concentrations of AAAs in gastric juice( MMP-2: ρ = 0.262,0.295,and 0.293,respectively,P = 0.004,0.001,and 0.001,respectively; MMP-9: ρ =0.442,0.437,and 0.400,respectively,all P = 0.000),but the expression of Col Ⅳ was negatively correlated with them( ρ =-0.283,-0.280,and-0.273,respectively,P = 0.002,0.002,and 0.003,respectively).Conclusion The overexpression of MMP-2/9 resulting in the degradation of Col Ⅳ in basement membrane and extracellular matrix may lead to the variation of AAAs' levels in gastric juice of GC patients.
Objective To investigate the expression of matrix metalloproteinase-2/9( MMP-2/9) and type Ⅳ collagen( ColⅣ) in gastric tissues and their relations with abnormal elevation of aromatic amino acids'( AAAs) concentrations in gastric juice in gastric cancer( GC) patients.Methods Gastric mucosal specimens and gastric juice samples were simultaneously collected from 29 GC patients and 91 non-neoplastic gastric disease( NGD) patients.The expression levels of MMP-2/9 and Col Ⅳ in gastric tissues were examined by immunohistochemical staining while the levels of AAAs( tyrosine,phenylalanine and tryptophan) in gastric juice were determined by liquid chromatography-tandem mass spectrometry.The expression of MMP-2/9 and Col Ⅳ was compared between GC group and NGD group,and relation with levels of AAAs was evaluated by the Spearman correlation analysis.Results The expression intensity of MMP-2/9 in the GC group was significantly higher than that in the NGD group,while the expression of ColⅣ was markedly lower than that in the NGD group( P = 0.000).Moreover,there was a positive correlation between the expression level of MMP-2 and MMP-9( ρ = 0.418,P = 0.000),but they were both negatively correlated with Col Ⅳ( ρ =-0.454,P = 0.000;ρ =-0.383,P = 0.000).The levels of AAAs in gastric juice were significantly higher in GC patients than those in NGD individuals( P = 0.000).The expression levels of MMP-2/9 in gastric tissues were both positively correlated with the concentrations of AAAs in gastric juice( MMP-2: ρ = 0.262,0.295,and 0.293,respectively,P = 0.004,0.001,and 0.001,respectively; MMP-9: ρ =0.442,0.437,and 0.400,respectively,all P = 0.000),but the expression of Col Ⅳ was negatively correlated with them( ρ =-0.283,-0.280,and-0.273,respectively,P = 0.002,0.002,and 0.003,respectively).Conclusion The overexpression of MMP-2/9 resulting in the degradation of Col Ⅳ in basement membrane and extracellular matrix may lead to the variation of AAAs' levels in gastric juice of GC patients.
引文
1刘健,闫秀娥,周丽雅,等.胃液固有荧光光谱在胃癌诊断中的应用进展.中国微创外科杂志,2018,18(1):64-67.
2 Deng K,Lin S,Zhou L,et al.Three aromatic amino acids in gastric juice as potential biomarkers for gastric malignancies.Anal Chim Acta,2011,694(1-2):100-107.
3 Deng K,Lin S,Zhou L,et al.High levels of aromatic amino acids in gastric juice during the early stages of gastric cancer progression.PLo S One,2012,7(11):e49434.
4 Huang L,Xu A.Detection of digestive malignancies and postgastrectomy complications via gastrointestinal fluid examination.Front Med,2017,11(1):20-31.
5 Pinheiro Ddo R,Ferreira WA,Barros MB,et al.Perspectives on new biomarkers in gastric cancer:diagnostic and prognostic applications.World J Gastroenterol,2014,20(33):11574-11585.
6 Wu W,Chung MC.The gastric fluid proteome as a potential source of gastric cancer biomarkers.J Proteomics,2013,90:3-13.
7 Wiggins T,Kumar S,Markar SR,et al.Tyrosine,phenylalanine,and tryptophan in gastroesophageal malignancy:a systematic review.Cancer Epidemiol Biomarkers Prev,2015,24(1):32-38.
8 Li ZP,Li Y,Liu J,et al.Overexpression of cytoplasmic p62 protein is associated with poor prognosis in gastric adenocarcinoma.Int J Clin Exp Pathol,2016,9(8):8492-8498.
9 Hwang TL,Lee LY,Wang CC,et al.Claudin-4 expression is associated with tumor invasion,MMP-2 and MMP-9 expression in gastric cancer.Exp Ther Med,2010,1(5):789-797.
10 Ruan HL,Hong RT,Xie HJ,et al.Significance of elevated levels of collagen typeⅣand hyaluronic acid in gastric juice and serum in gastric cancer and precancerous lesion.Dig Dis Sci,2011,56(7):2001-2008.
11 Wang HL,Zhou PY,Zhang Y,et al.Relationships between abnormal MMP2 expression and prognosis in gastric cancer:a meta-analysis of cohort studies.Cancer Biother Radiopharm,2014,29(4):166-172.
12 Chen J,Chen LJ,Zhou HC,et al.Prognostic value of matrix metalloproteinase-9 in gastric cancer:a meta-analysis.Hepatogastroenterology,2014,61(130):518-524.
13 Bornschein J,Seidel T,Langner C,et al.MMP2 and MMP7 at the invasive front of gastric cancer are not associated with m TORexpression.Diagn Pathol,2015,10:212.
14 Gurgel DC,Valena-Junior JT,Dornelas CA,et al.Immunoexpression of metalloproteinases 2 and 14 and TIMP-2 inhibitor in main types of primary gastric carcinomas and lymph node metastasis.Pathol Oncol Res,2015,21(1):73-81.
15 Bergin PJ,Anders E,Sicheng W,et al.Increased production of matrix metalloproteinases in Helicobacter pylori-associated human gastritis.Helicobacter,2004,9(3):201-210.
16 Brown GT,Murray GI.Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis.JPathol,2015,237(3):273-281.
17 Peng CW,Liu XL,Liu X,et al.Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion:laboratory evidence and clinical significance.J Transl Med,2010,8:101.
18 Mrena J,Wiksten JP,Nordling S,et al.MMP-2 but not MMP-9associated with COX-2 and survival in gastric cancer.J Clin Pathol,2006,59(6):618-623.
2 Deng K,Lin S,Zhou L,et al.Three aromatic amino acids in gastric juice as potential biomarkers for gastric malignancies.Anal Chim Acta,2011,694(1-2):100-107.
3 Deng K,Lin S,Zhou L,et al.High levels of aromatic amino acids in gastric juice during the early stages of gastric cancer progression.PLo S One,2012,7(11):e49434.
4 Huang L,Xu A.Detection of digestive malignancies and postgastrectomy complications via gastrointestinal fluid examination.Front Med,2017,11(1):20-31.
5 Pinheiro Ddo R,Ferreira WA,Barros MB,et al.Perspectives on new biomarkers in gastric cancer:diagnostic and prognostic applications.World J Gastroenterol,2014,20(33):11574-11585.
6 Wu W,Chung MC.The gastric fluid proteome as a potential source of gastric cancer biomarkers.J Proteomics,2013,90:3-13.
7 Wiggins T,Kumar S,Markar SR,et al.Tyrosine,phenylalanine,and tryptophan in gastroesophageal malignancy:a systematic review.Cancer Epidemiol Biomarkers Prev,2015,24(1):32-38.
8 Li ZP,Li Y,Liu J,et al.Overexpression of cytoplasmic p62 protein is associated with poor prognosis in gastric adenocarcinoma.Int J Clin Exp Pathol,2016,9(8):8492-8498.
9 Hwang TL,Lee LY,Wang CC,et al.Claudin-4 expression is associated with tumor invasion,MMP-2 and MMP-9 expression in gastric cancer.Exp Ther Med,2010,1(5):789-797.
10 Ruan HL,Hong RT,Xie HJ,et al.Significance of elevated levels of collagen typeⅣand hyaluronic acid in gastric juice and serum in gastric cancer and precancerous lesion.Dig Dis Sci,2011,56(7):2001-2008.
11 Wang HL,Zhou PY,Zhang Y,et al.Relationships between abnormal MMP2 expression and prognosis in gastric cancer:a meta-analysis of cohort studies.Cancer Biother Radiopharm,2014,29(4):166-172.
12 Chen J,Chen LJ,Zhou HC,et al.Prognostic value of matrix metalloproteinase-9 in gastric cancer:a meta-analysis.Hepatogastroenterology,2014,61(130):518-524.
13 Bornschein J,Seidel T,Langner C,et al.MMP2 and MMP7 at the invasive front of gastric cancer are not associated with m TORexpression.Diagn Pathol,2015,10:212.
14 Gurgel DC,Valena-Junior JT,Dornelas CA,et al.Immunoexpression of metalloproteinases 2 and 14 and TIMP-2 inhibitor in main types of primary gastric carcinomas and lymph node metastasis.Pathol Oncol Res,2015,21(1):73-81.
15 Bergin PJ,Anders E,Sicheng W,et al.Increased production of matrix metalloproteinases in Helicobacter pylori-associated human gastritis.Helicobacter,2004,9(3):201-210.
16 Brown GT,Murray GI.Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis.JPathol,2015,237(3):273-281.
17 Peng CW,Liu XL,Liu X,et al.Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion:laboratory evidence and clinical significance.J Transl Med,2010,8:101.
18 Mrena J,Wiksten JP,Nordling S,et al.MMP-2 but not MMP-9associated with COX-2 and survival in gastric cancer.J Clin Pathol,2006,59(6):618-623.
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