胃癌组织中PPARγ与MMP-2、MMP-9的表达及其临床意义
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摘要
目的
研究MMP-2(matrix metalloproteinase 2)、MMP-9(matrix metalloproteinase 9)和PPAR_γ(peroxisome proliferators activated receptorγ)在人体胃癌组织中的表达及其与胃癌生物学行为的关系，了解MMP-2、MMP-9和PPAR_γ与胃癌的侵袭及淋巴结转移的关系，寻找预测胃癌淋巴结转移的分子标志物，并为MMP及PPARs靶向个体化治疗提供证据。探讨正常胃粘膜、胃癌组织中MMP-2、MMP-9及PPARs的表达及其临床意义。
方法
收集75例有完整随访资料的胃腺癌手术切除标本及15例非肿瘤性胃粘膜组织标本，经溶脂法获取每例标本的全部淋巴结，所有淋巴结均进行连续间断切片、常规HE染色和CK18+EMA免疫组织化学染色，以确定有无淋巴结转移及微转移；N分期按照UICC／AJCC标准，即No：无淋巴结转移，N1：1-6个淋巴结转移，N2：7-15个淋巴结转移，N3：15个以上淋巴结转移。用免疫组织化学方法检测MMP-2、MMP-9及PPAR_γ在人体胃癌组织中的表达。
全部数据经SAS8.1及SPSS13.0统计学软件处理。胃癌MMP-2、MMP-9和PPAR_γ的表达与有无淋巴结转移之间的差异用χ~2检验，P值＜0.05为有统计学意义。
结果
1、75例胃腺癌组织中，以MMP-2、MMP-9和PPAR_γ为一抗进行免疫组织化学染色后，可分析病例分别为75例、75例和75例。组织可利用率为100％。
2、PPAR_γ与MMP-2、MMP-9的阳性表达率与胃癌的浸润深度、淋巴转移、临床分期呈正相关(P＜0.05)，随肿瘤浸润深度的加深、淋巴转移的产生、临床分期的提高而明显增高；与肿瘤的病理分化程度呈负相关(P＜0.05)，其阳性表达率随着肿瘤病理分化程度的降低而增高。
3、Spearman等级相关分析显示，PPAR_γ与MMP-2、MMP-9表达呈负相关(r=-0.336、-0.401，P＜0.05)。
结论
1、胃癌组织中PPAR_γ与MMP-2、MMP-9呈现异常表达。
2、胃癌组织中PPAR_γ与MMP-2、MMP-9的阳性率与肿瘤淋巴转移、临床分期、肿瘤病理分化程度密切相关，提示它们在胃癌的发生发展和浸润转移过程中有抑制或促进作用。
3、胃癌组织中PPAR_γ与MMP-2、MMP-9的表达呈负相关，提示其在胃癌的发生发展以及浸润转移中存在着相互制约的作用。
4、PPAR_γ与MMP-2、MMP-9各自都可以成为胃癌诊断和预后判断的指标。
Objective
To study the expression of MMP-2 (matrix metalloproteinase 2)、MMP-9 (matrix metalloproteinase 9) and PPARγ(peroxisomeproliferators activated receptorγ) in gastric adenocarcinoma and search predicting markers for lymph node metastasis in gastric adenocarcinoma. To investigate the relationship among MMP-2、MMP-9 and PPARγin the development of gastric carcinoma.
Methods
Tumor specimens were collected from 75 gastric adenocarcinoma cases and 20 cases non-tumor gastric tissue in which lymph nodes were also checked.All tumor specimens were consecutively cut into serial sections and examined by microscope. Total number of metastatic lymph nodes was counted. And staging was conducted according to the Classification of UICC/AJCC standard. N0:no lymph node metastasis, N1:1-6 lymph nodesmetastasis, N2:7-15 lymph nodes metastasis, N3:＞15 lymph nodes metastasis. The expression of MMP-2、MMP-9 and PPARγwas detected on the section of tissue microarray by immunohistochemistry.
All data were processed using SAS 8.1 and SPSS 13.0 software. The difference of the expression of MMP-2、MMP-9 and PPARγin gastric adenocarcinoma with or without lymph node metastasis was processed usingχ~2-test, and P＜0.05 was considered statistical significance.
Results
1、After using immunohistochemistry stain, MMP-2、MMP-9 and PPARγ, there were 75 cases left. The usable rate was 100％.
2、The positive MMP-2、MMP-9 and PPARγexpression rate has positive correlation with infiltrated depth、lymphatic metastasis、clinical stage of gastric cancer (P＜0.05), and with deepening of the tumorous infiltrated depth, generating lymphatic metastasis, happening of far distance metastasis and increasing of clinical stage, positive MMP-2、MMP-9 and PPARγexpression rate rises obviously. Positive MMP-2、MMP-9 and PPARγexpression rate is negatively related with pathological differentiated degree of tumor (P＜0.05);it rises when pathological differentiated degree of tumor decreases.
3、The expression of PPARγwas negative related to that of MMP-2, MMP-9 protein (r=-0.336、-0.401, P＜0.05).
Conclusions
1、Expression of PPARγand MMP-2、MMP-9 is abnormal in the gastric cancerous tissue.
2、The close relationship between positive expression rate of PPARγ、MMP-2、MMP-9 in the gastric cancerous tissue and tumorous lymphatic metastasis、clinicalstage、pathological differentiated degree shows that they have suppressed or promotive effect in the development and infiltrating metastasis of gastric carcinoma.
3、Negative correlation between PPARγand MMP-2、MMP-9 expression displays that they restrict each other in the process of gastric caicinoma happening、growth、infliltration and metastasis.
4、PPARγand MMP-2、MMP-9 could be three markers to the diagnose and predict the prognosis of gastric cancer.
研究MMP-2(matrix metalloproteinase 2)、MMP-9(matrix metalloproteinase 9)和PPAR_γ(peroxisome proliferators activated receptorγ)在人体胃癌组织中的表达及其与胃癌生物学行为的关系，了解MMP-2、MMP-9和PPAR_γ与胃癌的侵袭及淋巴结转移的关系，寻找预测胃癌淋巴结转移的分子标志物，并为MMP及PPARs靶向个体化治疗提供证据。探讨正常胃粘膜、胃癌组织中MMP-2、MMP-9及PPARs的表达及其临床意义。
方法
收集75例有完整随访资料的胃腺癌手术切除标本及15例非肿瘤性胃粘膜组织标本，经溶脂法获取每例标本的全部淋巴结，所有淋巴结均进行连续间断切片、常规HE染色和CK18+EMA免疫组织化学染色，以确定有无淋巴结转移及微转移；N分期按照UICC／AJCC标准，即No：无淋巴结转移，N1：1-6个淋巴结转移，N2：7-15个淋巴结转移，N3：15个以上淋巴结转移。用免疫组织化学方法检测MMP-2、MMP-9及PPAR_γ在人体胃癌组织中的表达。
全部数据经SAS8.1及SPSS13.0统计学软件处理。胃癌MMP-2、MMP-9和PPAR_γ的表达与有无淋巴结转移之间的差异用χ~2检验，P值＜0.05为有统计学意义。
结果
1、75例胃腺癌组织中，以MMP-2、MMP-9和PPAR_γ为一抗进行免疫组织化学染色后，可分析病例分别为75例、75例和75例。组织可利用率为100％。
2、PPAR_γ与MMP-2、MMP-9的阳性表达率与胃癌的浸润深度、淋巴转移、临床分期呈正相关(P＜0.05)，随肿瘤浸润深度的加深、淋巴转移的产生、临床分期的提高而明显增高；与肿瘤的病理分化程度呈负相关(P＜0.05)，其阳性表达率随着肿瘤病理分化程度的降低而增高。
3、Spearman等级相关分析显示，PPAR_γ与MMP-2、MMP-9表达呈负相关(r=-0.336、-0.401，P＜0.05)。
结论
1、胃癌组织中PPAR_γ与MMP-2、MMP-9呈现异常表达。
2、胃癌组织中PPAR_γ与MMP-2、MMP-9的阳性率与肿瘤淋巴转移、临床分期、肿瘤病理分化程度密切相关，提示它们在胃癌的发生发展和浸润转移过程中有抑制或促进作用。
3、胃癌组织中PPAR_γ与MMP-2、MMP-9的表达呈负相关，提示其在胃癌的发生发展以及浸润转移中存在着相互制约的作用。
4、PPAR_γ与MMP-2、MMP-9各自都可以成为胃癌诊断和预后判断的指标。
Objective
To study the expression of MMP-2 (matrix metalloproteinase 2)、MMP-9 (matrix metalloproteinase 9) and PPARγ(peroxisomeproliferators activated receptorγ) in gastric adenocarcinoma and search predicting markers for lymph node metastasis in gastric adenocarcinoma. To investigate the relationship among MMP-2、MMP-9 and PPARγin the development of gastric carcinoma.
Methods
Tumor specimens were collected from 75 gastric adenocarcinoma cases and 20 cases non-tumor gastric tissue in which lymph nodes were also checked.All tumor specimens were consecutively cut into serial sections and examined by microscope. Total number of metastatic lymph nodes was counted. And staging was conducted according to the Classification of UICC/AJCC standard. N0:no lymph node metastasis, N1:1-6 lymph nodesmetastasis, N2:7-15 lymph nodes metastasis, N3:＞15 lymph nodes metastasis. The expression of MMP-2、MMP-9 and PPARγwas detected on the section of tissue microarray by immunohistochemistry.
All data were processed using SAS 8.1 and SPSS 13.0 software. The difference of the expression of MMP-2、MMP-9 and PPARγin gastric adenocarcinoma with or without lymph node metastasis was processed usingχ~2-test, and P＜0.05 was considered statistical significance.
Results
1、After using immunohistochemistry stain, MMP-2、MMP-9 and PPARγ, there were 75 cases left. The usable rate was 100％.
2、The positive MMP-2、MMP-9 and PPARγexpression rate has positive correlation with infiltrated depth、lymphatic metastasis、clinical stage of gastric cancer (P＜0.05), and with deepening of the tumorous infiltrated depth, generating lymphatic metastasis, happening of far distance metastasis and increasing of clinical stage, positive MMP-2、MMP-9 and PPARγexpression rate rises obviously. Positive MMP-2、MMP-9 and PPARγexpression rate is negatively related with pathological differentiated degree of tumor (P＜0.05);it rises when pathological differentiated degree of tumor decreases.
3、The expression of PPARγwas negative related to that of MMP-2, MMP-9 protein (r=-0.336、-0.401, P＜0.05).
Conclusions
1、Expression of PPARγand MMP-2、MMP-9 is abnormal in the gastric cancerous tissue.
2、The close relationship between positive expression rate of PPARγ、MMP-2、MMP-9 in the gastric cancerous tissue and tumorous lymphatic metastasis、clinicalstage、pathological differentiated degree shows that they have suppressed or promotive effect in the development and infiltrating metastasis of gastric carcinoma.
3、Negative correlation between PPARγand MMP-2、MMP-9 expression displays that they restrict each other in the process of gastric caicinoma happening、growth、infliltration and metastasis.
4、PPARγand MMP-2、MMP-9 could be three markers to the diagnose and predict the prognosis of gastric cancer.
引文
1 Tahara E.Genetic alterations in human gastro-intestinal cancers-application to moleculer diagnosis[J].Cancer.2005;75(suppl):1410-1417
2 Isseman I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome prolifterators [J].Nature.1990;347:645-650
3 Visse Nagase H.Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases:Structure,Function,andBiochemistry.Circula-tion Research.2003;92(8) :827-839
4 Brew K,Dinakarpandian D,Nagase H.Tissue inhibitors of metallo-proteinases:evolution,structure and function.Biochim BiophysActa.2000;1477(1-2) :267-283
5 Yoon SO,Park SJ,Yun CH,et al.Roles of Matrix Metalloproteinases in Tumor Metastasis and Angiogenesis.Journal of Biochemistry and Molecular Biology.2003;36(1) :128-137
6 Bogenrieder T,Herlyn M.Axisofevil:molecular mechanisms of cancer metastasis oneogene.2003;22(42) :6524-6536
7 Isseman I,Green S.Activation of a member of the steroidhormone receptor Superfamily by peroxisome proliferators[J].Nature.1990;347:645-650
8 Houseknecht KL,Cole BM,Steele PJ.Peroxisome proliferators-activated receptor gamma (PPARgamma) and its ligands:a review[J].Domest Anim Endocrinol.2002;22:1-23
9 Sato H,Ishihara S,Kawashima K,et al.Expression of peroxisome proliferator-activated Receptor (PPAR) in gastric cancer and inhibitory effecys of PPAR-gamma agonists.Br J Cancer.2000;83:1394-1400
10 Motomuea W,Okumura T,Takahashi N,et al.Activation of peroxisome proliferators activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KIPI in human pancreatic carcinoma cells.Cancer.2000;60:5558-5564
11 Gelman L,Fruchart JC Auwerx J.An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer.Cell Mol Life Sci.1999;55:932-943
12 Sato H,Ishihara S,Kawashima K,et al.Expression of peroxisome Proliferator activated Receptor (PPAR) in gastric cancer and inhibitory effecys of PPAR-gamma agonists.Br J Cancer.2000;83:1394-1400
13 HanSU,LeeJH,KimWH,ChoYK.Significant corregulation between serum level of hepatocyte growth factor and progression of gastric carcinoma.World J Surg.2000;23:1176-1180
14 SternlichtMD,Werb Z.How matrix metalloproteinases regulate cell behavior.Annu Rev Cel Dev Biol.2001;17:463
15 Jiajun Liu,Huiling Lu,Renwei Huang,Dongjun Lin,Xiangyuan Wu, Qu Lin,Xinyao Wu, et al.Peroxisome proliferators activated receptor-γligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemiacells.Cancer Chemother Phamacol.2005;56:400-408
16 Zhao MD,Hu XM,Sun DJ,Zhang Q,Meng W.Expression of some tumor associated factors in human carcinogenesis and development of gastric carcinoma.World J Gastro-enterol.2005; 11 (21):3217-3221
17 Forsyth PA,Wong H,Laing TD,et al.MMP-2,MMP-9 and MT1-MMP are involved in different aspects of the pathophysiology of malignant[J].Br J Cancer. 1999;79(11-12): 1828
18 Liu J,Lu H,Huang R, Lin D,et al.Peroxisome proliferators activated receptor-gamma ligands induced cell growth inhibition and its influence on matrix metallo proteinase activity in human myeloid leukemia cells.Cancer Chemother Pharmacol.2005;19(1):1-10
19 Zhang Min,YOU Yong,ZOU Ping,LIU Fang,BAI Ming,TAO Xiaoman,HE Wei.Expression of PPAR-γ in Lung Cancer and the Role of PPAR-γ in Apoptosis of Lung Cancer. The Chinese-German Journal of Clinical Oncology.2005;4(1):36-39
20 SatoH,IshiharaS,KawashimaK,et al.Expression of peroxisone proliferator activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPAR2 gamma agonists[J].Br J Cancer.2000;83(10):1394
21 幺立萍，吴开春，吴汉平，等．胃癌组织中过氧化物酶体增殖因子活化受体γ和维甲酸受体α表达的意义[J]．中华消化杂志．2001；21(7)：393
22 Yoshida K, Tanabe K,FujiiD,et al.Induction mechanism of apoptosis by troglitazone through peroxisome proliferators activated receptor2 gamma in gastric carcinoma cells [J].Anticancer Res.2003;23(1A):267
23 Nagamine M,OkumuraT,TannoS,et al.PPAR gamma ligand2 induced Apoptosis through a p532 dependent mechanism in human gastric cancer cells [J].Cancer Sci.2003;94(4):338
24 Kitamura S,Miyazaki Y, Hiraoka s,et al.PPARgamma inhibits the expression of c2MET in gastric cells through the suppression of Ets [J].Biochem Biophys ReCommun. 1999;265 (2):453
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27 Nomura H,Fujimoto N,Seiki,et al.Elhanced production of matrix metalloproteinases activation of matrix metalloproteinase 2 (gelatiA) in human gastric carcinomas.IntJLcaer. 1996;69(1):9-16
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15 Farrow B,Evers BM.Activation of PPARgamma increases PTEN expression in pancreatic cancer cells[J]. Biochem Biop hys Res Commun.2003;301(1):50
16 Sato H,ishihara S,Kawashima K,Moriyama N,et al.Expression of Peroxisome Proliferator-activated receptor (PPAR)γin gastric cancer and inhibitory effects of PPARγ agonists.British Journal of Cancer.2000;83(10): 1394
17 幺立萍，吴开春，吴汉平，等．胃癌组织中过氧化物酶体增殖因子活化受体γ和维甲酸受体α表达的意义[J]．中华消化杂志．2001；21(7)：393
18 Kitamura S,Miyazaki Y, Shinomura Y, et al.Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation makers of human colon cancer cells. Japanese Journal of Cancer Research. 1999;90(1):75
19 Yoshida K,Tanabe K,Fujii D,et al.Induction mechanism of apoptosis by troglitazone through peroxisome proliferators-activated receptor gamma in gastric carcinoma cells[J].Anticancer Res.2003;23 (1 A):267
20 Nagamine M,Okumura T, Tanno S,et al.PPARgamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells[J].Cancer Sci.2003;94(4):338
21 Kitamura S,Miyazaki Y, Hiraoka S,et al.PPARγinhibits the expression of c-Met in human gastric cancer cells through the suppression of Ets.Biochemical and Biophysial Research Communications.1999;265(2) :453 22 Gambarotta G,Boccaccio C,Giordano S,et al.Ets up-regulates MET transcription.Oncogene.2005;13(9) :1911
2 Isseman I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome prolifterators [J].Nature.1990;347:645-650
3 Visse Nagase H.Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases:Structure,Function,andBiochemistry.Circula-tion Research.2003;92(8) :827-839
4 Brew K,Dinakarpandian D,Nagase H.Tissue inhibitors of metallo-proteinases:evolution,structure and function.Biochim BiophysActa.2000;1477(1-2) :267-283
5 Yoon SO,Park SJ,Yun CH,et al.Roles of Matrix Metalloproteinases in Tumor Metastasis and Angiogenesis.Journal of Biochemistry and Molecular Biology.2003;36(1) :128-137
6 Bogenrieder T,Herlyn M.Axisofevil:molecular mechanisms of cancer metastasis oneogene.2003;22(42) :6524-6536
7 Isseman I,Green S.Activation of a member of the steroidhormone receptor Superfamily by peroxisome proliferators[J].Nature.1990;347:645-650
8 Houseknecht KL,Cole BM,Steele PJ.Peroxisome proliferators-activated receptor gamma (PPARgamma) and its ligands:a review[J].Domest Anim Endocrinol.2002;22:1-23
9 Sato H,Ishihara S,Kawashima K,et al.Expression of peroxisome proliferator-activated Receptor (PPAR) in gastric cancer and inhibitory effecys of PPAR-gamma agonists.Br J Cancer.2000;83:1394-1400
10 Motomuea W,Okumura T,Takahashi N,et al.Activation of peroxisome proliferators activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KIPI in human pancreatic carcinoma cells.Cancer.2000;60:5558-5564
11 Gelman L,Fruchart JC Auwerx J.An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer.Cell Mol Life Sci.1999;55:932-943
12 Sato H,Ishihara S,Kawashima K,et al.Expression of peroxisome Proliferator activated Receptor (PPAR) in gastric cancer and inhibitory effecys of PPAR-gamma agonists.Br J Cancer.2000;83:1394-1400
13 HanSU,LeeJH,KimWH,ChoYK.Significant corregulation between serum level of hepatocyte growth factor and progression of gastric carcinoma.World J Surg.2000;23:1176-1180
14 SternlichtMD,Werb Z.How matrix metalloproteinases regulate cell behavior.Annu Rev Cel Dev Biol.2001;17:463
15 Jiajun Liu,Huiling Lu,Renwei Huang,Dongjun Lin,Xiangyuan Wu, Qu Lin,Xinyao Wu, et al.Peroxisome proliferators activated receptor-γligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemiacells.Cancer Chemother Phamacol.2005;56:400-408
16 Zhao MD,Hu XM,Sun DJ,Zhang Q,Meng W.Expression of some tumor associated factors in human carcinogenesis and development of gastric carcinoma.World J Gastro-enterol.2005; 11 (21):3217-3221
17 Forsyth PA,Wong H,Laing TD,et al.MMP-2,MMP-9 and MT1-MMP are involved in different aspects of the pathophysiology of malignant[J].Br J Cancer. 1999;79(11-12): 1828
18 Liu J,Lu H,Huang R, Lin D,et al.Peroxisome proliferators activated receptor-gamma ligands induced cell growth inhibition and its influence on matrix metallo proteinase activity in human myeloid leukemia cells.Cancer Chemother Pharmacol.2005;19(1):1-10
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20 SatoH,IshiharaS,KawashimaK,et al.Expression of peroxisone proliferator activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPAR2 gamma agonists[J].Br J Cancer.2000;83(10):1394
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