血通灵冲剂抗肿瘤侵袭转移相关机制研究
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摘要
金属蛋白酶-9是肿瘤细胞侵袭和转移中起关键作用的酶。本文探讨中药传统方剂血通灵抑制PMA诱导人乳腺癌细胞(MCF-7)金属蛋白酶-9表达的作用机制。
研究中发现,血通灵的乙酸乙酯提取物(HE:Hyul-Tong-Ryung EtOAt extract,根据药物韩文名发音的首写子母和提取溶剂的首写子母组合而成)在低剂量条件下选择性的显著抑制不同癌细胞及正常细胞中金属蛋白酶活性的表达,同时在细胞侵袭实验中发现,该提取物能显著抑制豆蔻酰佛波醇乙酯(PMA)诱导人乳腺癌细胞侵入人工基底膜的能力。
蛋白印迹实验(Western blot)发现,HE抑制MMP-9的蛋白表达,提示HE的活性作用靶点可能位于MMP-9基因转录调控部位。RT-PCR及启动子活性分析实验表明,此推测的正确性。
Western blot和电泳迁移率(EMSA)实验进一步对人乳腺癌细胞信号通路检测中发现,激活蛋白(AP-1)转录因子的异源二聚体c-Jun磷酸化在给药后显著下调,因此阻止了AP-1的激活,相关文献报导指出,在AP-1的上游信号通路中丝裂原活化蛋白激酶(MAPKs)家族的ERK1/2,JNK,p38,在MMP-9表达调中,发挥重要作用。实验表明,在PMA诱导下的MCF-7细胞中,ERK1/2和部分JNK对MMP-9表达起决定作用,与此同时,HE通过抑制MAPKs信号通路中的调控蛋白因子ERK1/2,部分抑制JNK,阻断了下游AP-1转录因子的激活,抑制金属蛋白酶的表达,发挥其潜在抗肿瘤细胞的侵袭和转移作用。
The expression of matrix metalloproteinase-9(MMP-9) has been implicated in the invasion and metastasis of cancer cells. We concentrated on the mechanism of inhibitory effect of traditional Chinese formula Hyul-Tong-Ryung EtOAt extract (HE) on the PMA-induced MMP-9 secretion and expression in the human cell lines.
Here we found that in zymography assay, HE inhibits the PMA-induced MMP-9 induction in different human cell lines in the non-toxicity concentration. Based on this reason, HE drastically decreased the invasion ability of PMA-induced MCF-7 cells. In order to find out if the inhibitory effect is dues to the amount of protein expression, Western blot was used to detect the MMP-9 protein expression. The results show the same trend as zymograpgy test .These results suggested that the selective inhibitory effect of HE on the PMA induced MMP-9 secretion is correlated with the synthesis of MMP-9 protein.
Furturemore as evidenced by MMP-9 promoter, RT-PCR and electrophoretic mobility shift (EMSA) assays, HE significantly and specifically inhibited MMP-9 gene expression by blocking PMA-simulated activation of activator protein-1 (AP-1) which is through the phosphorylated c-Jun the heterodimer protein of AP-1.
Study about the regulation of MMP-9 transcription and expression indicated that, gene expression could be activated by MAPK signal transduction pathways including ERK1/2, p38, and JNK, which are the upstream modulators of AP-1 and NF-kB. Our data showed that the activation of ERK1/2 and JNK play the major role in regulating the MMP-9 expression. At the same time, HE dramatically suppressed the phosphorylation of ERK1/2 and partial of JNK, which suggested that HE suppressed PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7.
研究中发现,血通灵的乙酸乙酯提取物(HE:Hyul-Tong-Ryung EtOAt extract,根据药物韩文名发音的首写子母和提取溶剂的首写子母组合而成)在低剂量条件下选择性的显著抑制不同癌细胞及正常细胞中金属蛋白酶活性的表达,同时在细胞侵袭实验中发现,该提取物能显著抑制豆蔻酰佛波醇乙酯(PMA)诱导人乳腺癌细胞侵入人工基底膜的能力。
蛋白印迹实验(Western blot)发现,HE抑制MMP-9的蛋白表达,提示HE的活性作用靶点可能位于MMP-9基因转录调控部位。RT-PCR及启动子活性分析实验表明,此推测的正确性。
Western blot和电泳迁移率(EMSA)实验进一步对人乳腺癌细胞信号通路检测中发现,激活蛋白(AP-1)转录因子的异源二聚体c-Jun磷酸化在给药后显著下调,因此阻止了AP-1的激活,相关文献报导指出,在AP-1的上游信号通路中丝裂原活化蛋白激酶(MAPKs)家族的ERK1/2,JNK,p38,在MMP-9表达调中,发挥重要作用。实验表明,在PMA诱导下的MCF-7细胞中,ERK1/2和部分JNK对MMP-9表达起决定作用,与此同时,HE通过抑制MAPKs信号通路中的调控蛋白因子ERK1/2,部分抑制JNK,阻断了下游AP-1转录因子的激活,抑制金属蛋白酶的表达,发挥其潜在抗肿瘤细胞的侵袭和转移作用。
The expression of matrix metalloproteinase-9(MMP-9) has been implicated in the invasion and metastasis of cancer cells. We concentrated on the mechanism of inhibitory effect of traditional Chinese formula Hyul-Tong-Ryung EtOAt extract (HE) on the PMA-induced MMP-9 secretion and expression in the human cell lines.
Here we found that in zymography assay, HE inhibits the PMA-induced MMP-9 induction in different human cell lines in the non-toxicity concentration. Based on this reason, HE drastically decreased the invasion ability of PMA-induced MCF-7 cells. In order to find out if the inhibitory effect is dues to the amount of protein expression, Western blot was used to detect the MMP-9 protein expression. The results show the same trend as zymograpgy test .These results suggested that the selective inhibitory effect of HE on the PMA induced MMP-9 secretion is correlated with the synthesis of MMP-9 protein.
Furturemore as evidenced by MMP-9 promoter, RT-PCR and electrophoretic mobility shift (EMSA) assays, HE significantly and specifically inhibited MMP-9 gene expression by blocking PMA-simulated activation of activator protein-1 (AP-1) which is through the phosphorylated c-Jun the heterodimer protein of AP-1.
Study about the regulation of MMP-9 transcription and expression indicated that, gene expression could be activated by MAPK signal transduction pathways including ERK1/2, p38, and JNK, which are the upstream modulators of AP-1 and NF-kB. Our data showed that the activation of ERK1/2 and JNK play the major role in regulating the MMP-9 expression. At the same time, HE dramatically suppressed the phosphorylation of ERK1/2 and partial of JNK, which suggested that HE suppressed PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7.
引文
[1]Zhou,H.,Wong Y.E,Cai,X.,Liu Z.Q.,Jiang,Z.H.,Bian Z.X.Xu,H.X.,Liu L.Suppressive effects of JCICM-6,the extract of an anti-arthritic herbal formula on the experimental inflammatory and nociceptive models in rodents.Biol.Pharm.Bull,(2006),29:253-260
[2]林建银,杨怡.《医学分子生物学》中国协和医科大学出版社,2002年1月
[3]陈震,刘鲁明,宋明志《第六届全国中西医结合肿瘤学术研讨会论文集》
[4]吕秀娟,王琴.抗肿瘤中药的研究进展.中国现代中药,(2006),8:35-36.
[5]Ide R.,Mizoue T.,Fujino Y.,Cigarette smoking,alcohol drinking,and oral andpharyngeal cancer mortality in Japan.Oral Dis,(2008),14:314-319
[6]Tetsuya Otani.,Motoki Iwasaki.,Seiichiro Yamamoto.,Alcohol Consumption,Smoking,and Subsequent Risk of Colorectal Cancer in Middle-Aged and Elderly Japanese Men and Women:Japan Public Health Center-based Prospective Study.Cancer Epidemiology,Biomarkers & Prevention,(2003),12:1492-1500.
[7]Jensen TJ.,Novak P.,Eblin EK.,Epigenetic Remodeling During Arsenical-Induced Malignant Transformation.Carcinogenesis,2008,30:1-37
[8]Elitza Germanov.,Jason N.Berman.,Duanel.Guernsey,.Current and future approaches for the therapeutic targeting of metastasis(Review).International Journal of Molecular Medicine,2006,18:1025-1036
[9]Isaiah.Fidler.,The pathogenesis of cancer metastasis:"seed and soil" hypothesis revisited.Nature reviews/CANCER,2003,3:1-6
[10]So-Young Kim.Dong-Hyun Kim.,Sang-Jun Han.,Represion of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells.Biochmical Pharmacology,2007,74:1642-1651
[11]培奇.,抗肿瘤转移药物研究现状.上海医药情报研究,1996,40:1-6
[12]GohjiK.,Fujimoto N.,Serum martixmeatlloporetinase2 and densiytin men wiht prostate Cancer as a new predictor of disease extension.Int J Cnaecr,1998,:79(11):96-101
[13]LiottaLA.,Tumor invasion and metastases-role of the extracellular marx:Rhoads Memorial Award lecture.Cancer Res,1996,46:1-7
[14]Gross J,Lapiere CM Collagenogenolytic activity in amphibian tissue;a tissue culture assay.Proc Natl.Acad.Sci.USA,1962,48:1041-1050
[15]Krane SM.,Byrne MH.,Lemaitru.,et al.Differetn collagenase gene products have different roles in degradation of Type Ⅰ collage.Biol Chem,1996,271:28509
[16]王一,徐毅,基质金属蛋白酶,医学综述,1999,5(4)174-176
[17]X iaT.,AkesrK.EisenAZ.,Comparison of celeavage site specificity of gelatinases A and B using Collagenous peptides.BioPhys Acta,1996,1293(2):259-266
[18]VadayGG.,LideyO.,Extracellular matrixmotictis,Cytokines,anden-zymes,dymatic effects on immune cell behavior and inflammation.J Leukoe Biol,2000,67:149-159
[19]Naiyer A.,L Jod Y.,Ahn J.,et al.Stromal derived factor-1 induced Chemokines of cord blood CD 34+cell(long time culture in itiating cells)through endothelial cell sismediates by E-selectin.Blood,1999,94:4011-4019
[20]KleinerD.,Settler-Stevenosn W.,Matrix metalloproteinase and metasitasis.Cancer Chemother Pharmcol,1999,43:42-51
[21]Ivan Stamenkovic.,Extracellular matrix remodelling:the role of matrix metalloproteinases.Journal of pathology,2003,200:448-464
[22]Manuel Hidalgo,S.,Gail Eckhardt.,Development of matrix metalloproteinase inhibitors in Cancer Therapy.Journal of the National Cancer institute,2001,93(3):178-193
[23]韩溟,许丽艳,恶性肿瘤中MMP-9表达调控机制研究进展,国外医学分子生物学分册,2003,25(1):24-26
[24]Massoval.,KortaL P.,Fridmna R.,et al.Matrix metallopreoteinases:structure,evolution and diversification.ASEBJ,1998,12(12):1075-1095
[25]Kleiner.,D.E.,Stetler-Stevenson.,W.G Matrix metalloproteinases and metastasis.Cancer Chemother.Pharmacol..1999,43:42-51
[26]Ujanen.,E.S.,Vaisanen.,A.,Zheng,A.,Tryggvason,K.,Turpeenniemi-Hujanen,T.Modulation of M(r)72,000 and M(r)92,000 type-Ⅳ collagenase(gelatinase A and B)gene expression by interferons and in human melanoma.Int.J.Cancer,1994,58:582-586
[27]Jones,J.L.,Glynn,P.,Walker,R.A.Expression of MMP-2 and MMP-9,their inhibitors,and the activator MT1-MMP in primary breast carcinomas.J.Pathol.1999,189:161-168
[28]Canete SR.Gui YH,Linask KK,et al.MMP-9(gelatinase B)mRNA is expressed during mouse neurogenesis and may be associated with vascularization.Dev.Brain Res 1995,88:37-42
[29]Canete SR,Gui YH,Linask KK,et a.l.Developmental expression of MMP-9(gelatinase B)mRNA in mouse embryos.Develop.Dynamics1995,204:30-38
[30]Heppner KJ,Matrisian LM,Jensen RA,et al.Expression of most MMPs family numbers in breast cancer represents a tumor-induced host response.Am J Pathol,1996,149:273
[31]Iwata H,Kobayashi S,Iwase H,et al.Production of MMPs and TIMPs in human breast carcinoma.Jap.J.cancer Res,1996,87:602
[32]Ueda Y,Tsuchiya H,Fujimoto N,et al.MMP-9 is expressed in multinucleated gianc cells of human giant cell tumor of bone and is associated with vascular invasion.Am J Pathol,1996,148:611-616
[33]Fini ME,Girard MT,Matsubara M,et al.Unique regulation of the MMP-9.In vest Ophthalmol Vis.Sci,1995,36:622-630.
[34]Houde M,Tremblay P,Masure S,et al.Synergistic and selective stimulation of MMP-9 production in macrophage by LPS,trans-retinoic acid and PKC regulator.Biochim Biophys,Acta1996,1310:193-200
[35]Soo-Hyun Jung1,Moon-Sook Woo1,et al.Ginseng saponin metabolite suppresses phorbol ester-induced matrix metalloproteinase-9 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathways in human astroglioma cells.Int.J.Cancer,2006,118:490-497
[36]Maeda,K.,Kuzuya,M.,Cheng,X.W.,et al.Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier.Atherosclerosis,2003,166:23-30
[37]Ki-Tae Ha,June-Ki Kim,et al.Inhibitory effect of Daesungki-Tang on the invasiveness potential of hepatocellular carcinoma through inhibition of matrix metalloproteinase-2 and -9 activities.Toxiclolgy and Applied Parmacology,2004,200:1-6
[38]豆长明,中药抗肿瘤作用机制研究态势评析,中医药学刊,2003,21(3):361-36
[39]韩晨光,王佐妤,郑爱青,MMP-9在恶性乳腺肿瘤中的表达及其对浸润转移的作用,武警医学院学报.2007,16.(4):362-364.
[40]董德刚,郭恩绵,张瑶,桂枝茯苓对宫颈癌HeLa细胞侵袭转移及MMP-2、MMP-9表达的影响,山东医药.2007,47(27):49-51.
[41]韩晨光,毛中鹏,乳腺癌组织中MMP29表达与癌细胞局部侵袭的关系,山东医药.2007,47(33):65-66.
[42]吴梧桐.《生物化学》人民卫生出版社,2003年6月
[43]Rapti M,nauper Vet al.Characterization of the AB loop region of TIMP-2,Involvement in pro-MMP-2activation.J Biol Chem,2006,281(33):23386-23394.
[44]BoulikasT:PhosPhorylation of trancctription factors and control of the cell cycle.Crit Rev Eukaryot Gene Exp.1995,5:1-77.
[45]Angel P,Karin M:The role of Jun,Fos and the AP-1 complex in cell proliferation and transformation. Bioehim Biophys Acta,1991,1072:129-157
[46]SatakeM.,Ibaraki T.,YamaguehiY.,ItoY:Loss of responsiveness of an API-related factor,PEBPI,to 12-O-tetradecanoylphorbol-13-acetate afte rtransfornation of NIH3T3cells by the Ha-ras oncogene.J Virol,1989,63:3669-3677
[47]邱伟,金属蛋白酶类组织抑制剂及其基因多态性与肿瘤,2007,34(10):738-740
[48]Park,K.K.et al Inhibitory effects of novel E2F decoy oligodeoxynucleotides on mesangial cell proliferation by co-expression of E2F/DP.Biochem.Biophys.Res.Commun,2003,308:689-697
[49]Eferl,R.et al.AP-1:a double-edged sword in tumorigenesis.Nat.Rev.Cancer,2003,3:859-868
[50]Syng-Ook Lee.,Yun-Jeong Jeong.,Suppression of PMA-induced tumor cell invasion by capillarisin via the inhibition of NF-jB-dependent MMP-9 expression.Biochemical and Biophysical Research Communications,2008,366:1019-1024
[51]T.W.Chung.,S.K.Moon.,Y.C.Chang.,J.H.Ko.,Y.C.Lee G.Cho.,S.H.Kim.,J.G.Kim.,C.H.Kim.,Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells:complete regression of hepatoma growth and metastasis by dual mechanism,.FASEB J,2004,18:1670-1681
[52]S.Hong.,K.K.Park.,J.Magae.,K.Ando.,T.S.Lee.,T.K.Kwon.,J.Y.Kwak.,C.H.Kim.,Y.C.Chang.,Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway:inhibitoryeffects of ascochlorin on the invasion of renal carcinoma cells,J.Biol.Chem,2005,280:25202-25209
[53]S.O.Lee.,Y.J.Jeong.,H.G.Im.,C.H.Kim.,Y.C.Chang.,I.S.Lee.,Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells,Biochem.Biophys.Res.Commun.,2007,354:165-171
[54]M.Aouadi.,B.Binetruy.,L.Caron.,Y.Le Marchand-Brustel.,F.Bost.,Role of MAPKs in development and differentiation:lessons from knockout mice.Biochemie,2006,88:1091-1098
[55]Hyun-Ji Cho.,Jeong Han Kang.,Jong-Young Kwak.,Tae-Sung Lee.,In-Seon Lee.,Nam Gyu Park..,Hiroo Nakajima.,Junji Magae6 and Young-Chae Chang.,Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK1/2 and Apl-dependent mechanisms.Carcinogenesis,2007,28:1104-1110
[56]M.Aouadi,B.Binetmy1,L.Caron,et al.,Role of MAPKs in development and differentiation:lessons from knockout mice.Biochimie.2006,88:1091-1098
[57]Tae-Wook Chung.,Sung-Kwon Moom.,et al.,Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells:complete regression of hepatoma growth and metastasis by dual mechanism.The FASEB Journal · Research Communication,2004,11(18):1670-1681.
[2]林建银,杨怡.《医学分子生物学》中国协和医科大学出版社,2002年1月
[3]陈震,刘鲁明,宋明志《第六届全国中西医结合肿瘤学术研讨会论文集》
[4]吕秀娟,王琴.抗肿瘤中药的研究进展.中国现代中药,(2006),8:35-36.
[5]Ide R.,Mizoue T.,Fujino Y.,Cigarette smoking,alcohol drinking,and oral andpharyngeal cancer mortality in Japan.Oral Dis,(2008),14:314-319
[6]Tetsuya Otani.,Motoki Iwasaki.,Seiichiro Yamamoto.,Alcohol Consumption,Smoking,and Subsequent Risk of Colorectal Cancer in Middle-Aged and Elderly Japanese Men and Women:Japan Public Health Center-based Prospective Study.Cancer Epidemiology,Biomarkers & Prevention,(2003),12:1492-1500.
[7]Jensen TJ.,Novak P.,Eblin EK.,Epigenetic Remodeling During Arsenical-Induced Malignant Transformation.Carcinogenesis,2008,30:1-37
[8]Elitza Germanov.,Jason N.Berman.,Duanel.Guernsey,.Current and future approaches for the therapeutic targeting of metastasis(Review).International Journal of Molecular Medicine,2006,18:1025-1036
[9]Isaiah.Fidler.,The pathogenesis of cancer metastasis:"seed and soil" hypothesis revisited.Nature reviews/CANCER,2003,3:1-6
[10]So-Young Kim.Dong-Hyun Kim.,Sang-Jun Han.,Represion of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells.Biochmical Pharmacology,2007,74:1642-1651
[11]培奇.,抗肿瘤转移药物研究现状.上海医药情报研究,1996,40:1-6
[12]GohjiK.,Fujimoto N.,Serum martixmeatlloporetinase2 and densiytin men wiht prostate Cancer as a new predictor of disease extension.Int J Cnaecr,1998,:79(11):96-101
[13]LiottaLA.,Tumor invasion and metastases-role of the extracellular marx:Rhoads Memorial Award lecture.Cancer Res,1996,46:1-7
[14]Gross J,Lapiere CM Collagenogenolytic activity in amphibian tissue;a tissue culture assay.Proc Natl.Acad.Sci.USA,1962,48:1041-1050
[15]Krane SM.,Byrne MH.,Lemaitru.,et al.Differetn collagenase gene products have different roles in degradation of Type Ⅰ collage.Biol Chem,1996,271:28509
[16]王一,徐毅,基质金属蛋白酶,医学综述,1999,5(4)174-176
[17]X iaT.,AkesrK.EisenAZ.,Comparison of celeavage site specificity of gelatinases A and B using Collagenous peptides.BioPhys Acta,1996,1293(2):259-266
[18]VadayGG.,LideyO.,Extracellular matrixmotictis,Cytokines,anden-zymes,dymatic effects on immune cell behavior and inflammation.J Leukoe Biol,2000,67:149-159
[19]Naiyer A.,L Jod Y.,Ahn J.,et al.Stromal derived factor-1 induced Chemokines of cord blood CD 34+cell(long time culture in itiating cells)through endothelial cell sismediates by E-selectin.Blood,1999,94:4011-4019
[20]KleinerD.,Settler-Stevenosn W.,Matrix metalloproteinase and metasitasis.Cancer Chemother Pharmcol,1999,43:42-51
[21]Ivan Stamenkovic.,Extracellular matrix remodelling:the role of matrix metalloproteinases.Journal of pathology,2003,200:448-464
[22]Manuel Hidalgo,S.,Gail Eckhardt.,Development of matrix metalloproteinase inhibitors in Cancer Therapy.Journal of the National Cancer institute,2001,93(3):178-193
[23]韩溟,许丽艳,恶性肿瘤中MMP-9表达调控机制研究进展,国外医学分子生物学分册,2003,25(1):24-26
[24]Massoval.,KortaL P.,Fridmna R.,et al.Matrix metallopreoteinases:structure,evolution and diversification.ASEBJ,1998,12(12):1075-1095
[25]Kleiner.,D.E.,Stetler-Stevenson.,W.G Matrix metalloproteinases and metastasis.Cancer Chemother.Pharmacol..1999,43:42-51
[26]Ujanen.,E.S.,Vaisanen.,A.,Zheng,A.,Tryggvason,K.,Turpeenniemi-Hujanen,T.Modulation of M(r)72,000 and M(r)92,000 type-Ⅳ collagenase(gelatinase A and B)gene expression by interferons and in human melanoma.Int.J.Cancer,1994,58:582-586
[27]Jones,J.L.,Glynn,P.,Walker,R.A.Expression of MMP-2 and MMP-9,their inhibitors,and the activator MT1-MMP in primary breast carcinomas.J.Pathol.1999,189:161-168
[28]Canete SR.Gui YH,Linask KK,et al.MMP-9(gelatinase B)mRNA is expressed during mouse neurogenesis and may be associated with vascularization.Dev.Brain Res 1995,88:37-42
[29]Canete SR,Gui YH,Linask KK,et a.l.Developmental expression of MMP-9(gelatinase B)mRNA in mouse embryos.Develop.Dynamics1995,204:30-38
[30]Heppner KJ,Matrisian LM,Jensen RA,et al.Expression of most MMPs family numbers in breast cancer represents a tumor-induced host response.Am J Pathol,1996,149:273
[31]Iwata H,Kobayashi S,Iwase H,et al.Production of MMPs and TIMPs in human breast carcinoma.Jap.J.cancer Res,1996,87:602
[32]Ueda Y,Tsuchiya H,Fujimoto N,et al.MMP-9 is expressed in multinucleated gianc cells of human giant cell tumor of bone and is associated with vascular invasion.Am J Pathol,1996,148:611-616
[33]Fini ME,Girard MT,Matsubara M,et al.Unique regulation of the MMP-9.In vest Ophthalmol Vis.Sci,1995,36:622-630.
[34]Houde M,Tremblay P,Masure S,et al.Synergistic and selective stimulation of MMP-9 production in macrophage by LPS,trans-retinoic acid and PKC regulator.Biochim Biophys,Acta1996,1310:193-200
[35]Soo-Hyun Jung1,Moon-Sook Woo1,et al.Ginseng saponin metabolite suppresses phorbol ester-induced matrix metalloproteinase-9 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathways in human astroglioma cells.Int.J.Cancer,2006,118:490-497
[36]Maeda,K.,Kuzuya,M.,Cheng,X.W.,et al.Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier.Atherosclerosis,2003,166:23-30
[37]Ki-Tae Ha,June-Ki Kim,et al.Inhibitory effect of Daesungki-Tang on the invasiveness potential of hepatocellular carcinoma through inhibition of matrix metalloproteinase-2 and -9 activities.Toxiclolgy and Applied Parmacology,2004,200:1-6
[38]豆长明,中药抗肿瘤作用机制研究态势评析,中医药学刊,2003,21(3):361-36
[39]韩晨光,王佐妤,郑爱青,MMP-9在恶性乳腺肿瘤中的表达及其对浸润转移的作用,武警医学院学报.2007,16.(4):362-364.
[40]董德刚,郭恩绵,张瑶,桂枝茯苓对宫颈癌HeLa细胞侵袭转移及MMP-2、MMP-9表达的影响,山东医药.2007,47(27):49-51.
[41]韩晨光,毛中鹏,乳腺癌组织中MMP29表达与癌细胞局部侵袭的关系,山东医药.2007,47(33):65-66.
[42]吴梧桐.《生物化学》人民卫生出版社,2003年6月
[43]Rapti M,nauper Vet al.Characterization of the AB loop region of TIMP-2,Involvement in pro-MMP-2activation.J Biol Chem,2006,281(33):23386-23394.
[44]BoulikasT:PhosPhorylation of trancctription factors and control of the cell cycle.Crit Rev Eukaryot Gene Exp.1995,5:1-77.
[45]Angel P,Karin M:The role of Jun,Fos and the AP-1 complex in cell proliferation and transformation. Bioehim Biophys Acta,1991,1072:129-157
[46]SatakeM.,Ibaraki T.,YamaguehiY.,ItoY:Loss of responsiveness of an API-related factor,PEBPI,to 12-O-tetradecanoylphorbol-13-acetate afte rtransfornation of NIH3T3cells by the Ha-ras oncogene.J Virol,1989,63:3669-3677
[47]邱伟,金属蛋白酶类组织抑制剂及其基因多态性与肿瘤,2007,34(10):738-740
[48]Park,K.K.et al Inhibitory effects of novel E2F decoy oligodeoxynucleotides on mesangial cell proliferation by co-expression of E2F/DP.Biochem.Biophys.Res.Commun,2003,308:689-697
[49]Eferl,R.et al.AP-1:a double-edged sword in tumorigenesis.Nat.Rev.Cancer,2003,3:859-868
[50]Syng-Ook Lee.,Yun-Jeong Jeong.,Suppression of PMA-induced tumor cell invasion by capillarisin via the inhibition of NF-jB-dependent MMP-9 expression.Biochemical and Biophysical Research Communications,2008,366:1019-1024
[51]T.W.Chung.,S.K.Moon.,Y.C.Chang.,J.H.Ko.,Y.C.Lee G.Cho.,S.H.Kim.,J.G.Kim.,C.H.Kim.,Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells:complete regression of hepatoma growth and metastasis by dual mechanism,.FASEB J,2004,18:1670-1681
[52]S.Hong.,K.K.Park.,J.Magae.,K.Ando.,T.S.Lee.,T.K.Kwon.,J.Y.Kwak.,C.H.Kim.,Y.C.Chang.,Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway:inhibitoryeffects of ascochlorin on the invasion of renal carcinoma cells,J.Biol.Chem,2005,280:25202-25209
[53]S.O.Lee.,Y.J.Jeong.,H.G.Im.,C.H.Kim.,Y.C.Chang.,I.S.Lee.,Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells,Biochem.Biophys.Res.Commun.,2007,354:165-171
[54]M.Aouadi.,B.Binetruy.,L.Caron.,Y.Le Marchand-Brustel.,F.Bost.,Role of MAPKs in development and differentiation:lessons from knockout mice.Biochemie,2006,88:1091-1098
[55]Hyun-Ji Cho.,Jeong Han Kang.,Jong-Young Kwak.,Tae-Sung Lee.,In-Seon Lee.,Nam Gyu Park..,Hiroo Nakajima.,Junji Magae6 and Young-Chae Chang.,Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK1/2 and Apl-dependent mechanisms.Carcinogenesis,2007,28:1104-1110
[56]M.Aouadi,B.Binetmy1,L.Caron,et al.,Role of MAPKs in development and differentiation:lessons from knockout mice.Biochimie.2006,88:1091-1098
[57]Tae-Wook Chung.,Sung-Kwon Moom.,et al.,Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells:complete regression of hepatoma growth and metastasis by dual mechanism.The FASEB Journal · Research Communication,2004,11(18):1670-1681.