丝氨酸蛋白酶抑制剂在肿瘤细胞迁移中的作用
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摘要
肿瘤细胞的转移(Migration)与侵袭(Invasion)是恶性肿瘤扩散的关键步骤,在这一过程中,一种丝氨酸蛋白酶:尿激酶型纤溶酶原激活因子(uP A)能够对基质金属蛋白酶(MMPs)进行剪切进而诱导其活化。活化的MMPs能够水解细胞外基质(ECM)实现肿瘤细胞的转移与侵袭作用。uP A是肿瘤细胞转移与侵袭的调控枢纽,发现和筛选其抑制剂在恶性肿瘤诊疗,特别是预防恶性肿瘤转移与复发中具有重要意义。人体内源性丝氨酸蛋白酶抑制剂Serpins具有明确的抑制恶性肿瘤相关丝氨酸蛋白酶的活性,是潜在的抗肿瘤治疗药物。为更好地研究与开发Serpins相关药物,本研究系统总结了人体内与恶性肿瘤转移及侵袭相关的7种Serpins的研究现状,并对最新的研究进展进行介绍。
Metastasis and invasion of tumor cells are a key step in the spread of malignant tumors. In this process,a serine protease: Urokinase-type plasminogen activator(uP A) can cut the inactive matrix metalloproteinase(MMPs),then the matrix metalloproteinase(MMPs) becomes active. The activated MMPs can hydrolyze extracellular matrix(ECM) to facilitate tumor cell metastasis and invasion. uP A is a regulatory hub for tumor cell metastasis and invasion,therefore its inhibitors play an important role in the diagnosis and treatment of malignant tumors,especially in the prevention of metastasis and recurrence of malignant tumors. The human endogenous serine protease inhibitor Serpins(Srine protease inhibitor) can inhibit malignant tumor-associated serine protease and is a potential antitumor drug. In order to better understand and develop Serpins-related drugs,this study systematically summarizes the research of seven Serpins related to malignant tumor metastasis and invasion in human,and introduces the latest research progress.
Metastasis and invasion of tumor cells are a key step in the spread of malignant tumors. In this process,a serine protease: Urokinase-type plasminogen activator(uP A) can cut the inactive matrix metalloproteinase(MMPs),then the matrix metalloproteinase(MMPs) becomes active. The activated MMPs can hydrolyze extracellular matrix(ECM) to facilitate tumor cell metastasis and invasion. uP A is a regulatory hub for tumor cell metastasis and invasion,therefore its inhibitors play an important role in the diagnosis and treatment of malignant tumors,especially in the prevention of metastasis and recurrence of malignant tumors. The human endogenous serine protease inhibitor Serpins(Srine protease inhibitor) can inhibit malignant tumor-associated serine protease and is a potential antitumor drug. In order to better understand and develop Serpins-related drugs,this study systematically summarizes the research of seven Serpins related to malignant tumor metastasis and invasion in human,and introduces the latest research progress.
引文
[1]Lucas A,Yaron JR,Zhang L,et al.Serpins:development for therapeutic applications[J].Methods Mol Biol,2018,1826:255-265.
[2]魏敏,邢国.甘露聚糖结合凝集素相关丝氨酸蛋白酶3的研究现状[J].中国免疫学杂志,2018,33(2):317-321.Wei M,Xing G.Advances in research of mannan-binding lectin-associated serine protease 3[J].Chin J Immunol,2018,33(2):317-321.
[3]赵丽芳,陶美林,潘国庆,丝氨酸蛋白酶抑制剂超家族的研究进展[J].蚕业科学,2016,42(3):532-540.Zhao LF,Tao ML,Pan GQ.Advances in serine protease inhibitors(Serpin)super family[J].Sci Sericulture,2016,42(3):532-540.
[4]Van De Craen B,Declerck P,Gils A.The biochemistry,physiology and pathological roles of pai-1 and the requirements for pai-1 inhibition in vivo[J].Thromb Res,2012,130(4):576-585.
[5]Hjortland GO,Bjornland K,Pettersen S,et al.Modulation of glioma cell invasion and motility by adenoviral gene transfer of pai-1[J].Clin Exp Metastas,2003,20(4):301-309.
[6]Palmieri D,Lee JW,Juliano RL,et al.Plasminogen activator inhibitor-1 and-3 increase cell adhesion and motility of MDA-MB-435breast cancer cells[J].J Bio Chem,2002,277(43):40950-40957.
[7]Ferroni P,Roselli M,Portarena I,et al.Plasma plasminogen activator inhibitor-1(pai-1)levels in breast cancer-relationship with clinical outcome[J].Anti Cancer Res,2014,34(3):1153-1161.
[8]Wang S,Cao Q,Wang X,et al.Pai-1 4g/5g polymorphism contributes to cancer susceptibility:Evidence from meta-analysis[J].PLoSOne,2013,8(2):e56797.
[9]Nishioka N,Matsuoka T,Yashiro M,et al.Plasminogen activator inhibitor 1 rnai suppresses gastric cancer metastasis in vivo[J].Cancer Sci,2012,103(2):228-232.
[10]Choi JW,Lee JH,Park HS,et al.Pai-1 expression and its regulation by promoter 4g/5g polymorphism in clear cell renal cell carcinoma[J].Int J Cli Exp Pathology,2011,64(10):893-897.
[11]Offersen BV,Pfeiffer P,Andreasen P,et al.Urokinase plasminogen activator and plasminogen activator inhibitor type-1in nonsmall-cell lung cancer:Relation to prognosis and angiogenesis[J].Lung Cancer,2007,56(1):43-50.
[12]Jing Y,Kovacs K,Kurisetty V,et al.Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects[J].Mol Cancer Res,2012,10(10):1271-1281.
[13]Chazaud B,Ricoux R,Christov C,et al.Promigratory effect of plasminogen activator inhibitor-1 on invasive breast cancer cell populations[J].Am J Pathol,2002,160(1):237-246.
[14]Degryse B,Neels JG,Czekay RP,et al.The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1[J].J Biol Chem,2004,279(21):22595-22604.
[15]Czekay RP,Loskutoff DJ,Plasminogen activator inhibitors regulate cell adhesion through a uPAR-dependent mechanism[J].J Cell Physiol,2009,220(3):655-663.
[16]Kamikubo Y,Neels JG,Degryse B.Vitronectin inhibits plasminogen activator inhibitor-1-induced signalling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein[J].Int JBiochem Cell B,2009,41(3):578-585.
[17]Fortenberry YM,Plasminogen activator inhibitor-1 inhibitors:a patent review(2006-present)[J].Exp Opin Ther Pa,2013,23(7):801-815.
[18]Rsnen K,Itkonen O,Koistinen H,et al.Emerging roles of SPINK1 in cancer[J].Clin Chem,2016,62(3):449-457.
[19]Bundela S,Sharma A,Bisen PS.Potential therapeutic targets for oral cancer:ADM,TP53,EGFR,LYN,CTLA4,SKIL,CTGF,CD70[J].PLoS One,2014,9(7):e102610.
[20]Lobov S,Ranson M,Molecular competition between plasminogen activator inhibitors type-1 and-2 for urokinase:Implications for cellular proteolysis and adhesion in cancer[J].Cancer Lett,2011,303(2):118-127.
[21]Croucher D,Saunders D,Lobov S,et al.Revisiting the biological roles of pai2(serpinb2)in cancer[J].Nat Rev Cancer,2008,8(7):535-545.
[22]Cao Y,Becker C,Lundwall A,et al.Expression of protein c inhibitor(PCI)in benign and malignant prostatic tissues[J].Prostata,2003,57(3):196-204.
[23]Wakita T,Hayashi T,Nishioka J,et al.Regulation of carcinoma cell invasion by protein c inhibitor whose expression is decreased in renal cell carcinoma[J].Int J Cancer,2004,108(4):516-523.
[24]Sieben NL,Oosting J,Flanagan AM,et al.Differential gene expression in ovarian tumors reveals dusp 4 and serpina 5 as key regulators for benign behavior of serous borderline tumors[J].JClin Oncol,2005,23(29):7257-7264.
[25]Asanuma K,Yoshikawa T,Hayashi T,et al.Protein C inhibitor inhibits breast cancer cell growth,metastasis and angiogenesis independently of its protease inhibitory activity[J].Int J Cancer,2007,121(5):955-965.
[26]Bijsmans IT,Smits KM,De Graeff P,et al.Loss of serpinA5protein expression is associated with advanced-stage serous ovarian tumors[J].Modern Pathol,2011,24(3):463-470.
[27]Fortenberry YM,Brandal S,Bialas RC,et al.Protein c inhibitor regulates both cathepsin Lactivity and cell-mediated tumor cell migration[J].Bio Chim Biophys Acta,2010,1800(6):580-590.
[28]Selbonne S,Azibani F,Iatmanen S,et al.In vitro and in vivo antiangiogenic properties of the serpin protease nexin-1[J].Mol Biol Cell,2012,32(8):1496-1505.
[29]Pagliara V,Adornetto A,Mammi M,et al.Protease nexin-1 affects the migration and invasion of c6 glioma cells through the regulation of urokinase plasminogen activator and matrix metalloproteinase-9/2[J].BBA-Mol cell Res,2014,1843(11):2631-2644.
[30]Candia BJ,Hines WC,Heaphy CM,et al.Protease nexin-1 expression is altered in human breast cancer[J].Cancer Cell Int,2006,31:6-16.
[31]Buchholz M,Biebl A,Neesse A,et al.Serpine2(protease nexin I)promotes extracellular matrix production and local invasion of pancreatic tumors in vivo[J].Cancer Res,2003,63(16):4945-4951.
[32]Gao S,Krogdahl A,Sorensen JA,et al.Overexpression of protease nexin-1 mRNA and protein in oral squamous cell carcinomas[J].Oral Oncol,2008,44(3):309-313.
[33]Valiente M,Obenauf AC,Jin X,et al.Serpins promote cancer cell survival and vascular co-option in brain metastasis[J].Cell,2014,156(5):1002-1016.
[34]Luo JL,Tan W,Ricono JM,et al.Nuclear cytokine-activated ikkalpha controls prostate cancer metastasis by repressing maspin[J].Nature,2007,446(7136):690-694.
[35]Goulet B,Chan G,Chambers AF,et al.An emerging role for the nuclear localization of maspin in the suppression of tumor progression and metastasis[J].Biochem Cell Biol,2012,90(1):22-38.
[36]Maass N,Hojo T,Rosel F,et al.Down regulation of the tumor suppressor gene maspin in breast carcinoma is associated with a higher risk of distant metastasis[J].Clin Biochem,2001,34(4):303-307.
[37]Abraham S,Zhang W,Greenberg N,et al.Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells[J].J Urol,2013,169(3):1157-1161.
[38]Teoh SS,Vieusseux J,Prakash M,et al.Maspin is not required for embryonic development or tumour suppression[J].Nat Commun,2014,5:3164.
[39]Chandolu V,Dass CR,Cell and molecular biology underpinning the effects of PEDF on cancers in general and osteosarcoma in particular[J].J Biomed Biotechnol,2012,2012:740295.
[40]Fitzgerald D,JPSubramanian P,Deshpande M,et al.Opposing effects of pigment epithelium-derived factor on breast cancer cell versus neuronal survival:Implication for brain metastasis and metastasisinduced brain damage[J].Cancer Res,2012,72(1):144-153.
[41]Huang KC,Evans A,Donnelly B,et al.SPINK1 overexpression in localized prostate cancer:a rare event inversely associated with ERG expression and exclusive of homozygous PTEN deletion[J].Pathol Oncol Res,2017,23(2):399-407.
[42]黄红颜,谭金祥,任国胜.基质金属蛋白酶-11协同14促进乳腺癌发展[J].中国免疫学杂志,2016,32(7):996-999.Huang HY,Tan JX,Ren GS.Matrix metalloproteinases-11 collabrotive matrix metalloproteinases-14 promote development of breast carcinoma[J].Chin J Immunol,2016,32(7):996-999.
[43]Rio MC,Buache E,Thai R,et al.Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14[J].Cancer Med,2014,3(5):1197-1210.
[2]魏敏,邢国.甘露聚糖结合凝集素相关丝氨酸蛋白酶3的研究现状[J].中国免疫学杂志,2018,33(2):317-321.Wei M,Xing G.Advances in research of mannan-binding lectin-associated serine protease 3[J].Chin J Immunol,2018,33(2):317-321.
[3]赵丽芳,陶美林,潘国庆,丝氨酸蛋白酶抑制剂超家族的研究进展[J].蚕业科学,2016,42(3):532-540.Zhao LF,Tao ML,Pan GQ.Advances in serine protease inhibitors(Serpin)super family[J].Sci Sericulture,2016,42(3):532-540.
[4]Van De Craen B,Declerck P,Gils A.The biochemistry,physiology and pathological roles of pai-1 and the requirements for pai-1 inhibition in vivo[J].Thromb Res,2012,130(4):576-585.
[5]Hjortland GO,Bjornland K,Pettersen S,et al.Modulation of glioma cell invasion and motility by adenoviral gene transfer of pai-1[J].Clin Exp Metastas,2003,20(4):301-309.
[6]Palmieri D,Lee JW,Juliano RL,et al.Plasminogen activator inhibitor-1 and-3 increase cell adhesion and motility of MDA-MB-435breast cancer cells[J].J Bio Chem,2002,277(43):40950-40957.
[7]Ferroni P,Roselli M,Portarena I,et al.Plasma plasminogen activator inhibitor-1(pai-1)levels in breast cancer-relationship with clinical outcome[J].Anti Cancer Res,2014,34(3):1153-1161.
[8]Wang S,Cao Q,Wang X,et al.Pai-1 4g/5g polymorphism contributes to cancer susceptibility:Evidence from meta-analysis[J].PLoSOne,2013,8(2):e56797.
[9]Nishioka N,Matsuoka T,Yashiro M,et al.Plasminogen activator inhibitor 1 rnai suppresses gastric cancer metastasis in vivo[J].Cancer Sci,2012,103(2):228-232.
[10]Choi JW,Lee JH,Park HS,et al.Pai-1 expression and its regulation by promoter 4g/5g polymorphism in clear cell renal cell carcinoma[J].Int J Cli Exp Pathology,2011,64(10):893-897.
[11]Offersen BV,Pfeiffer P,Andreasen P,et al.Urokinase plasminogen activator and plasminogen activator inhibitor type-1in nonsmall-cell lung cancer:Relation to prognosis and angiogenesis[J].Lung Cancer,2007,56(1):43-50.
[12]Jing Y,Kovacs K,Kurisetty V,et al.Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects[J].Mol Cancer Res,2012,10(10):1271-1281.
[13]Chazaud B,Ricoux R,Christov C,et al.Promigratory effect of plasminogen activator inhibitor-1 on invasive breast cancer cell populations[J].Am J Pathol,2002,160(1):237-246.
[14]Degryse B,Neels JG,Czekay RP,et al.The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1[J].J Biol Chem,2004,279(21):22595-22604.
[15]Czekay RP,Loskutoff DJ,Plasminogen activator inhibitors regulate cell adhesion through a uPAR-dependent mechanism[J].J Cell Physiol,2009,220(3):655-663.
[16]Kamikubo Y,Neels JG,Degryse B.Vitronectin inhibits plasminogen activator inhibitor-1-induced signalling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein[J].Int JBiochem Cell B,2009,41(3):578-585.
[17]Fortenberry YM,Plasminogen activator inhibitor-1 inhibitors:a patent review(2006-present)[J].Exp Opin Ther Pa,2013,23(7):801-815.
[18]Rsnen K,Itkonen O,Koistinen H,et al.Emerging roles of SPINK1 in cancer[J].Clin Chem,2016,62(3):449-457.
[19]Bundela S,Sharma A,Bisen PS.Potential therapeutic targets for oral cancer:ADM,TP53,EGFR,LYN,CTLA4,SKIL,CTGF,CD70[J].PLoS One,2014,9(7):e102610.
[20]Lobov S,Ranson M,Molecular competition between plasminogen activator inhibitors type-1 and-2 for urokinase:Implications for cellular proteolysis and adhesion in cancer[J].Cancer Lett,2011,303(2):118-127.
[21]Croucher D,Saunders D,Lobov S,et al.Revisiting the biological roles of pai2(serpinb2)in cancer[J].Nat Rev Cancer,2008,8(7):535-545.
[22]Cao Y,Becker C,Lundwall A,et al.Expression of protein c inhibitor(PCI)in benign and malignant prostatic tissues[J].Prostata,2003,57(3):196-204.
[23]Wakita T,Hayashi T,Nishioka J,et al.Regulation of carcinoma cell invasion by protein c inhibitor whose expression is decreased in renal cell carcinoma[J].Int J Cancer,2004,108(4):516-523.
[24]Sieben NL,Oosting J,Flanagan AM,et al.Differential gene expression in ovarian tumors reveals dusp 4 and serpina 5 as key regulators for benign behavior of serous borderline tumors[J].JClin Oncol,2005,23(29):7257-7264.
[25]Asanuma K,Yoshikawa T,Hayashi T,et al.Protein C inhibitor inhibits breast cancer cell growth,metastasis and angiogenesis independently of its protease inhibitory activity[J].Int J Cancer,2007,121(5):955-965.
[26]Bijsmans IT,Smits KM,De Graeff P,et al.Loss of serpinA5protein expression is associated with advanced-stage serous ovarian tumors[J].Modern Pathol,2011,24(3):463-470.
[27]Fortenberry YM,Brandal S,Bialas RC,et al.Protein c inhibitor regulates both cathepsin Lactivity and cell-mediated tumor cell migration[J].Bio Chim Biophys Acta,2010,1800(6):580-590.
[28]Selbonne S,Azibani F,Iatmanen S,et al.In vitro and in vivo antiangiogenic properties of the serpin protease nexin-1[J].Mol Biol Cell,2012,32(8):1496-1505.
[29]Pagliara V,Adornetto A,Mammi M,et al.Protease nexin-1 affects the migration and invasion of c6 glioma cells through the regulation of urokinase plasminogen activator and matrix metalloproteinase-9/2[J].BBA-Mol cell Res,2014,1843(11):2631-2644.
[30]Candia BJ,Hines WC,Heaphy CM,et al.Protease nexin-1 expression is altered in human breast cancer[J].Cancer Cell Int,2006,31:6-16.
[31]Buchholz M,Biebl A,Neesse A,et al.Serpine2(protease nexin I)promotes extracellular matrix production and local invasion of pancreatic tumors in vivo[J].Cancer Res,2003,63(16):4945-4951.
[32]Gao S,Krogdahl A,Sorensen JA,et al.Overexpression of protease nexin-1 mRNA and protein in oral squamous cell carcinomas[J].Oral Oncol,2008,44(3):309-313.
[33]Valiente M,Obenauf AC,Jin X,et al.Serpins promote cancer cell survival and vascular co-option in brain metastasis[J].Cell,2014,156(5):1002-1016.
[34]Luo JL,Tan W,Ricono JM,et al.Nuclear cytokine-activated ikkalpha controls prostate cancer metastasis by repressing maspin[J].Nature,2007,446(7136):690-694.
[35]Goulet B,Chan G,Chambers AF,et al.An emerging role for the nuclear localization of maspin in the suppression of tumor progression and metastasis[J].Biochem Cell Biol,2012,90(1):22-38.
[36]Maass N,Hojo T,Rosel F,et al.Down regulation of the tumor suppressor gene maspin in breast carcinoma is associated with a higher risk of distant metastasis[J].Clin Biochem,2001,34(4):303-307.
[37]Abraham S,Zhang W,Greenberg N,et al.Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells[J].J Urol,2013,169(3):1157-1161.
[38]Teoh SS,Vieusseux J,Prakash M,et al.Maspin is not required for embryonic development or tumour suppression[J].Nat Commun,2014,5:3164.
[39]Chandolu V,Dass CR,Cell and molecular biology underpinning the effects of PEDF on cancers in general and osteosarcoma in particular[J].J Biomed Biotechnol,2012,2012:740295.
[40]Fitzgerald D,JPSubramanian P,Deshpande M,et al.Opposing effects of pigment epithelium-derived factor on breast cancer cell versus neuronal survival:Implication for brain metastasis and metastasisinduced brain damage[J].Cancer Res,2012,72(1):144-153.
[41]Huang KC,Evans A,Donnelly B,et al.SPINK1 overexpression in localized prostate cancer:a rare event inversely associated with ERG expression and exclusive of homozygous PTEN deletion[J].Pathol Oncol Res,2017,23(2):399-407.
[42]黄红颜,谭金祥,任国胜.基质金属蛋白酶-11协同14促进乳腺癌发展[J].中国免疫学杂志,2016,32(7):996-999.Huang HY,Tan JX,Ren GS.Matrix metalloproteinases-11 collabrotive matrix metalloproteinases-14 promote development of breast carcinoma[J].Chin J Immunol,2016,32(7):996-999.
[43]Rio MC,Buache E,Thai R,et al.Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14[J].Cancer Med,2014,3(5):1197-1210.