MMP-2、TIMP-2及CD147与垂体腺瘤侵袭性关系的研究
摘要
目的:从基因水平对 MMP-2、TIMP-2 及 CD147 在垂体腺瘤中的表达作出进一步研究。结合第一部分结果,了解它们在基因和蛋白质水平中的表达是否具有一致性,探讨它们在垂体腺瘤侵袭性中的作用机制。
方法:将临床资料分为侵袭性腺瘤组和非侵袭性腺瘤组,应用逆转录 PCR(RT-PCR)对 55 例垂体腺瘤患者标本 MMP-2、TIMP-2 及CD147 的 mRNA 表达进行检测。分析该三项指标表达与肿瘤侵袭性的关系以及 CD147、TIMP-2 mRNA 与 MMP-2 mRNA 表达的相关性。
结果:55 例垂体瘤患者中,32 例为侵袭性垂体腺瘤,23 例为非侵袭性垂体腺瘤。侵袭性垂体腺瘤组的 CD147 与 MMP-2 mRNA 表达均较非侵袭性腺瘤组增高,而 TIMP-2 mRNA 表达则下降,差异均具有统计学意义(P <0.01)。侵袭性腺瘤组中 MMP-2 与 CD147 mRNA 的表达成正相关(r=0.73,P<0.05), 非侵袭性腺瘤组中 MMP-2 与 CD147 的表达无相关性(r=0.34,P>0.05)。侵袭性腺瘤组中 MMP-2 与 TIMP-2 mRNA表达呈负相关(r=-0.67,P<0.05),而非侵袭性腺瘤组中无相关性(r=-0.24, P>0.05)。
结论:垂体腺瘤的侵袭性与 CD147 与 MMP-2 mRNA 高表达及TIMP-2 mRNA 低表达密切相关,在肿瘤侵袭过程中 CD147 与 MMP-2的产生关系密切。侵袭性垂体腺瘤中基质降解活性程度高,TIMP-2 对IV 型胶原的降解起到一定抑制作用。结合第一部分,MMP-2、TIMP-2及 CD147 在基因与蛋白表达水平上具有一致性,CD147、MMP-2 及TIMP-2 可以作为垂体腺瘤侵袭性的有效指标。
Part 1 The Relationship Between Protein Expression of MMP-2、 TIMP-2、CD147 and Invasiveness of Pituitary Adenomas
Objective:To detect protein expression of MMP-2、TIMP-2 andCD147 in pituitary adenomas,and explore the relationship betweenexpression of MMP-2、TIMP-2 and CD147 and invasiveness of pituitaryadenomas and investigate its mechanisms and clinical value.
Methods:In tissue samples from 55 pituitary adenomas,MMP-2、TIMP-2 and CD147 were detected by immunohistochemical staining.Therelationship between MMP-2、TIMP-2、CD147 and tumor invasivenesswere studied. Results: There were 32 invasive and 23 noninvasive cases in55 patients with pituitary adenomas. The intense and total expression rateof CD147 of pituitary adenomas patients with invasion were significantlyhigher than those without invasion (P<0.01),and the intense expression andtotal expression rate of MMP-2 of pituitary adenomas patients withinvasion were significantly higher than those without invasion (P<0.05),butthe intense expression and total expression rate of TIMP-2 in invasivepituitary adenomas were significantly lower than those withoutinvasion(P<0.01 or0.05).And the incidence of the invasiveness has nosignificantly difference with the sexuality of patients and secretion ofadenomas.
Conclusion:Higher CD147、MMP-2 protein expression and lowerTIMP-2 protein expression may play important roles in the invasiveness ofpituitary adenoms and may be useful markers to predict theinvasiveness.But the invasiveness of Pituitary Adenomas has norelationship with the sexuality of patients and secretion of adenomas.
Part 2 The Relationship Between mRNA Expression of MMP-2、 TIMP-2 、CD147 and Invasiveness of Pituitary Adenomas
Objective:To detect messenger RNA (mRNA) expression of CD147、MMP-2、and TIMP-2 in pituitary adenomas,and explore the relationshipbetween expression of CD147、MMP-2、TIMP-2 mRNA and invasivenessof pituitary adenomas,and investigate its clinical value.
Methods:CD147 、 MMP-2 and TIMP-2 mRNA expression wasdetermined in 32 invasive pituitary adenomas and 23 noninvasive pituitaryadenomas by reverse transcription polymerise chain reaction(RT-PCR). Therelationship between mRNA expression of CD147、MMP-2、TIMP-2 andtumor invasiveness were studied. Results: Both mRNA expression ofCD147 and MMP-2 increased in invasive pituitary adenomas (P<0.01).TIMP-2 mRNA was poorly expressed in invasive pituitaryadenomas (P <0.01) .There was a positive correlation between CD147 andMMP-2 at mRNA level,and there was a reverse correlation betweenMMP-2 and TIMP-2 at mRNA level.
Conclusion:There were a high expression of CD147 and MMP-2 andlow expression of TIMP-2 in invasive pituitary adenomas, by whichcollagen IV inside basement membrance of pituitary tissue was damaged.Higher CD147、MMP-2 mRNA expression and lower TIMP-2 mRNAexpression may play important roles in the invasiveness of pituitary
adenoms. By compared with Part 1,the expressions of CD147、MMP-2 andTIMP-2 at protein level accord with that at gene level,so it was suggestedthat monitoring the expression of CD147、MMP-2 or TIMP-2 could be ofclinical value. MMP-2 and TIMP-2、CD147 are three useful tools forassessing the invasion of pituitary adenomas. CD147 has closelyrelationship with the creating of MMP-2 in the invasion of pituitaryadenomas.There have subtle relationship between MMP-2 and TIMP-2.
方法:将临床资料分为侵袭性腺瘤组和非侵袭性腺瘤组,应用逆转录 PCR(RT-PCR)对 55 例垂体腺瘤患者标本 MMP-2、TIMP-2 及CD147 的 mRNA 表达进行检测。分析该三项指标表达与肿瘤侵袭性的关系以及 CD147、TIMP-2 mRNA 与 MMP-2 mRNA 表达的相关性。
结果:55 例垂体瘤患者中,32 例为侵袭性垂体腺瘤,23 例为非侵袭性垂体腺瘤。侵袭性垂体腺瘤组的 CD147 与 MMP-2 mRNA 表达均较非侵袭性腺瘤组增高,而 TIMP-2 mRNA 表达则下降,差异均具有统计学意义(P <0.01)。侵袭性腺瘤组中 MMP-2 与 CD147 mRNA 的表达成正相关(r=0.73,P<0.05), 非侵袭性腺瘤组中 MMP-2 与 CD147 的表达无相关性(r=0.34,P>0.05)。侵袭性腺瘤组中 MMP-2 与 TIMP-2 mRNA表达呈负相关(r=-0.67,P<0.05),而非侵袭性腺瘤组中无相关性(r=-0.24, P>0.05)。
结论:垂体腺瘤的侵袭性与 CD147 与 MMP-2 mRNA 高表达及TIMP-2 mRNA 低表达密切相关,在肿瘤侵袭过程中 CD147 与 MMP-2的产生关系密切。侵袭性垂体腺瘤中基质降解活性程度高,TIMP-2 对IV 型胶原的降解起到一定抑制作用。结合第一部分,MMP-2、TIMP-2及 CD147 在基因与蛋白表达水平上具有一致性,CD147、MMP-2 及TIMP-2 可以作为垂体腺瘤侵袭性的有效指标。
Part 1 The Relationship Between Protein Expression of MMP-2、 TIMP-2、CD147 and Invasiveness of Pituitary Adenomas
Objective:To detect protein expression of MMP-2、TIMP-2 andCD147 in pituitary adenomas,and explore the relationship betweenexpression of MMP-2、TIMP-2 and CD147 and invasiveness of pituitaryadenomas and investigate its mechanisms and clinical value.
Methods:In tissue samples from 55 pituitary adenomas,MMP-2、TIMP-2 and CD147 were detected by immunohistochemical staining.Therelationship between MMP-2、TIMP-2、CD147 and tumor invasivenesswere studied. Results: There were 32 invasive and 23 noninvasive cases in55 patients with pituitary adenomas. The intense and total expression rateof CD147 of pituitary adenomas patients with invasion were significantlyhigher than those without invasion (P<0.01),and the intense expression andtotal expression rate of MMP-2 of pituitary adenomas patients withinvasion were significantly higher than those without invasion (P<0.05),butthe intense expression and total expression rate of TIMP-2 in invasivepituitary adenomas were significantly lower than those withoutinvasion(P<0.01 or0.05).And the incidence of the invasiveness has nosignificantly difference with the sexuality of patients and secretion ofadenomas.
Conclusion:Higher CD147、MMP-2 protein expression and lowerTIMP-2 protein expression may play important roles in the invasiveness ofpituitary adenoms and may be useful markers to predict theinvasiveness.But the invasiveness of Pituitary Adenomas has norelationship with the sexuality of patients and secretion of adenomas.
Part 2 The Relationship Between mRNA Expression of MMP-2、 TIMP-2 、CD147 and Invasiveness of Pituitary Adenomas
Objective:To detect messenger RNA (mRNA) expression of CD147、MMP-2、and TIMP-2 in pituitary adenomas,and explore the relationshipbetween expression of CD147、MMP-2、TIMP-2 mRNA and invasivenessof pituitary adenomas,and investigate its clinical value.
Methods:CD147 、 MMP-2 and TIMP-2 mRNA expression wasdetermined in 32 invasive pituitary adenomas and 23 noninvasive pituitaryadenomas by reverse transcription polymerise chain reaction(RT-PCR). Therelationship between mRNA expression of CD147、MMP-2、TIMP-2 andtumor invasiveness were studied. Results: Both mRNA expression ofCD147 and MMP-2 increased in invasive pituitary adenomas (P<0.01).TIMP-2 mRNA was poorly expressed in invasive pituitaryadenomas (P <0.01) .There was a positive correlation between CD147 andMMP-2 at mRNA level,and there was a reverse correlation betweenMMP-2 and TIMP-2 at mRNA level.
Conclusion:There were a high expression of CD147 and MMP-2 andlow expression of TIMP-2 in invasive pituitary adenomas, by whichcollagen IV inside basement membrance of pituitary tissue was damaged.Higher CD147、MMP-2 mRNA expression and lower TIMP-2 mRNAexpression may play important roles in the invasiveness of pituitary
adenoms. By compared with Part 1,the expressions of CD147、MMP-2 andTIMP-2 at protein level accord with that at gene level,so it was suggestedthat monitoring the expression of CD147、MMP-2 or TIMP-2 could be ofclinical value. MMP-2 and TIMP-2、CD147 are three useful tools forassessing the invasion of pituitary adenomas. CD147 has closelyrelationship with the creating of MMP-2 in the invasion of pituitaryadenomas.There have subtle relationship between MMP-2 and TIMP-2.
引文
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[3] Asa SL,Ezzat S,The cytogenesis and pathogenesis of pituitary adenomas[J]. Endocrine Reviews,1998,19(6):798-827
[4] Scheithauer BW,Kovacs KT,Laws ER,et al. Pathology of invasive pituitary tumors with special reference to functional classification[J].J Neurosurg , 1986,65(6):733-744
[5] Selman WR,Laws ER,Scheithauer BW,et al. The occurence of dural invasion in pituitary adenomas[J].J Neurosurg,1986,64:402-407
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[10]Pestell RG,Albanese C,Reutens AT,et al.The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation[J].Endocrine Rev,1999,20(4):501-534
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[20]Jaalinoja J,Herva R,Korpela M,et al. Matrix metalloproteinase-2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms[J].J Neurooncol,2000,46:81-90
[21]Schoenermark MP,Mitchell TI,Rutter T,et al,Retinoid-mediated suppression of tumor invasion and matrix metalloproteinase synthesis[J].Ann NY Acad Sci,1999,878:466-486
[22]Kenagy RD,Vergel S,Mattsson E,et al. The role of plasminogen,plasminogen activators,and matrix metalloproteinases in primatearterial smooth muscle cell migration[J].Arterioscler Thromb Vasc Biol,1996,16: 1373 -1382
[23]Liu weiping,KUNISHIO Katsuzo,MAT-SUMOTO Yoshihito,et al.Matrix metalloproteinase 2 expression in invasive pituitary adenomas[J].Chin J Neurosury Dis Res, 2003, 2 (1):7-11
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[25]Gomez DE,Alonso DF,Yoshiji H,et al. Tissue inhibitors of metalloproteinases: Structure,regulation and biological functions[J]. Eur J cell boil,1997,74:111-122
[26]Velasco G,Lopez Otin C,Strategies for cloning new MUPs and Tzmps[J]. Methods Mol Bid, 2001,151:25-44
[27]Westernmark J,Kahari VM. Regulation of matrix metalloproteinase erpression in tumor inuasion[J]. FABSEB J,1999,13:381-392
[28]Hidalgo M,Eckhardt SG. Development of matrik metalloproteinase inhititors in cancer therapy[J]. J Natl Cancer Inst,2001,93(3):178-193
[29]Zuker S,Hymowitz M,Corner C,et al.Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues:Clinical and exprimental applications[J].Ann NYAcad Sci,1999,878: 212-217
[30]Kawamoto H, Uozumi T, Kawamoto K, et al. Type IV collagenase activity and cavernous sinus invasion in human pituitary adenomas[J]. Acta Neurochir (Wien). 1996, 13(4):390-395
[31]Kawamoto H, Kawamoto K, Mizoue T, et al. Matrix metalloproteinase-9 secretion by human pituitary adenomas detected by cell immunoblot analysis[J]. Acta Neurochir Wien,1996,138(12):1442-1448
[32]Tomita T.Matrix metalloproteinases and tissue inhibitors of metalloproteinases in thyroid C-cells and medullary thyroid carcinomas[J].Histopathology,1997,31(2): 150-156
[33]Goldberg GI,Strongin A,Collier IE,et al. Interaction of 92-Kda type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization,complex formation with interstitial collagenase,and activation of the proenzyme with stromelysis[J].J Bid chem,1992,267:4583-4591
[34]Strongin AY,Collier I,Bannikov G,et al. Mechanism of cell surface activation of 72-KDa type W collagenase:Isolation of the activated form of the membrane metalloprotease[J].J Biol chem,1995,272:5331-5338
[35]Mohanam S,Wang SW,Rayford A,et al.Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo[J]. Clin Exp Metastasis,1995,15:57-62
[36]Valente P,Fassina G,Melchiori A,et al. TIMP-2 over-expression reduces invasion and angiogenesis and protects B16 F10 melanoma cells from apoptosis[J]. Int J Cancer, 1998,75:246-253
[37]Beaulieu E,Kachra Z,Mousseau N,et al. Matrix metalloproteinases and their inhibitors in human pituitary tumors[J]. Neurosurgery,1999,45: 1432- 1440
[38]Biswas C ,ZhangY,Decastro R,et al.The human tumor cell derived collagenase stimulating factor (renamed CD147) is a member of the immunoglobulin superfamily[J].Cancer Res,1995,55:434-439
[39]Shapiro SD .Matrix metalloproteinases degradation of extracellular matrix:biological consequences[J].Curr Opin Cell Biol 1998;10:602-608
[40]Miyauchi T,Kanekura T.Basigin,a new broadly distributed member of the immunoglobulin superfamily has strong homology with both the immunoglobulin V domain and the β-chain of major histocompatibility complex class II antigen[J]. J Biochem,1990,07:316-323
[41]Fossum S,Mallrtt S,Barclay A.N.The MR.C OX-47antigen is a member of the immunoglobulin sumperfamily with an unusual transmembrane sequence[J]. Eur J Immuno.1991,21:671-679
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[49]Lundberg PO, Drettner B, Hemmingsson A, et al. The invasive pituitary adenoma. A prolactin-producing tumor[J]. Arch NeuroL 1997; 34(12): 742-749
[50]Seandel M, Noack-Kunnmann K, Zhu D, et al.Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen[J]. Blood,2001, 97(8): 2323- 2332
[2] Knosp E, Steiner E, Kitz K, et al. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings[J].Neurosurgery,1993,33(4):610-618
[3] Asa SL,Ezzat S,The cytogenesis and pathogenesis of pituitary adenomas[J]. Endocrine Reviews,1998,19(6):798-827
[4] Scheithauer BW,Kovacs KT,Laws ER,et al. Pathology of invasive pituitary tumors with special reference to functional classification[J].J Neurosurg , 1986,65(6):733-744
[5] Selman WR,Laws ER,Scheithauer BW,et al. The occurence of dural invasion in pituitary adenomas[J].J Neurosurg,1986,64:402-407
[6] Ikeda H,Yoshimoto T.The relationship between c-myc protein expression, the bromodeoxyuridine labeling index and the biological behavior of pituitery adenomas[J]. Acta Neuropathol(Berl),1992,83(4):361-364
[7] Zhang X,Horwitz GA,Prezant TR,et al. Structure,expression,and function of human pituitary tumor-transforming gene(PTTG) [J].Mol Endocrinol,1999, 13(1):156-166
[8] Seemann N,Kuhn D,Wrocklage C,et al. CDKN 2A/pl6 inactivation is related to pituitary adenoma type and size[J].J Pathol,2001,193:491-497
[9] Dahia PL,Grossman AB. The molecular pathogenesis of corticotroph tumors[J]. Endocrine Rev,1999,20(2):136-155
[10]Pestell RG,Albanese C,Reutens AT,et al.The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation[J].Endocrine Rev,1999,20(4):501-534
[11]Pegdo G,Faizan,Vize G,et al. Pituitary adenomas,correlation of the cytological appearance with biological behavior[J].Acta Cytol,1995,39(5): 887-892
[12]Saeger W,Bosse U,Pfingst E,et al. Prolactin producing hypophyseal carcinoma. Case report of an extremely rare metastatic tumor[J]. Pathology,1995,16(5):354-358
[13]Scheithauer BW, Kovacs KT, Laws ER Jr,et al.Pathology of invasive pituitary tumors with special reference to functional classification[J].J Neurosurg,1986,65:733-744
[14]Kawamoto H, Uozumi T, Kawamoto . K, et al. Analysis of the growth rate and cavernous sinus invasion of pituitary adenomas[J].Acta Neurochir(Wien), 1995,136:37-43
[15]Blevins LS Jr, Verity DK, Allen G.Aggressive pituitary tumors[J]. Oncology, 1998, 12:1307-1312
[16]Thapar K,Kouacs K,Scheithauer BW,et al.Proliferative activity and invasiveness among pituitary adenomas and carcinomas. An analysis using the MIB-1 antibody[J].Neurosurgery,1996,38(1):99-107
[17]Stearns M,Stearns ME.Evidence for increased activated matrix metalloproteinase-2 (MMP-2) expression associated with human prostate cancer progression[J]. Oncol Res,1996,8: 69-75
[18]Lampert K,Machein U,Machein MR,et al.Expression of Matrix metalloproteinases and their tissue inhibitors in human brain tumors[J].Am J Pathol,1998, 153(2):429-437
[19]Kachra Z,Beaulieu E,Delbechi L,et al.Expression of matrix metalloproteinases and their inhibitors in human brain tumors[J]. Clin Exp Metastasis,1999,17(7): 555-566
[20]Jaalinoja J,Herva R,Korpela M,et al. Matrix metalloproteinase-2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms[J].J Neurooncol,2000,46:81-90
[21]Schoenermark MP,Mitchell TI,Rutter T,et al,Retinoid-mediated suppression of tumor invasion and matrix metalloproteinase synthesis[J].Ann NY Acad Sci,1999,878:466-486
[22]Kenagy RD,Vergel S,Mattsson E,et al. The role of plasminogen,plasminogen activators,and matrix metalloproteinases in primatearterial smooth muscle cell migration[J].Arterioscler Thromb Vasc Biol,1996,16: 1373 -1382
[23]Liu weiping,KUNISHIO Katsuzo,MAT-SUMOTO Yoshihito,et al.Matrix metalloproteinase 2 expression in invasive pituitary adenomas[J].Chin J Neurosury Dis Res, 2003, 2 (1):7-11
[24]Paez Pereda M,Ledda MF,Goldberg V,et al.High levels of matrix metallo- proteinases regulate proliferation and hormone secretion in pituitary cells[J]. J Clin Endocrinol Metab, 2000,85: 263-269
[25]Gomez DE,Alonso DF,Yoshiji H,et al. Tissue inhibitors of metalloproteinases: Structure,regulation and biological functions[J]. Eur J cell boil,1997,74:111-122
[26]Velasco G,Lopez Otin C,Strategies for cloning new MUPs and Tzmps[J]. Methods Mol Bid, 2001,151:25-44
[27]Westernmark J,Kahari VM. Regulation of matrix metalloproteinase erpression in tumor inuasion[J]. FABSEB J,1999,13:381-392
[28]Hidalgo M,Eckhardt SG. Development of matrik metalloproteinase inhititors in cancer therapy[J]. J Natl Cancer Inst,2001,93(3):178-193
[29]Zuker S,Hymowitz M,Corner C,et al.Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues:Clinical and exprimental applications[J].Ann NYAcad Sci,1999,878: 212-217
[30]Kawamoto H, Uozumi T, Kawamoto K, et al. Type IV collagenase activity and cavernous sinus invasion in human pituitary adenomas[J]. Acta Neurochir (Wien). 1996, 13(4):390-395
[31]Kawamoto H, Kawamoto K, Mizoue T, et al. Matrix metalloproteinase-9 secretion by human pituitary adenomas detected by cell immunoblot analysis[J]. Acta Neurochir Wien,1996,138(12):1442-1448
[32]Tomita T.Matrix metalloproteinases and tissue inhibitors of metalloproteinases in thyroid C-cells and medullary thyroid carcinomas[J].Histopathology,1997,31(2): 150-156
[33]Goldberg GI,Strongin A,Collier IE,et al. Interaction of 92-Kda type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization,complex formation with interstitial collagenase,and activation of the proenzyme with stromelysis[J].J Bid chem,1992,267:4583-4591
[34]Strongin AY,Collier I,Bannikov G,et al. Mechanism of cell surface activation of 72-KDa type W collagenase:Isolation of the activated form of the membrane metalloprotease[J].J Biol chem,1995,272:5331-5338
[35]Mohanam S,Wang SW,Rayford A,et al.Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo[J]. Clin Exp Metastasis,1995,15:57-62
[36]Valente P,Fassina G,Melchiori A,et al. TIMP-2 over-expression reduces invasion and angiogenesis and protects B16 F10 melanoma cells from apoptosis[J]. Int J Cancer, 1998,75:246-253
[37]Beaulieu E,Kachra Z,Mousseau N,et al. Matrix metalloproteinases and their inhibitors in human pituitary tumors[J]. Neurosurgery,1999,45: 1432- 1440
[38]Biswas C ,ZhangY,Decastro R,et al.The human tumor cell derived collagenase stimulating factor (renamed CD147) is a member of the immunoglobulin superfamily[J].Cancer Res,1995,55:434-439
[39]Shapiro SD .Matrix metalloproteinases degradation of extracellular matrix:biological consequences[J].Curr Opin Cell Biol 1998;10:602-608
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