凝血酶激活的纤溶抑制物（TAFI）与乳腺癌关系的研究
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摘要
第一部分临床研究
目的探讨乳腺癌患者血浆凝血酶激活的纤溶抑制物(TAFI)水平及其编码区基因位点Thr147Ala (rs3742264)和Thr325lle (rs1926447)的基因多态性的改变在临床诊治中的作用以及与高凝状态的关系。
方法选取256例乳腺癌患者为研究对象,健康体检正常的192例为对照组,ELISA及发色底物法分别测定血浆TAFI抗原、活性(TAFI Ag、TAFI Act)水平,应用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测TAFI Thr147Ala和Thr325lle位点的基因多态性。
结果①TAFI的活性及抗原(TAFI Act、TAFI Ag)在病例组和对照组分别为30.5±2.8μg/ml、100.6±15.2%和23.5±1.6μg/ml、82.7±11.2%,病例组TAFI水平明显高于对照组,差异有显著性(P<0.001)。②乳腺癌患者TAFI抗原含量与活性水平随临床分期而增高,各期之间的差异具有显著性(P<0.001)。③TAFI Thr325lle基因多态性中,3种基因型Thr/Thr(CC)、Thr/lle(CT)、lle/lle (TT)的分布频率分别是19.9%,51.6%和28.5%,而对照组分别为34.4%,49.5%和16.1%,可见病例组含Ⅱe的形式,即lle/lle和Thr/lle显著高于对照组[OR:2.106;(95%CI:1.379-3.217, P<0.001)]。等位基因T在病例组的分布亦显著高于对照组[OR:1.718;(95%CI:1.316-2.243); P<0.001]。④病例组和对照组Thr325Thr、Thr325lle、lle325lle三种基因型之间血浆’TAFI抗原水平具有显著性差异,其中Thr325Thr者血浆TAFI抗原水平最高,lle325lle者血浆TAFI抗原水平最低,差异有统计学意义(P<0.05)。⑤Thr147Ala基因多态性在病例组与对照组中的频率分布、以及与-TAFI抗原水平均无显著性差异(P>0.05)。
结论①乳腺癌患者血浆TAFI水平显著高于对照组,且随临床分期而逐渐增高。②乳腺癌患者TAFI Thr325lle位点多态性表现为lle325lle (TT基因型)频率增高,提示热稳定性及抗纤溶活性增高。③TAFI抗原水平受Thr325lle位点多态性的影响,其中Thr325Thr(CC基因型)型最高,lle325lle(TT基因型)最低。④检测血浆TAFI水平及Thr325lle位点多态性可作为乳腺癌诊断及病情严重程度的指标。⑤乳腺癌患者体内呈现高凝状态,其原因既有凝血激活(血浆纤维蛋白原及D-二聚体水平增高),又有纤溶活性降低(血浆TAFI抗原及活性水平增高)。提示临床对肿瘤病人应进行适当的抗凝治疗。
第二部分实验研究
目的探讨靶向CPB2基因的RNA干扰(RNAi)对乳腺癌MDA-MB-231细胞TAFI表达以及对乳腺癌细胞的生长和转移性的影响。方法以乳腺癌MDA-MB-231细胞系为研究对象,利用RNA干扰技术,通过设计小干扰RNA (siRNA),靶向抑制乳腺癌MDA-MB-231细胞系中CPB2基因的表达,逆转录-聚合酶链反应(RT-PCR)、蛋白质免疫印迹(Western Blot)检测转染脂质体siRNA后乳腺癌细胞中TAFI mRNA及蛋白的表达水平；应用Transwell侵袭实验检测干扰后MDA-MB-231细胞的侵袭能力；MTT实验测定转染后MDA-MB-231细胞的存活和生长情况。
结果siRNA抑制CPB2表达后,’TAFI mRNA及其蛋白表达水平显著下降,蛋白抑制率从42.6%到55.4%；Transwell侵袭实验发现siRNA转染组穿膜细胞数84.80±4.82,显著低于对照组140.20±11.78(P<0.05); MTT实验测定转染后MDA-MB-231细胞24和48小时的吸光度为0.750±0.034和0.420±0.042,显著低于对照组0.840±0.044和0.755±0.046(P<0.05)；乳腺癌MDA-MB-231细胞干扰后其生长、侵袭及转移能力均显著性被抑制。
结论①RNAi技术成功抑制乳腺癌MDA-MB-231细胞系中TAFI的表达,使得乳腺癌细胞TAFI mRNA和TAFI蛋白含量明显降低。②TAFI水平的降低能够抑制乳腺癌细胞的生长活性,同时能够明显降低乳腺癌细胞的侵袭力。③TAFI在乳腺癌细胞的发生和转移中具有重要作用,它可能成为新的乳腺癌肿瘤转移防治靶点之一。
Part I Clinical investigation
Objective The aim of this study was to investigate if thrombin activatable fibrinolysis inhibitor antigen and activity (TAFI Ag and TAFI Act) levels and TAFI Thr325lle and Thr147Ala polymorphism could be a risk marker of breast cancer in Chinese Han patients.
Methods:The plasma TAFI Ag and Act was determined using ELISA and chromogenic assay in256patients with breast cancer and192healthy controls. Besides fibrinogen and D-dimer levels were routinely measured, TAFI Thr325lle (rs1926447) and Thr147Ala (rs3742264) polymorphism was genotyped in both patient and control groups using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Results:TAFI Ag and Act levels were significantly higher in breast cancer patients than in controls (100.6±15.2%vs82.7±11.2%and30.5±2.8μg/ml vs23.5±1.6μg/ml, P<0.001respectively). The plasma fibrinogen and D-dimer levels were also significant increased in comparison with those in controls (3.7±1.2g/L vs.2.6±1.4g/L and598.5±115.3ng/mL vs.125.2±55.4ng/mL, P<0.001, respectively). TAFI Ag levels are correlated with metastasis of breast cancer (P<0.001). The Thr/lle (CT) and lle/lle (TT) genotypes were more frequently in patients group compared with the control group [OR:2.106;(95%CI:1.379-3.217); P<0.001]. The high-risk T alleles frequency was also higher in patients compared with healthy controls [OR:1.718;(95%CI:1.316-2.243); P<0.001]. The polymorphism was significantly correlated with TAFI Ag levels in either group (P<0.001). The lle/lle (TT) genotype had the lowest TAFI Ag level, while the Thr/Thr (CC) had the highest one. Thr147Ala gene polymorphism in the case group and control group in the frequency distribution, as well as TAFI antigen level were no significant difference.
Conclusions:The plasma TAFI levels and TAFI Thr325lle genotypes were associated with breast cancer patients in Chinese Han populations and can be considered as the risk markers of breast cancer. Patients with breast cancer are at high risk of high coagulation state, which pathogenesis is complex involves both coagulation activation and fibrinolytic inhibition.
Part Ⅱ Experiment research
Objective To investigate the effects of CPB2gene silencing on thrombin activated fibrinolysis inhibitor (TAFI) expression and metastatic in the breast cancer cell line MDA-MB-231.
Methods Based on the sequence of CPB2, three siRNA were designed and chemically synthesized. They were transfected into the breast cancer cell line MDA-MB-231with LipofectamineTM2000. The TAFI mRNA and protein levels were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Cell invasive and metastasis ability and growth inhibition were determined by transwell assay and MTT assay.
Results siRNAs targeting CPB2significantly down-regulated the mRNA and the protein level of TAFI (P<0.05), and the inhibition ratio range from55.4%to42.6%. The growth of breast cell line MDA-MB-231were inhibited (P<0.05) and the invasive and metastasis ability were also significantly inhibited compared to the control group (P<0.05).
Conclusions CPB2-siRNA can significantly down-regulate TAFI expression in transcriptional and translational levels, inhibit cell growth, invasive and metastasis ability in the breast cell line MDA-MB-231. It can be used as a new target for the breast cancer in therapy of metastasis.
目的探讨乳腺癌患者血浆凝血酶激活的纤溶抑制物(TAFI)水平及其编码区基因位点Thr147Ala (rs3742264)和Thr325lle (rs1926447)的基因多态性的改变在临床诊治中的作用以及与高凝状态的关系。
方法选取256例乳腺癌患者为研究对象,健康体检正常的192例为对照组,ELISA及发色底物法分别测定血浆TAFI抗原、活性(TAFI Ag、TAFI Act)水平,应用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测TAFI Thr147Ala和Thr325lle位点的基因多态性。
结果①TAFI的活性及抗原(TAFI Act、TAFI Ag)在病例组和对照组分别为30.5±2.8μg/ml、100.6±15.2%和23.5±1.6μg/ml、82.7±11.2%,病例组TAFI水平明显高于对照组,差异有显著性(P<0.001)。②乳腺癌患者TAFI抗原含量与活性水平随临床分期而增高,各期之间的差异具有显著性(P<0.001)。③TAFI Thr325lle基因多态性中,3种基因型Thr/Thr(CC)、Thr/lle(CT)、lle/lle (TT)的分布频率分别是19.9%,51.6%和28.5%,而对照组分别为34.4%,49.5%和16.1%,可见病例组含Ⅱe的形式,即lle/lle和Thr/lle显著高于对照组[OR:2.106;(95%CI:1.379-3.217, P<0.001)]。等位基因T在病例组的分布亦显著高于对照组[OR:1.718;(95%CI:1.316-2.243); P<0.001]。④病例组和对照组Thr325Thr、Thr325lle、lle325lle三种基因型之间血浆’TAFI抗原水平具有显著性差异,其中Thr325Thr者血浆TAFI抗原水平最高,lle325lle者血浆TAFI抗原水平最低,差异有统计学意义(P<0.05)。⑤Thr147Ala基因多态性在病例组与对照组中的频率分布、以及与-TAFI抗原水平均无显著性差异(P>0.05)。
结论①乳腺癌患者血浆TAFI水平显著高于对照组,且随临床分期而逐渐增高。②乳腺癌患者TAFI Thr325lle位点多态性表现为lle325lle (TT基因型)频率增高,提示热稳定性及抗纤溶活性增高。③TAFI抗原水平受Thr325lle位点多态性的影响,其中Thr325Thr(CC基因型)型最高,lle325lle(TT基因型)最低。④检测血浆TAFI水平及Thr325lle位点多态性可作为乳腺癌诊断及病情严重程度的指标。⑤乳腺癌患者体内呈现高凝状态,其原因既有凝血激活(血浆纤维蛋白原及D-二聚体水平增高),又有纤溶活性降低(血浆TAFI抗原及活性水平增高)。提示临床对肿瘤病人应进行适当的抗凝治疗。
第二部分实验研究
目的探讨靶向CPB2基因的RNA干扰(RNAi)对乳腺癌MDA-MB-231细胞TAFI表达以及对乳腺癌细胞的生长和转移性的影响。方法以乳腺癌MDA-MB-231细胞系为研究对象,利用RNA干扰技术,通过设计小干扰RNA (siRNA),靶向抑制乳腺癌MDA-MB-231细胞系中CPB2基因的表达,逆转录-聚合酶链反应(RT-PCR)、蛋白质免疫印迹(Western Blot)检测转染脂质体siRNA后乳腺癌细胞中TAFI mRNA及蛋白的表达水平；应用Transwell侵袭实验检测干扰后MDA-MB-231细胞的侵袭能力；MTT实验测定转染后MDA-MB-231细胞的存活和生长情况。
结果siRNA抑制CPB2表达后,’TAFI mRNA及其蛋白表达水平显著下降,蛋白抑制率从42.6%到55.4%；Transwell侵袭实验发现siRNA转染组穿膜细胞数84.80±4.82,显著低于对照组140.20±11.78(P<0.05); MTT实验测定转染后MDA-MB-231细胞24和48小时的吸光度为0.750±0.034和0.420±0.042,显著低于对照组0.840±0.044和0.755±0.046(P<0.05)；乳腺癌MDA-MB-231细胞干扰后其生长、侵袭及转移能力均显著性被抑制。
结论①RNAi技术成功抑制乳腺癌MDA-MB-231细胞系中TAFI的表达,使得乳腺癌细胞TAFI mRNA和TAFI蛋白含量明显降低。②TAFI水平的降低能够抑制乳腺癌细胞的生长活性,同时能够明显降低乳腺癌细胞的侵袭力。③TAFI在乳腺癌细胞的发生和转移中具有重要作用,它可能成为新的乳腺癌肿瘤转移防治靶点之一。
Part I Clinical investigation
Objective The aim of this study was to investigate if thrombin activatable fibrinolysis inhibitor antigen and activity (TAFI Ag and TAFI Act) levels and TAFI Thr325lle and Thr147Ala polymorphism could be a risk marker of breast cancer in Chinese Han patients.
Methods:The plasma TAFI Ag and Act was determined using ELISA and chromogenic assay in256patients with breast cancer and192healthy controls. Besides fibrinogen and D-dimer levels were routinely measured, TAFI Thr325lle (rs1926447) and Thr147Ala (rs3742264) polymorphism was genotyped in both patient and control groups using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Results:TAFI Ag and Act levels were significantly higher in breast cancer patients than in controls (100.6±15.2%vs82.7±11.2%and30.5±2.8μg/ml vs23.5±1.6μg/ml, P<0.001respectively). The plasma fibrinogen and D-dimer levels were also significant increased in comparison with those in controls (3.7±1.2g/L vs.2.6±1.4g/L and598.5±115.3ng/mL vs.125.2±55.4ng/mL, P<0.001, respectively). TAFI Ag levels are correlated with metastasis of breast cancer (P<0.001). The Thr/lle (CT) and lle/lle (TT) genotypes were more frequently in patients group compared with the control group [OR:2.106;(95%CI:1.379-3.217); P<0.001]. The high-risk T alleles frequency was also higher in patients compared with healthy controls [OR:1.718;(95%CI:1.316-2.243); P<0.001]. The polymorphism was significantly correlated with TAFI Ag levels in either group (P<0.001). The lle/lle (TT) genotype had the lowest TAFI Ag level, while the Thr/Thr (CC) had the highest one. Thr147Ala gene polymorphism in the case group and control group in the frequency distribution, as well as TAFI antigen level were no significant difference.
Conclusions:The plasma TAFI levels and TAFI Thr325lle genotypes were associated with breast cancer patients in Chinese Han populations and can be considered as the risk markers of breast cancer. Patients with breast cancer are at high risk of high coagulation state, which pathogenesis is complex involves both coagulation activation and fibrinolytic inhibition.
Part Ⅱ Experiment research
Objective To investigate the effects of CPB2gene silencing on thrombin activated fibrinolysis inhibitor (TAFI) expression and metastatic in the breast cancer cell line MDA-MB-231.
Methods Based on the sequence of CPB2, three siRNA were designed and chemically synthesized. They were transfected into the breast cancer cell line MDA-MB-231with LipofectamineTM2000. The TAFI mRNA and protein levels were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Cell invasive and metastasis ability and growth inhibition were determined by transwell assay and MTT assay.
Results siRNAs targeting CPB2significantly down-regulated the mRNA and the protein level of TAFI (P<0.05), and the inhibition ratio range from55.4%to42.6%. The growth of breast cell line MDA-MB-231were inhibited (P<0.05) and the invasive and metastasis ability were also significantly inhibited compared to the control group (P<0.05).
Conclusions CPB2-siRNA can significantly down-regulate TAFI expression in transcriptional and translational levels, inhibit cell growth, invasive and metastasis ability in the breast cell line MDA-MB-231. It can be used as a new target for the breast cancer in therapy of metastasis.
引文
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[1]A Falanga, L Russo, C Verzeroli. Mechanisms of thrombosis in cancer [J]. Thrombosis Research 2013; 131(Suppl.1):S59-S62
[2]Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies [J]. J Clin Oncol 2009; 27:4848-57.
[3]Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol [J].2005; 6:401-10.
[4]Falanga A, Panova-NoevaM, Russo L. Procoagulantmechanisms in tumour cells [J]. Best Pract Res Clin Haematol 2009; 22:49-60.
[5]Boffa MB, Koschinsky ML. Curiouser and curiouser:recent advances in measurement of thrombin-activatable fibrinolysis inhibitor (TAFI) and in understanding its molecular genetics, gene regulation, and biological roles [J]. Clin Biochem.2007; 40(7):431-42.
[6]王振义,李家增,阮长耿,等主编。血栓与止血基础理论与临床(第三版)[M].上海科学技术出版社,2004,669-678
[7]Cheng-Wei Xu, Xiao-Li Ma,Yuan Zhang, et al. The role of plasma thrombin-activatable fibrinolysis inhibitor levels and its Thr325lle polymorphisms in breast cancer [J] Blood Coagulation and Fibrinolysis DOI:10.1097/MBC.0b013e3283610381
[8]Hataji O, Taguchi O, Gabazza EC, et al. Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients [J]. American Journal of Hematology,2004; 76(3):214-9.
[9]Gavrilov K, Saltzman WM.Therapeutic siRNA:principles, challenges, and strategies [J].Yale J Biol Med.2012; 85(2):187-200.
[10]Kaftan O, Kasapoglu B, Koroglu M, et al. Thrombin-activatable fibrinolysis inhibitor in breast cancer patients[J]. Medical Principles and Practice.2011; 20(4):332-335.
[11]Demirkan B, Ozcan MA, Glu AA, et al. The effect of anthracycline-based (epirubicin) adjuvant chemotherapy on plasma TAFI and PAI-1 levels in operable breast cancer [J]. Clin Appl Thromb Hemost.2006; 12(1):9-14.
[12]王泽筠,徐成伟,马晓丽,郑燕,郏雁飞,肖东杰,汪运山.siRNA靶向抑制CPB2基因与乳腺癌细胞TAFI表达及生长和转移性的影响[J].山东大学学报(医学版),2011,49(4)：57-60
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[14]Liotta LA. Cancer cell invasion and metastasis [J]. Scientific American, 1992;266(2):54-62.
[15]Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG. Matrix metalloproteinases:changing roles in tumor progression and metastasis [J]. Am J Pathol.2012; 181 (6):1895-9.
[16]Germanov E, Berman JN, Guernsey DL. Current and future approaches for the therapeutic targeting of metastasis [J]. International Journal of Molecular Medicine 2006;18(6):1025-36.
[17]刘文峰,徐光,何跃等.肿瘤微转移的机制与检测[J].西南军医,2010；12(4)：735-737.
[18]Brinton LT, Brentnall TA, Smith JA, Kelly KA. Metastatic biomarker discovery through proteomics [J]. Cancer Genomics Proteomics.2012; 9(6):345-55.
[19]Wun T, White RH. Epidemiology of cancer-related venous thromboembolism [J]. Best Pract Res Clin Haematol 2009; 22(1):9-23.
[20]Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer [J]. Thromb Res 2001; 102(6):V215-24.
[21]Uusitalo-Jarvinen H, et al. Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis [J]. Arterioscler Thromb Vasc Biol 2007; 27(6):1456-62.
[22]Khorana AA, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients [J]. Cancer 2007; 110(10):2339-46
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