组织因子途径抑制物-2（hTFPI-2）与乳腺癌侵袭转移的相关性研究
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摘要
背景:组织因子途径抑制物-2(tissue factor pathway inhibitor-2,TFPI-2)是一种带有Kunitz型结构域的蛋白酶抑制剂,属于丝氨酸蛋白酶抑制物超家族成员。它可能通过影响细胞外基质的重塑参与组织发生、胚胎发育分化、伤口愈合、肿瘤的侵袭转移和动脉粥样硬化斑块破裂等生理病理过程。研究发现:hTFPI-2的表达下降与胶质瘤、纤维肉瘤和卵巢癌的远处侵袭转移相关,但与乳腺癌的关系尚无定论,我们课题组在先期的体外实验研究中发现hTFPI-2在恶性程度高的乳腺癌细胞MDA-MB-435中的表达下降,且表达沉默和核心启动子的异常高甲基化有关。进一步证实hTFPI-2与乳腺癌之间的关系,阐明hTFPI-2在乳腺癌中下调表达及其与乳腺癌复发转移的关系,有可能为乳腺癌预后的判定和防治乳腺癌的远处转移提供新的思路和方向。
方法:1)收集复旦大学附属中山医院普外科2005年1月～2008年3月间住院的184例乳腺肿瘤患者的石蜡标本,其中乳腺良性肿瘤40例,乳腺癌144例。用免疫组织化学法检测hTFPI-2的表达,用计算机图像分析检测计算肿瘤标本中hTFPI-2的相对量。根据患者病理学特征进行分组。采用软件SPSS17.0对数据进行统计分析,评价hTFPI-2表达水平在具有不同的生物病理学特征的组织标本中的差异性。2)对所有石蜡标本患者进行术后随访,记录首次出现复发转移的时间、无病生存时间和总生存时间。以免疫组织化学法所测得的hTFPI-2表达的相对量的中位数和上下四分位数将所有病例分组。采用软件SPSS17.0统计分析。用Kaplan-Meier方法分析患者复发转移的情况;用log-rank检验比较患者无病生存分布。用寿命表法估计各分组患者的1年、2年的无病生存率。COX模型进行多因素回归分析,辨认预测预后的因素。
结果:1)乳腺良性肿瘤中hTFPI-2表达水平明显高于乳腺癌组织。2)hTFPI-2表达水平与乳腺癌患者的患病年龄无关。3)hTFPI-2表达水平与乳腺癌肿瘤大小呈负相关。肿瘤直径小于2cm的组中的hTFPI-2表达水平高于肿瘤直径2-5cm和大于5cm的组,差异有统计学意义。肿瘤直径2-5cm的组和大于5cm的组比较P＞0.05,差异无统计学意义。4)无皮肤累及的乳腺癌肿瘤中hTFPI-2表达水平高于有皮肤累及的组。5)hTFPI-2表达水平随着乳腺癌淋巴结转移个数的增多而下降(P＜0.01)。以乳腺癌淋巴结转移个数(pN区域淋巴结病理分期)分组,无淋巴结转移组的hTFPI-2表达水平高于有转移的各组,差异有统计学意义,有淋巴结转移的各组间肿瘤组织的hTFPI-2表达水平差异无统计学意义。6)以乳腺癌患者的雌孕激素受体和Her-2的免疫组化指标为分组指标,ER,PR及Her-2各自的分组中的hTFPI-2表达水平差异无统计学意义。7)乳腺癌肿瘤分化Ⅱ级的TFPI-2表达水平高于分化Ⅱ-Ⅲ级和Ⅲ级的组,差异有统计学意义。肿瘤分化Ⅱ-Ⅲ级和分化Ⅲ级的组比较P＞0.05,差异无统计学意义。8)hTFPI-2表达水平随临床TNM分期的增加而递减。9)hTFPI-2表达与多种乳腺癌预后因素的偏回归分析表明hTFPI-2表达水平与乳腺癌转移淋巴结个数的相关性最大,与肿瘤大小的相关性最小。10)生存分析结果表明hTFPI-2低表达组术后1年和2年的无病生存率明显低于其余各组。Kaplan-Meier累积生存函数图和log-rank检验表明hTFPI-2低表达组的术后无病生存时间少于于高表达组。CoxRegression风险比例模型分析hTFPI-2低表达组和高表达组的术后复发转移的相对危险度为0.118。综合多种预后因素分析显示,hTFPI-2表达分组与患者的预后的关系具有显著性意义,hTFPI-2表达水平越高,患者术后无病生存时间越长。
结论:乳腺良性肿瘤组织中hTFPI-2表达水平明显高于乳腺癌,且随着乳腺癌临床分期和恶性程度的增高,hTFPI-2的表达明显下降直至沉默,并且在肿瘤发生转移后hTFPI-2的下降更明显。乳腺癌原发肿瘤的hTFPI-2表达水平与患者的预后相关,hTFPI-2高表达的乳腺癌患者术后的复发转移风险较小。上述研究结果说明hTFPI-2可能作为抑癌基因参与乳腺癌的发病过程,检测hTFPI-2的表达有助于乳腺癌预后的判定。
Background: Tissue factor pathway inhibitor-2 (TFPI-2), is a protease inhibitor with three Kunitz domains and belongs to the super family of serine protease inhibitor. TFPI-2, the ECM-associated serine protease inhibitors plays a major role in extra cell matrix (ECM) degradation during fetal development, wound healing, and angiogenesis, etc. Many researches indicate that hTFPI-2 is associated with many tumor cell invasion and metastasis. But it is not yet detected about the role of hTFPI-2 during invasion and metastasis of breast cancer. Our previous vitro experiment detected that both protein and mRNA of hTFPI-2 could not be detected in highly invasive breast cancer cell line MDA-MB-435. The silence expression of hTFPI-2 correlated with the abnormal hypermethylation of CpG dinucleotides in hTFPI-2 promoter. To understand the roles of hTFPI-2 and their potential predictive use in breast cancer, in this study, we analyzed the expression of hTFPI-2 in 184 breast paraffin-embedded samples. The analysis may find hTFPI-2 as new breast cancer biomarkers that could be useful for prevention and prognosis in breast cancer.
Method: 1) We collected 184 paraffin-embedded breast tumor samples of in-patients, Jan. 2005-Mar. 2008. 40 were benign and 144 were breast cancer tumor and we detected hTFPI-2 by immunohistochemistry. The relative expression of hTFPI-2 in breast cancer samples was analyzed by computer assisted image system. We grouped patients by biopathologic features. Statistical comparisons were done by SPSS17.0 software to evaluate whether differentially expression of hTFPI-2 in various biopathologic features associated with tumor specimens. 2) We followed up all the cases and recorded the relapse time, disease free survival and overall survival. The relative expression of hTFPI-2 was grouped by median and interquartile. Kaplan-Meier method was used to investigate the patients metastatic status. Log-rank test was applied to compare disease-free survival distribution. Life-table method was employed to evaluate the patients 1 year and 2 year disease free survival rates. Univariate and Cox's multivariate regression analysis were performed to evaluate the effect of all markers on prognosis.
Result: 1) We found that expression of hTFPI-2 was down regulated in breast cancer and one way ANOVA analysis revealed expression of hTFPI-2 was significantly higher in benign than in malignant tumors. 2) The patients age did not contribute to any significant difference in hTFPI-2 expression levels. 3) Breast tumor size reversely correlated with hTFPI-2 expression levels. Significant difference could be observed in group with tumor size less than 2cm comparing with groups with tumor size 2-5cm and more than 5cm. However non statistical distinction was showed between 2-5cm group and 5cm group. 4) The expression of hTFPI-2 is associated with cutaneous involvement. Higher expression was viewed in ones with cutaneous involvement than ones without cutaneous involvement. 5) The expression level of hTFPI-2 decreased gradually with the increasing of metastatic lymph nodes. Grouping by numbers of lymph nodes, higher expression of hTFPI-2 in lymph nodes positive groups than that in lymph node negative groups, however the expression level showed no significant relationship with numbers of metastatic lymph nodes. 6) Estrogen receptor, progesterone receptor and HER-2 status contributed nothing to any significant difference in hTFPI-2 expression levels. 7) The grade of tumor was related to hTFPI-2 expression level. The result revealed the expression was higher in II-grade tumor than II-III-grade tumor and Ill-grade tumor. However, there is non statistical distinction of hTFPI-2 expression level between II-III-grade tumor and Ill-grade tumor. 8) The expression level of hTFPI-2 decreased gradually with the increasing of cTNM staging. 9) Partial regression shows that the relationship between hTFPI-2 and numbers of metastatic lymph nodes has more significant than breast tumor size. 10) Survival analysis revealed that 1-year DFS and 2-year DFS were less in patients with lower expression of TFPI-2. Disease free survival time is shorter in lower ones when comparing with higher expression of TFPI-2. Cox' s multivariate regression analysis showed that with the increasing of hTFPI-2 expression, the patients disease free survival time is gradually longer.
Conclusion: We found that the expression of hTFPI-2 in benign tissue was significant higher than that in malignant tumor tissue. The more advanced malignancy of breast cancer, the lower expression of hTFPI-2. The trend appeared more clear as the emerging of metastatic events. Less risk of relapse and metastasis could be observed in breast cancer patients with higher expression level of hTFPI-2. The result find hTFPI-2, a probably tumor suppressor genes, participate the development of breast cancer. Testing expression of hTFPI-2 could be helpful for diagnosis and prognosis in breast cancer.
方法:1)收集复旦大学附属中山医院普外科2005年1月～2008年3月间住院的184例乳腺肿瘤患者的石蜡标本,其中乳腺良性肿瘤40例,乳腺癌144例。用免疫组织化学法检测hTFPI-2的表达,用计算机图像分析检测计算肿瘤标本中hTFPI-2的相对量。根据患者病理学特征进行分组。采用软件SPSS17.0对数据进行统计分析,评价hTFPI-2表达水平在具有不同的生物病理学特征的组织标本中的差异性。2)对所有石蜡标本患者进行术后随访,记录首次出现复发转移的时间、无病生存时间和总生存时间。以免疫组织化学法所测得的hTFPI-2表达的相对量的中位数和上下四分位数将所有病例分组。采用软件SPSS17.0统计分析。用Kaplan-Meier方法分析患者复发转移的情况;用log-rank检验比较患者无病生存分布。用寿命表法估计各分组患者的1年、2年的无病生存率。COX模型进行多因素回归分析,辨认预测预后的因素。
结果:1)乳腺良性肿瘤中hTFPI-2表达水平明显高于乳腺癌组织。2)hTFPI-2表达水平与乳腺癌患者的患病年龄无关。3)hTFPI-2表达水平与乳腺癌肿瘤大小呈负相关。肿瘤直径小于2cm的组中的hTFPI-2表达水平高于肿瘤直径2-5cm和大于5cm的组,差异有统计学意义。肿瘤直径2-5cm的组和大于5cm的组比较P＞0.05,差异无统计学意义。4)无皮肤累及的乳腺癌肿瘤中hTFPI-2表达水平高于有皮肤累及的组。5)hTFPI-2表达水平随着乳腺癌淋巴结转移个数的增多而下降(P＜0.01)。以乳腺癌淋巴结转移个数(pN区域淋巴结病理分期)分组,无淋巴结转移组的hTFPI-2表达水平高于有转移的各组,差异有统计学意义,有淋巴结转移的各组间肿瘤组织的hTFPI-2表达水平差异无统计学意义。6)以乳腺癌患者的雌孕激素受体和Her-2的免疫组化指标为分组指标,ER,PR及Her-2各自的分组中的hTFPI-2表达水平差异无统计学意义。7)乳腺癌肿瘤分化Ⅱ级的TFPI-2表达水平高于分化Ⅱ-Ⅲ级和Ⅲ级的组,差异有统计学意义。肿瘤分化Ⅱ-Ⅲ级和分化Ⅲ级的组比较P＞0.05,差异无统计学意义。8)hTFPI-2表达水平随临床TNM分期的增加而递减。9)hTFPI-2表达与多种乳腺癌预后因素的偏回归分析表明hTFPI-2表达水平与乳腺癌转移淋巴结个数的相关性最大,与肿瘤大小的相关性最小。10)生存分析结果表明hTFPI-2低表达组术后1年和2年的无病生存率明显低于其余各组。Kaplan-Meier累积生存函数图和log-rank检验表明hTFPI-2低表达组的术后无病生存时间少于于高表达组。CoxRegression风险比例模型分析hTFPI-2低表达组和高表达组的术后复发转移的相对危险度为0.118。综合多种预后因素分析显示,hTFPI-2表达分组与患者的预后的关系具有显著性意义,hTFPI-2表达水平越高,患者术后无病生存时间越长。
结论:乳腺良性肿瘤组织中hTFPI-2表达水平明显高于乳腺癌,且随着乳腺癌临床分期和恶性程度的增高,hTFPI-2的表达明显下降直至沉默,并且在肿瘤发生转移后hTFPI-2的下降更明显。乳腺癌原发肿瘤的hTFPI-2表达水平与患者的预后相关,hTFPI-2高表达的乳腺癌患者术后的复发转移风险较小。上述研究结果说明hTFPI-2可能作为抑癌基因参与乳腺癌的发病过程,检测hTFPI-2的表达有助于乳腺癌预后的判定。
Background: Tissue factor pathway inhibitor-2 (TFPI-2), is a protease inhibitor with three Kunitz domains and belongs to the super family of serine protease inhibitor. TFPI-2, the ECM-associated serine protease inhibitors plays a major role in extra cell matrix (ECM) degradation during fetal development, wound healing, and angiogenesis, etc. Many researches indicate that hTFPI-2 is associated with many tumor cell invasion and metastasis. But it is not yet detected about the role of hTFPI-2 during invasion and metastasis of breast cancer. Our previous vitro experiment detected that both protein and mRNA of hTFPI-2 could not be detected in highly invasive breast cancer cell line MDA-MB-435. The silence expression of hTFPI-2 correlated with the abnormal hypermethylation of CpG dinucleotides in hTFPI-2 promoter. To understand the roles of hTFPI-2 and their potential predictive use in breast cancer, in this study, we analyzed the expression of hTFPI-2 in 184 breast paraffin-embedded samples. The analysis may find hTFPI-2 as new breast cancer biomarkers that could be useful for prevention and prognosis in breast cancer.
Method: 1) We collected 184 paraffin-embedded breast tumor samples of in-patients, Jan. 2005-Mar. 2008. 40 were benign and 144 were breast cancer tumor and we detected hTFPI-2 by immunohistochemistry. The relative expression of hTFPI-2 in breast cancer samples was analyzed by computer assisted image system. We grouped patients by biopathologic features. Statistical comparisons were done by SPSS17.0 software to evaluate whether differentially expression of hTFPI-2 in various biopathologic features associated with tumor specimens. 2) We followed up all the cases and recorded the relapse time, disease free survival and overall survival. The relative expression of hTFPI-2 was grouped by median and interquartile. Kaplan-Meier method was used to investigate the patients metastatic status. Log-rank test was applied to compare disease-free survival distribution. Life-table method was employed to evaluate the patients 1 year and 2 year disease free survival rates. Univariate and Cox's multivariate regression analysis were performed to evaluate the effect of all markers on prognosis.
Result: 1) We found that expression of hTFPI-2 was down regulated in breast cancer and one way ANOVA analysis revealed expression of hTFPI-2 was significantly higher in benign than in malignant tumors. 2) The patients age did not contribute to any significant difference in hTFPI-2 expression levels. 3) Breast tumor size reversely correlated with hTFPI-2 expression levels. Significant difference could be observed in group with tumor size less than 2cm comparing with groups with tumor size 2-5cm and more than 5cm. However non statistical distinction was showed between 2-5cm group and 5cm group. 4) The expression of hTFPI-2 is associated with cutaneous involvement. Higher expression was viewed in ones with cutaneous involvement than ones without cutaneous involvement. 5) The expression level of hTFPI-2 decreased gradually with the increasing of metastatic lymph nodes. Grouping by numbers of lymph nodes, higher expression of hTFPI-2 in lymph nodes positive groups than that in lymph node negative groups, however the expression level showed no significant relationship with numbers of metastatic lymph nodes. 6) Estrogen receptor, progesterone receptor and HER-2 status contributed nothing to any significant difference in hTFPI-2 expression levels. 7) The grade of tumor was related to hTFPI-2 expression level. The result revealed the expression was higher in II-grade tumor than II-III-grade tumor and Ill-grade tumor. However, there is non statistical distinction of hTFPI-2 expression level between II-III-grade tumor and Ill-grade tumor. 8) The expression level of hTFPI-2 decreased gradually with the increasing of cTNM staging. 9) Partial regression shows that the relationship between hTFPI-2 and numbers of metastatic lymph nodes has more significant than breast tumor size. 10) Survival analysis revealed that 1-year DFS and 2-year DFS were less in patients with lower expression of TFPI-2. Disease free survival time is shorter in lower ones when comparing with higher expression of TFPI-2. Cox' s multivariate regression analysis showed that with the increasing of hTFPI-2 expression, the patients disease free survival time is gradually longer.
Conclusion: We found that the expression of hTFPI-2 in benign tissue was significant higher than that in malignant tumor tissue. The more advanced malignancy of breast cancer, the lower expression of hTFPI-2. The trend appeared more clear as the emerging of metastatic events. Less risk of relapse and metastasis could be observed in breast cancer patients with higher expression level of hTFPI-2. The result find hTFPI-2, a probably tumor suppressor genes, participate the development of breast cancer. Testing expression of hTFPI-2 could be helpful for diagnosis and prognosis in breast cancer.
引文
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[30] Kondraganti S, Gondi CS, Gujrati M, et al. Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line[J]. Int J Oncol, 2006, 29:25-32.
[31] Sun Y, Xie M, Liu M, et al. Growth suppression of human laryngeal squamous cell carcinoma by adenovirus-mediated tissue factor pathway inhibitor gene 2[J]. Laryngoscope, 2006, 116:596-601.
[32] Xu Z, Maiti D, Kisiel W, et al. Tissue factor pathway inhibitor-2 is upregulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells[J]. Arterioscler Thromb Vasc Biol, 2006, 26:2819-2825.
[33] Ruf W, Seftor EA, Petrovan RJ, et al. Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimicry[J]. Cancer Res, 2003, 63:5381-5389.
[34] Rao CN, Segawa T, Navari JR, et al. Methylation of TFPI-2 gene is not the sole cause of its silencing[J]. Int J Oncol, 2003, 22:843-848.
[35] Konduri SD, Srivenugopal KS, Yanamandra N, et al. Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells [J]. Oncogene, 2003, 22:4509-4516.
[36] Hube F, Reverdiau P, Iochmann S, et al. Transcriptional silencing of the TFPI-2 gene by promoter hypermethylation in choriocarcinoma cells[J]. Biol Chem, 2003, 384:1029-1034.
[37] Sato N, Parker AR, Fukushima N, et al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma[J]. Oncogene, 2005, 24:850-858.
[38] Steiner FA, Hong JA, Fischette MR, et al. Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells[J]. Oncogene, 2005, 24:2386-2397.
[39] Rollin J, Iochmann S, Blechet C, et al. Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer[J]. Br J Cancer, 2005, 92:775-783.
[40] Schrump DS, Nguyen DM. Novel molecular targeted therapy for esophageal cancer[J]. J Surg Oncol, 2005, 92:257-261.
[41] Key TJ, Verkasalo PK, Banks E: Epidemiology of breast cancer[J]. Lancet Oncol, 2001, 2:133-140.
[42] Duffy MJ, Maguire TM, Hill A, et al. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis[J]. Breast Cancer Res, 2000, 2:252-257.
[43] Steeg PS. Molecular biology of breast cancer metastasis. 'Has it spread?' : disarming one of the most terrifying questions[J]. Breast Cancer Res 2000, 2:396-399.
[44] Hongshen Guo, Yifeng Lin, Hongwei Zhang, et al. Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells[J]. BMC Molecular Biology, 2007, 8:110-121.
[45] Schedin P, Elias A. Multistep tumorigenesis and the microenvironment[J]. Breast Cancer Res, 2004, 6:93-101.
[46] Izumi H, Takahashi C, Oh J, et al. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes[J]. FEBS Lett, 2000; 481(1) :31-6.
[47] Konduri SD, Yanamandra N, Dinh DH, et al. Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells[J]. Int. J. Oncol, 22 (2003), 1277-1283.
[48] Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J]. J Clin Invest, 2001;107 (9):1117-26.
[49] Crawley JT, Goulding DA, Ferreira V, et al. Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels[J]. Arterioscler Thromb Vasc Biol, 2002;22 (2):218-24.
[50] Shinoda E, Yui Y, Hattori R, et al. Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells [J]. J Biol Chem, 1999:274(9): 5379-84.
[51] Rao CN, Mohanam S, Puppala A, et al. Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor[J]. Biochem Biophys Res Commun 1999;258 (2):497.
[52] Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J]. J Clin Invest. 2001;107 (9):1117-26
[53] Hanahan D, Weinberg RA. The hallmarks of cancerQ]. Cell, 2000, 100:57-70.
[54] Johnston SR. Systemic treatment of metastatic breast cancerQ]. Hosp Med, 2001,62:289-295.
[55] Hillner BE. The role of bisphosphonates in metastatic breast cancer[J]. Semin Radiat Oncol, 2000,10:250-253.
[56] Barse PM. Issues in the treatment of metastatic breast cancer [J]. Semin Oncol Nurs, 2000,16:197-205.
[57] Perez EA. Update on metastatic breast cancer[J]. Curr Oncol Rep, 1999, 1:11-15
[58] Ivanciu L, Gerard RD, Tang H, et al. Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesisQ]. Arterioscler Thromb Vasc Biol, 2007, 27:310-316.
[1] Jandial V, Horne CH, Glover RG, et al. The value of measurement of pregnancy-specific proteins in twin pregnancies[J]. Acta Genet Med Gemellol Roma, 1979;28(4):319-25.
[2] Sprecher CA, Kisiel W, Mathewes S, et al. Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor[J]. Proc Natl Acad Sci USA, 1994;91 (8):3353-7
[3]Rao CN, Reddy P, Liu Y, O'Toole E. Extracellular matrix-associated serine protease inhibitors (Mr 33,000, 31,000, and 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2[J]. Arch Biochem Biophys, 1996;335(1):82-92.
[4] Butzow R, Alfthan H, Stenman UH, et al. Immunofluorometric demonstration and quantification of placental protein 5 in the absence of pregnancy[J]. Clin Chem, 1988, 34:1591-1593.
[5] Sinosich MJ, Saunders DM, Grudzinskas JG. Pregnancy-associated plasma protein-A and placental protein 5 in human ovarian follicular fluid[J]. Ann N Y Acad Sci, 1985, 442:269-275.
[6] Lee JN, Lian JD, Lee JH, et al. Placental proteins (human chorionic gonadotropin, human placental lactogen, pregnancy-specific beta 1-glycoprotein, and placental protein 5) in seminal plasma of normal men and patients with infertility[J]. Fertil Steril, 1983, 39:704-706.
[7] Ranta T, Siiteri JE, Koistinen R, et al. Human seminal plasma contains a protein that shares physicochemical and immunochemical properties with placental protein 5 from the human placenta[J]. J Clin Endocrinol Metab, 1981, 53:1087-1089.
[8] Menabawey M, Silman R, Rice A, et al. Dramatic increase of placental protein 5 levels following injection of small doses of heparin[J]. Br J Obstet Gynaecol, 1985, 92:207-210.
[9] Liu Y, Stack SM, Lakka SS, et al. Matrix localization of tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor (TFPI-2/MSPI) involves arginine-mediated ionic interactions with heparin and dermatan sulfate: heparin accelerates the activity of TFPI-2/MSPI toward plasmin[J]. Arch Biochem Biophys, 1999, 370:112-118.
[10]Kamei S,Kazama Y,Kuijper JL,et al.Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene[J].Biochim Biophys Acta,2001;1517(3):430-5.
[11]lino M,Foster PC,Kisiel W.Quantification and characterization of human endothelial cell-derived tissue factor pathway inhibitor-2[J].Arterioscler rhromb Vasc Biol,1998 18(1):40-6.
[12]Neaud V,Duplantier JG,Mazzocco C,et al.rhrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclooxygenase-2-dependent,epidermal growth factor receptor-independent mechanism[J].J Biol Chem,2004 13;279(?):5200-6
[13]Christina Kast,Minglun Wang,Malcolm Whiteway.The ERK/MAPK Pathway Regulates the Activity of the Human Tissue Factor Pathway Inhibitor-2Promoter[J].J Biol Chem,2003 28;278(9):6787-94
[14]Rao CN,Mohanam S,Puppala A,et al.Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor.Biochem Biophys Res Commun,1999;258(2):497
[15]Herman MP,Sukhova GK,Kisiel W,et al.Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J].J Clin Invest,2001;107(9):1117-26
[16]Petersen LC,Sprecher CA,Foster De,et al.Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor[J].Biochemistry,1996;35(1):266-72
[17]Rao CN,Cook B,Liu Y,et al.HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI~J].Int J Cancer,1998;76(5):749-56
[19]Sato N,Parker AR,Fukushima N,et al.Epigenetic inactivation of TFPI-2 as a common mechanism associated with grow th and invasion of pancreatic ductal adenocarcinoma[J].Oncogene,2005,24(5):850-858.
[20]孙振阳,汤志刚,胡何节.胰腺癌TFPI-2蛋白表达与细胞凋亡[J].现代肿瘤医学,2008年16卷4期:586-588
[21]N eaud V,H isaka T,M onvoisin A,et al.Paradoxical pro-invasive effect of the serine p roteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells[J].J giol Chem,2000, 275(45):35565-35569
[22]Neaud V,Hisaka T,Monvoisin A,et al.Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells[J].J Biol Chem,2000;275(45):35565-9
[23]Jin M,Udagawa K,Miyagi E,et al.Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo[J].Gynecol Oncol,2001,83(2):325-333.
[24]Santin AD,Zhan F,Bigotti E,et al.Gene expression profiles of primary HPV162 and HPV182 infected early stage cervical cancers and normal cervical epithelium:identification of novel candidate molecular markers for cervical cancer diagnosis and therapy[J].Virology,2005,331(2):269-291.
[25]仲任,黄瑞滨,宋善俊.组织因子途径抑制物2表达抑制卵巢癌细胞浸润能力的实验研究[J].肿瘤,2004,24(5):444-447.
[26]Hongshen Guo,Yifeng Lin,Hongwei Zhang,et al.Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells[J].BMC Molecular Biology,2007,8:110-121.
[27]Chand HS,Du X,Ma D.The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice[J].Blood,103(2004),1069-1077.
[28]Konduri SD,Srivenugopal KS,Yanamandra N.Promoter methylation and silencing of the tissue factor pathway inhibitor-2(TFPI-2),a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells[J].Oncogene,22(2003),4509-4516.
[29]Konduri SD,Yanamandra N,Dinh DH.Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells[J].Int.J.Oncol,22(2003),1277-1283.
[30].Konduri SD,Rao CN,Chandrasekar N.A novel function of tissue factor pathway inhibitor-2(TFPI-2) in human glioma invasion[J].Oncogene,20(2001),6938-6945.
[31] Rao CN, Lakka SS, Konduri SD, et al. Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas[J]. Clin. Cancer Res, 7 (2001), 570-576.
[32] Zhong R, Huang RB, Song SJ. Role of tissue factor pathway inhibitor-2 in ovarian tumor migration and invasion[J]. Ai Zheng 22 (2003), 1038-1041.
[33] Jin M, UdagawaK, Miyagi E. Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo[J]. Gynecol. Oncol, 83 (2001), 325-333.
[34] Konduri SD, Tasiou A, Chandrasekar N. Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion[J]. Clin. Exp. Metastasis, 18 (2000), 303-308.
[35] Lakka SS, Konduri SD, Mohanam S. In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2[J]. Clin. Exp. Metastasis, 18 (2000), 239-244.
[36] Konduri SD, Osman FA, Rao CN, et al. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas[J]. Oncogene, 2002;21(6):921-8.
[37] Izumi H, Takahashi C, Oh J, et al. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes[J]. FEBS Lett, 2000;481(1):31-6
[2] Butzow R, Alfthan H, Stenman UH, et al. Immunofluorometric demonstration and quantification of placental protein 5 in the absence of pregnancy[J]. Clin Chem, 1988, 34:1591-1593.
[3] SinosichMJ, Saunders DM, Grudzinskas JG. Pregnancy-associated plasma protein-A and placental protein 5 in human ovarian follicular fluid[J]. Ann N Y Acad Sci, 1985, 442:269-275.
[4] Lee JN, Lian JD, Lee JH, et al. Placental proteins (human chorionic gonadotropin, human placental lactogen, pregnancy-specific beta 1-glycoprotein, and placental protein 5) in seminal plasma of normal men and patients with infertility[J]. Fertil Steril, 1983, 39:704-706.
[5] Ranta T, Siiteri JE, Koistinen R, et al. Human seminal plasma contains a protein that shares physicochemical and immunochemical properties with placental protein 5 from the human placenta [J]. J Clin Endocrinol Metab, 1981, 53:1087-1089.
[6] Menabawey M, Silman R, Rice A. Dramatic increase of placental protein 5 levels following injection of small doses of heparin[J]. Br J Obstet Gynaecol, 1985, 92:207-210.
[7] Liu Y, Stack SM, Lakka SS, Khan AJ, et al. Matrix localization of tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor (TFPI-2/MSPI) involves arginine-mediated ionic interactions with heparin and dermatan sulfate: heparin accelerates the activity of TFPI-2/MSPI toward plasmin[J]. Arch Biochem Biophys, 1999, 370:112-118.
[8] Rao CN, Reddy P, Liu Y, et al. Extracellular matrix-associated serine protease inhibitors (Mr 33,000, 31,000, and 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2[J]. Arch Biochem Biophys, 1996, 335:82-92.
[9] Miyagi Y, Koshikawa N, Yasumitsu H, et al. cDNA cloning and mRNA expression of a serine proteinase inhibitor secreted by cancer cells: identification as placental protein 5 and tissue factor pathway inhibitor-2[J]. J Biochem (Tokyo), 1994, 116:939-942.
[10] Kisiel W, Sprecher CA, Foster DC. Evidence that a second human tissue factor pathway inhibitor (TFPI-2) and human placental protein 5 are equivalent[J]. Blood, 1994, 84:4384-4385.
[11] Sprecher CA, Kisiel W, Mathewes S, et al. Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor[J]. Proc Natl Acad Sci USA, 1994, 91:3353-3357.
[12] Miyagi Y, Yasumitsu H, Eki T, et al. Assignment of the human PP5/TFPI-2 gene to 7q22 by FISH and PCR-based human/rodent cell hybrid mapping panel analysis [J]. Genomics, 1996, 35:267-268.
[13] Kamei S, Kazama Y, Kui jper JL, et al. Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene[J]. Biochim Biophys Acta, 2001, 1517:430-435.
[14] Hube F, Reverdiau P, Iochmann S, et al. Characterization and functional analysis of TFPI-2 gene promoter in a human choriocarcinoma cell line[J]. Thromb Res, 2003, 109:207-215.
[15] Konduri SD, Osman FA, Rao CN, et al. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas[J]. Oncogene, 2002, 21:921-928.
[16] Petersen LC, Sprecher CA, Foster DC, et al. Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor[J]. Biochemistry, 1996, 35:266-272.
[17] Rao CN, Mohanam S, Puppala A, et al. Regulation of ProMMP-1 andProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor[J]. Biochem Biophys Res Commun, 1999, 255:94-98.
[18] Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J]. J Clin Invest, 2001, 107:1117-1126.
[19] Du X, Chand HS, Kisiel W. Human tissue factor pathway inhibitor-2 does not bind or inhibit activated matrix metalloproteinase-1 [J]. Biochim Biophys Acta, 2003, 1621:242-245.
[20] Rao CN, Lakka SS, Kin Y, et al. Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas[J]. Clin Cancer Res, 2001, 7:570-576.
[21] Rao CN, Cook B, Liu Y, et al. HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI[J]. Int J Cancer, 1998, 76:749-756.
[22] Konduri SD, Tasiou A, Chandrasekar N, et al. Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro[J]. Int J Oncol, 2001, 18:127-131.
[23] Jin M, Udagawa K, Miyagi E, et al. Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo[J]. Gynecol Oncol, 2001, 83:325-333.
[24] Konduri SD, Tasiou A, Chandrasekar N, et al. Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion[J]. Clin Exp Metastasis, 2000, 18:303-308.
[25] Lakka SS, Konduri SD, Mohanam S, et al. In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2[J]. Clin Exp Metastasis, 2000, 18:239-244.
[26] Tasiou A, Konduri SD, Yanamandra N, et al. A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas[J]. Int J Oncol, 2001, 19:591-597.
[27] Konduri SD, Rao CN, Chandrasekar N, et al. A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion [J]. Oncogene, 2001, 20:6938-6945.
[28] Chand HS, Du X, Ma D, et al. The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice[J]. Blood, 2004, 103:1069-1077.
[29] Yanamandra N, Kondraganti S, Gondi CS, et al. Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line[J]. Int J Cancer, 2005, 115:998-1005.
[30] Kondraganti S, Gondi CS, Gujrati M, et al. Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line[J]. Int J Oncol, 2006, 29:25-32.
[31] Sun Y, Xie M, Liu M, et al. Growth suppression of human laryngeal squamous cell carcinoma by adenovirus-mediated tissue factor pathway inhibitor gene 2[J]. Laryngoscope, 2006, 116:596-601.
[32] Xu Z, Maiti D, Kisiel W, et al. Tissue factor pathway inhibitor-2 is upregulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells[J]. Arterioscler Thromb Vasc Biol, 2006, 26:2819-2825.
[33] Ruf W, Seftor EA, Petrovan RJ, et al. Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimicry[J]. Cancer Res, 2003, 63:5381-5389.
[34] Rao CN, Segawa T, Navari JR, et al. Methylation of TFPI-2 gene is not the sole cause of its silencing[J]. Int J Oncol, 2003, 22:843-848.
[35] Konduri SD, Srivenugopal KS, Yanamandra N, et al. Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells [J]. Oncogene, 2003, 22:4509-4516.
[36] Hube F, Reverdiau P, Iochmann S, et al. Transcriptional silencing of the TFPI-2 gene by promoter hypermethylation in choriocarcinoma cells[J]. Biol Chem, 2003, 384:1029-1034.
[37] Sato N, Parker AR, Fukushima N, et al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma[J]. Oncogene, 2005, 24:850-858.
[38] Steiner FA, Hong JA, Fischette MR, et al. Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells[J]. Oncogene, 2005, 24:2386-2397.
[39] Rollin J, Iochmann S, Blechet C, et al. Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer[J]. Br J Cancer, 2005, 92:775-783.
[40] Schrump DS, Nguyen DM. Novel molecular targeted therapy for esophageal cancer[J]. J Surg Oncol, 2005, 92:257-261.
[41] Key TJ, Verkasalo PK, Banks E: Epidemiology of breast cancer[J]. Lancet Oncol, 2001, 2:133-140.
[42] Duffy MJ, Maguire TM, Hill A, et al. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis[J]. Breast Cancer Res, 2000, 2:252-257.
[43] Steeg PS. Molecular biology of breast cancer metastasis. 'Has it spread?' : disarming one of the most terrifying questions[J]. Breast Cancer Res 2000, 2:396-399.
[44] Hongshen Guo, Yifeng Lin, Hongwei Zhang, et al. Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells[J]. BMC Molecular Biology, 2007, 8:110-121.
[45] Schedin P, Elias A. Multistep tumorigenesis and the microenvironment[J]. Breast Cancer Res, 2004, 6:93-101.
[46] Izumi H, Takahashi C, Oh J, et al. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes[J]. FEBS Lett, 2000; 481(1) :31-6.
[47] Konduri SD, Yanamandra N, Dinh DH, et al. Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells[J]. Int. J. Oncol, 22 (2003), 1277-1283.
[48] Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J]. J Clin Invest, 2001;107 (9):1117-26.
[49] Crawley JT, Goulding DA, Ferreira V, et al. Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels[J]. Arterioscler Thromb Vasc Biol, 2002;22 (2):218-24.
[50] Shinoda E, Yui Y, Hattori R, et al. Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells [J]. J Biol Chem, 1999:274(9): 5379-84.
[51] Rao CN, Mohanam S, Puppala A, et al. Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor[J]. Biochem Biophys Res Commun 1999;258 (2):497.
[52] Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis[J]. J Clin Invest. 2001;107 (9):1117-26
[53] Hanahan D, Weinberg RA. The hallmarks of cancerQ]. Cell, 2000, 100:57-70.
[54] Johnston SR. Systemic treatment of metastatic breast cancerQ]. Hosp Med, 2001,62:289-295.
[55] Hillner BE. The role of bisphosphonates in metastatic breast cancer[J]. Semin Radiat Oncol, 2000,10:250-253.
[56] Barse PM. Issues in the treatment of metastatic breast cancer [J]. Semin Oncol Nurs, 2000,16:197-205.
[57] Perez EA. Update on metastatic breast cancer[J]. Curr Oncol Rep, 1999, 1:11-15
[58] Ivanciu L, Gerard RD, Tang H, et al. Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesisQ]. Arterioscler Thromb Vasc Biol, 2007, 27:310-316.
[1] Jandial V, Horne CH, Glover RG, et al. The value of measurement of pregnancy-specific proteins in twin pregnancies[J]. Acta Genet Med Gemellol Roma, 1979;28(4):319-25.
[2] Sprecher CA, Kisiel W, Mathewes S, et al. Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor[J]. Proc Natl Acad Sci USA, 1994;91 (8):3353-7
[3]Rao CN, Reddy P, Liu Y, O'Toole E. Extracellular matrix-associated serine protease inhibitors (Mr 33,000, 31,000, and 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2[J]. Arch Biochem Biophys, 1996;335(1):82-92.
[4] Butzow R, Alfthan H, Stenman UH, et al. Immunofluorometric demonstration and quantification of placental protein 5 in the absence of pregnancy[J]. Clin Chem, 1988, 34:1591-1593.
[5] Sinosich MJ, Saunders DM, Grudzinskas JG. Pregnancy-associated plasma protein-A and placental protein 5 in human ovarian follicular fluid[J]. Ann N Y Acad Sci, 1985, 442:269-275.
[6] Lee JN, Lian JD, Lee JH, et al. Placental proteins (human chorionic gonadotropin, human placental lactogen, pregnancy-specific beta 1-glycoprotein, and placental protein 5) in seminal plasma of normal men and patients with infertility[J]. Fertil Steril, 1983, 39:704-706.
[7] Ranta T, Siiteri JE, Koistinen R, et al. Human seminal plasma contains a protein that shares physicochemical and immunochemical properties with placental protein 5 from the human placenta[J]. J Clin Endocrinol Metab, 1981, 53:1087-1089.
[8] Menabawey M, Silman R, Rice A, et al. Dramatic increase of placental protein 5 levels following injection of small doses of heparin[J]. Br J Obstet Gynaecol, 1985, 92:207-210.
[9] Liu Y, Stack SM, Lakka SS, et al. Matrix localization of tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor (TFPI-2/MSPI) involves arginine-mediated ionic interactions with heparin and dermatan sulfate: heparin accelerates the activity of TFPI-2/MSPI toward plasmin[J]. Arch Biochem Biophys, 1999, 370:112-118.
[10]Kamei S,Kazama Y,Kuijper JL,et al.Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene[J].Biochim Biophys Acta,2001;1517(3):430-5.
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