血管内皮生长因子和缺氧诱导因子-1α在结核性和肿瘤性心包积液诊断中的价值
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摘要
目的:探讨血管内皮生长因子(VEGF)和缺氧诱导因子-1_α(HIF-1_α)在结核性和肿瘤性心包积液诊断中的作用。
方法:入选行心包穿刺并引流出渗出性心包积液的患者共80例分成恶性肿瘤组和结核组,采用双抗体夹心酶联免疫吸附法检测患者血清和心包积液中VEGF、HIF-1a、乳酸脱氢酶(LDH)和腺苷脱氨酶(ADA),并进行心包积液常规和细胞学检查,两组间进行比较,并分析其相关血液指标和临床特点。结果:肿瘤性心包积液47例,男性25例,女性22例,其中肺癌26例,乳腺癌6例,肝癌4例,淋巴瘤3例,纵隔肿瘤3例,膀胱癌、直肠癌、心包肉瘤、横纹肌肉瘤和黑色素瘤各1例。结核性心包积液33例,男性18例,女性15例。肿瘤性心包积液组VEGF和HIF-1_α水平明显高于结核性心包积液组(VEGF 865.87±427.53 pg/ml vs 384.99±343.19 pg/ml,HIF-1_α2010.28±591.61 pg/ml vs 1005.38±328.49 pg/ml, P<0.01),两者之间呈正相关(r =0.79,P<0.01),两者联合检测,其敏感性为90.8%,特异性为88.3%。而两组之间性别、发热情况、血清VEGF、HIF-1_α,LDH、ADA和血沉、血红蛋白水平均无明显差异。
结论:VEGF和HIF-1_α在恶性肿瘤和结核引起的心包积液的鉴别诊断中具有一定的价值。
Objective: To investigate the clinical value of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1ɑ(HIF-1ɑ) in diagnosing malignant and tuberculous pericardial effusion.
Methods: 80 patients with exudative pericardial effusion undergoing pericardiocentesis and drainage were classified into malignancy and tuberculosis groups. The levels of HIF-1ɑ, VEGF, lactate dehydrogenase (LDH) and adenosine deaminase (ADA) in pericardial fluid and serum were measured. Routine and cytological examination of pericardial fluid, clinical characteristics and some blood parameters were compared between the two groups.
Results: There were 33 patients with tuberculous pericardial effusion and 47 cases with malignant pericardial effusion. The levels of VEGF and HIF-1ɑin pericardial fluid in the malignancy group were significantly higher than that in the tuberculosis group (P < 0.01), between the levels of VEGF and HIF-1a there were moderate positive correlation (r = 0.79, P < 0.01). The sensitivity and specificity of combining VEGF and HIF-1a were 90.8% and 88.3% respectively. The two groups showed no differences in gender distribution, fever, erythrocyte sedimentation rate, the levels of hemoglobin, LDH, ADA, serum HIF-1ɑand VEGF, the routine of pericardial fluid.
Conclusion: Both VEGF and HIF-1ɑof pericardial fluid have determinate value in the differential diagnosis of malignant and tuberculous pericardial effusion.
方法:入选行心包穿刺并引流出渗出性心包积液的患者共80例分成恶性肿瘤组和结核组,采用双抗体夹心酶联免疫吸附法检测患者血清和心包积液中VEGF、HIF-1a、乳酸脱氢酶(LDH)和腺苷脱氨酶(ADA),并进行心包积液常规和细胞学检查,两组间进行比较,并分析其相关血液指标和临床特点。结果:肿瘤性心包积液47例,男性25例,女性22例,其中肺癌26例,乳腺癌6例,肝癌4例,淋巴瘤3例,纵隔肿瘤3例,膀胱癌、直肠癌、心包肉瘤、横纹肌肉瘤和黑色素瘤各1例。结核性心包积液33例,男性18例,女性15例。肿瘤性心包积液组VEGF和HIF-1_α水平明显高于结核性心包积液组(VEGF 865.87±427.53 pg/ml vs 384.99±343.19 pg/ml,HIF-1_α2010.28±591.61 pg/ml vs 1005.38±328.49 pg/ml, P<0.01),两者之间呈正相关(r =0.79,P<0.01),两者联合检测,其敏感性为90.8%,特异性为88.3%。而两组之间性别、发热情况、血清VEGF、HIF-1_α,LDH、ADA和血沉、血红蛋白水平均无明显差异。
结论:VEGF和HIF-1_α在恶性肿瘤和结核引起的心包积液的鉴别诊断中具有一定的价值。
Objective: To investigate the clinical value of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1ɑ(HIF-1ɑ) in diagnosing malignant and tuberculous pericardial effusion.
Methods: 80 patients with exudative pericardial effusion undergoing pericardiocentesis and drainage were classified into malignancy and tuberculosis groups. The levels of HIF-1ɑ, VEGF, lactate dehydrogenase (LDH) and adenosine deaminase (ADA) in pericardial fluid and serum were measured. Routine and cytological examination of pericardial fluid, clinical characteristics and some blood parameters were compared between the two groups.
Results: There were 33 patients with tuberculous pericardial effusion and 47 cases with malignant pericardial effusion. The levels of VEGF and HIF-1ɑin pericardial fluid in the malignancy group were significantly higher than that in the tuberculosis group (P < 0.01), between the levels of VEGF and HIF-1a there were moderate positive correlation (r = 0.79, P < 0.01). The sensitivity and specificity of combining VEGF and HIF-1a were 90.8% and 88.3% respectively. The two groups showed no differences in gender distribution, fever, erythrocyte sedimentation rate, the levels of hemoglobin, LDH, ADA, serum HIF-1ɑand VEGF, the routine of pericardial fluid.
Conclusion: Both VEGF and HIF-1ɑof pericardial fluid have determinate value in the differential diagnosis of malignant and tuberculous pericardial effusion.
引文
1.徐成胜,吴勇波,何涛,等.心包积液住院患者的病因分析(附384例报告).临床心血管病杂志,2008,24:794-795
2.刘成加,童步高,徐腊生,等.心包积液206例临床分析.医学文选,2006,25:217-218
3. Cornily JC,Pennec PY,Castellant P,et al. Cardiac tamponade in medical patients:a 10-year follow-up survey. Cardiology,2008,111:197-201
4. Sugiura T,Kumon Y,Kataoka H,et al. Asymptomatic pericardial effusion in patients with rheumatoid arthritis. Cardiology,2008,110:87-91
5. Rapose A,Sarvat B,Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology,2008,110:142-144
6. Mayosi BM,Burgess LJ,Doubell AF. Tuberculous pericarditis. Circulation,2005,112: 3608–3616
7. Jiang BH,Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res,2009,102;19-65
8. Grépin R,Pagès G. The Vascular Endothelial Growth Factor (VEGF):a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol,2009,203;181-192
9. Argyriou AA,Giannopoulou E,Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology,2009,77;1-11
10. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med,2009,87:549-560
11. Zhou WB,Bai M,Jin Y. Diagnostic value of vascular endothelial growth factor and endostatin in malignant pleural effusion. Int J Tuberc Lung Dis,2009,13:381-386
12. Hsu IL,Su WC,Yan JJ,et al. Angiogenetic biomarkers in non-small cell lung cancer with malignant pleural effusion:Correlations with patient survival and pleural effusion control. Lung Cancer,2009,65:371-376
13. Duysinx BC,Corhay JL,Hubin L,et al. Diagnostic value of interleukine-6,transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusion. Respir Med,2008,102:1708-1714
14. Economidou F,Antoniou KM,Tzanakis N,et al. Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusion. Respir Med,2008,102:774-779
15. Shu J,Sun G,Liu H. Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusion. Acta Oncol,2007,46:1004-1011
16. Kaya A,Poyraz B,Celik G,et al. Vascular endothelial growth factor in benign and malignant pleural effusion. Arch Bronconeumol,2005,41:376-379
17. Sack U,Hoffmann M,Zhao XJ,et al. Vascular endothelial growth factor in pleural effusion of different origin. Eur Respir J,2005,25:600-604
18. Hamed EA,El-Noweihi AM,Mohamed AZ,et al. Vasoactive mediators (VEGF and TNF-alpha) in patients with malignant and tuberculous pleural effusion. Respirology,2004,9:81-86
19. Rafajlovski S,Tati? V,Ili? S,et al. Frequency of metastatic tumors in the heart. Vojnosanit Pregl,2005,62:915-920
20. Koga S,Ikeda S,Urata J,et al. Primary high-grade myofibroblastic sarcoma arising from the pericardium. Circ J,2008,72;337-339
1. Xu CS,Wu YB,He T,et al. Etiology of 384 cases with pericardial effusion. Lin Chuang Xin Xue Guan Bing Za Zhi,2008,24: 794-795 (Chinese)
2. Liu CJ,Tong BG,Xu LS,et al. Clinical analysis of 206 cases with pericardial effusion. Yi Xue Wen Xuan,2006,25:217-218 (Chinese)
3. Cornily JC,Pennec PY,Castellant P,et al. Cardiac tamponade in medical patients:a 10-year follow-up survey. Cardiology,2008,111:197-201
4. Sugiura T,Kumon Y,Kataoka H,et al. Asymptomatic pericardial effusion in patients with rheumatoid arthritis. Cardiology,2008,110:87-91
5. Rapose A,Sarvat B,Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology,2008,110:142-144
6. Mayosi BM,Burgess LJ,Doubell AF. Tuberculous pericarditis. Circulation,2005,112: 3608–3616
7. Jiang BH,Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res,2009,102;19-65
8. Grépin R,Pagès G. The Vascular Endothelial Growth Factor (VEGF):a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol,2009,203;181-192
9. Argyriou AA,Giannopoulou E,Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology,2009,77;1-11
10. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med,2009,87:549-560
11. Zhou WB,Bai M,Jin Y. Diagnostic value of vascular endothelial growth factor and endostatin in malignant pleural effusion. Int J Tuberc Lung Dis,2009,13:381-386
12. Hsu IL,Su WC,Yan JJ,et al. Angiogenetic biomarkers in non-small cell lung cancer with malignant pleural effusion:Correlations with patient survival and pleural effusion control. Lung Cancer,2009,65:371-376
13. Duysinx BC,Corhay JL,Hubin L,et al. Diagnostic value of interleukine-6,transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusion. Respir Med,2008,102:1708-1714
14. Economidou F,Antoniou KM,Tzanakis N,et al. Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusion. Respir Med,2008,102:774-779
15. Shu J,Sun G,Liu H. Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusion. Acta Oncol,2007,46:1004-1011
16. Kaya A,Poyraz B,Celik G,et al. Vascular endothelial growth factor in benign and malignant pleural effusion. Arch Bronconeumol,2005,41:376-379
17. Sack U,Hoffmann M,Zhao XJ,et al. Vascular endothelial growth factor in pleural effusion of different origin. Eur Respir J,2005,25:600-604
18. Hamed EA,El-Noweihi AM,Mohamed AZ,et al. Vasoactive mediators (VEGF and TNF-alpha) in patients with malignant and tuberculous pleural effusion. Respirology,2004,9:81-86
19. Rafajlovski S,Tati? V,Ili? S,et al. Frequency of metastatic tumors in the heart. Vojnosanit Pregl,2005,62:915-920
20. Koga S,Ikeda S,Urata J,et al. Primary high-grade myofibroblastic sarcoma arising from the pericardium. Circ J,2008,72;337-339
1. Folkman J. Tumor angiogenesis: therapeutic implications. NEngl J Med,1971,285:1182-1186
2. O'Reilly MS,Boehm T,Shing Y,et al. an endogenousinhibitor of angiogenesis and tumor growth. Cell,1997,88:277-285
3. Folkman J and Klagsbrun M. Angiogenic factors. Science,1987,235:442-447
4. Namiki A,Brogi E,Kearney M,et al. Hypoxia induces vascular endothelial growth factor in cultured human endo?thelial cells. J Biol Chem,1995,270:31189-95
5. Liao JK,Zulueta JJ,Yu F-S,et al. Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. J Clin Invest,1995,96:2661-66
6. Moreno PR , Purushothaman KR , SirelM et al. Neovascularization in Human Atherosclerosis. Circulation,2006,113:2245– 2252
7.金惠铭,卢建,殷莲华,等.细胞分子病理生理学[M].河南:郑州大学出版社,2002. 267
8. Veikkola T,Karkkainen M,Claesson Welsh,et al. Regulation of anglogenesis via vascular endothelial growth factor receptors[ J ]. Cancer Res,2000,60 (2): 203
9. Salceda S and Caro J. Hypoxia-inducible factor 1α(HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions:its stabilization by hypoxic depends upon redox-induced changes. J Biol Chem,1997, 272: 22642-22647
10. Cockman ME,Masson N,Mole DR,et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem,2000,275: 25733-25741
11. Richard DE,Berra E,Gothie E,et al. p42/p44 mitogen-activated protein kinases phosphorylate hypoxiainducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem,1999,274:32631-32637
12. Semenza GL. Expression of hypoxia inducible factor 1 alpha:mechanisms and consequence [J ]. Biochem Pharmacol,2000,59:47～53
13.左顺庆,王建军,郭家龙.缺氧诱导因子-1α与血管内皮生长因子-C在非小细胞肺癌中的表达及相关性.实用医学杂志,2009,25(1):59-61
14.朱德淳,刘禄成,黄海龙,等.缺氧诱导因子-1及血管内皮生长因子在膀胱癌中的表达及临床意义.中国老年学杂志,2009,29(2):477-478
15.周秋洁,钱群,陶琦,等. HIF-1α、VEGF在家族性息肉病中的表达及相关性研究.武汉大学学报(医学版),2009,30(2):263-268
16. L’Allemaln G. The hypoxia - inducible factor HIF as a new target incancer research[ J ]. Bull Cancer,2002,89 (3):257– 260
17. Tomimoto H,Yano S,Muguruma H,et al. Levels of soluble vascular endothelial growth factor receptor 1 are elevated in the exudative pleural effusions. J Med Invest,2007,54 (1-2):146-153
18.曾艳,刘启功,程燕子,等.血管内皮生长因子在心包积液病因诊断中的价值研究.内科急危重症杂志,2008,14(1):27-28
19. Bianco F,Basini G,Grasselli F. Angiogenic activity of swine,granulosacells:effects of hypoxia and vascular endothelial growth factor trapR IR2,a VEGF blocker [ J ]. Domest Anita Endocrinol,2005,28 (3):308
20. Goldbrunner RH,BendszusM,Wood J,et al. an inhibitor of vascular endothelial growth factor receptor tyrosine kinases,decreases glioma growth and vascularization[ J ]. Neurosurgery,2004,55(2):426
2.刘成加,童步高,徐腊生,等.心包积液206例临床分析.医学文选,2006,25:217-218
3. Cornily JC,Pennec PY,Castellant P,et al. Cardiac tamponade in medical patients:a 10-year follow-up survey. Cardiology,2008,111:197-201
4. Sugiura T,Kumon Y,Kataoka H,et al. Asymptomatic pericardial effusion in patients with rheumatoid arthritis. Cardiology,2008,110:87-91
5. Rapose A,Sarvat B,Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology,2008,110:142-144
6. Mayosi BM,Burgess LJ,Doubell AF. Tuberculous pericarditis. Circulation,2005,112: 3608–3616
7. Jiang BH,Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res,2009,102;19-65
8. Grépin R,Pagès G. The Vascular Endothelial Growth Factor (VEGF):a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol,2009,203;181-192
9. Argyriou AA,Giannopoulou E,Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology,2009,77;1-11
10. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med,2009,87:549-560
11. Zhou WB,Bai M,Jin Y. Diagnostic value of vascular endothelial growth factor and endostatin in malignant pleural effusion. Int J Tuberc Lung Dis,2009,13:381-386
12. Hsu IL,Su WC,Yan JJ,et al. Angiogenetic biomarkers in non-small cell lung cancer with malignant pleural effusion:Correlations with patient survival and pleural effusion control. Lung Cancer,2009,65:371-376
13. Duysinx BC,Corhay JL,Hubin L,et al. Diagnostic value of interleukine-6,transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusion. Respir Med,2008,102:1708-1714
14. Economidou F,Antoniou KM,Tzanakis N,et al. Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusion. Respir Med,2008,102:774-779
15. Shu J,Sun G,Liu H. Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusion. Acta Oncol,2007,46:1004-1011
16. Kaya A,Poyraz B,Celik G,et al. Vascular endothelial growth factor in benign and malignant pleural effusion. Arch Bronconeumol,2005,41:376-379
17. Sack U,Hoffmann M,Zhao XJ,et al. Vascular endothelial growth factor in pleural effusion of different origin. Eur Respir J,2005,25:600-604
18. Hamed EA,El-Noweihi AM,Mohamed AZ,et al. Vasoactive mediators (VEGF and TNF-alpha) in patients with malignant and tuberculous pleural effusion. Respirology,2004,9:81-86
19. Rafajlovski S,Tati? V,Ili? S,et al. Frequency of metastatic tumors in the heart. Vojnosanit Pregl,2005,62:915-920
20. Koga S,Ikeda S,Urata J,et al. Primary high-grade myofibroblastic sarcoma arising from the pericardium. Circ J,2008,72;337-339
1. Xu CS,Wu YB,He T,et al. Etiology of 384 cases with pericardial effusion. Lin Chuang Xin Xue Guan Bing Za Zhi,2008,24: 794-795 (Chinese)
2. Liu CJ,Tong BG,Xu LS,et al. Clinical analysis of 206 cases with pericardial effusion. Yi Xue Wen Xuan,2006,25:217-218 (Chinese)
3. Cornily JC,Pennec PY,Castellant P,et al. Cardiac tamponade in medical patients:a 10-year follow-up survey. Cardiology,2008,111:197-201
4. Sugiura T,Kumon Y,Kataoka H,et al. Asymptomatic pericardial effusion in patients with rheumatoid arthritis. Cardiology,2008,110:87-91
5. Rapose A,Sarvat B,Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology,2008,110:142-144
6. Mayosi BM,Burgess LJ,Doubell AF. Tuberculous pericarditis. Circulation,2005,112: 3608–3616
7. Jiang BH,Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res,2009,102;19-65
8. Grépin R,Pagès G. The Vascular Endothelial Growth Factor (VEGF):a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol,2009,203;181-192
9. Argyriou AA,Giannopoulou E,Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology,2009,77;1-11
10. Fong GH. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med,2009,87:549-560
11. Zhou WB,Bai M,Jin Y. Diagnostic value of vascular endothelial growth factor and endostatin in malignant pleural effusion. Int J Tuberc Lung Dis,2009,13:381-386
12. Hsu IL,Su WC,Yan JJ,et al. Angiogenetic biomarkers in non-small cell lung cancer with malignant pleural effusion:Correlations with patient survival and pleural effusion control. Lung Cancer,2009,65:371-376
13. Duysinx BC,Corhay JL,Hubin L,et al. Diagnostic value of interleukine-6,transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusion. Respir Med,2008,102:1708-1714
14. Economidou F,Antoniou KM,Tzanakis N,et al. Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusion. Respir Med,2008,102:774-779
15. Shu J,Sun G,Liu H. Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusion. Acta Oncol,2007,46:1004-1011
16. Kaya A,Poyraz B,Celik G,et al. Vascular endothelial growth factor in benign and malignant pleural effusion. Arch Bronconeumol,2005,41:376-379
17. Sack U,Hoffmann M,Zhao XJ,et al. Vascular endothelial growth factor in pleural effusion of different origin. Eur Respir J,2005,25:600-604
18. Hamed EA,El-Noweihi AM,Mohamed AZ,et al. Vasoactive mediators (VEGF and TNF-alpha) in patients with malignant and tuberculous pleural effusion. Respirology,2004,9:81-86
19. Rafajlovski S,Tati? V,Ili? S,et al. Frequency of metastatic tumors in the heart. Vojnosanit Pregl,2005,62:915-920
20. Koga S,Ikeda S,Urata J,et al. Primary high-grade myofibroblastic sarcoma arising from the pericardium. Circ J,2008,72;337-339
1. Folkman J. Tumor angiogenesis: therapeutic implications. NEngl J Med,1971,285:1182-1186
2. O'Reilly MS,Boehm T,Shing Y,et al. an endogenousinhibitor of angiogenesis and tumor growth. Cell,1997,88:277-285
3. Folkman J and Klagsbrun M. Angiogenic factors. Science,1987,235:442-447
4. Namiki A,Brogi E,Kearney M,et al. Hypoxia induces vascular endothelial growth factor in cultured human endo?thelial cells. J Biol Chem,1995,270:31189-95
5. Liao JK,Zulueta JJ,Yu F-S,et al. Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. J Clin Invest,1995,96:2661-66
6. Moreno PR , Purushothaman KR , SirelM et al. Neovascularization in Human Atherosclerosis. Circulation,2006,113:2245– 2252
7.金惠铭,卢建,殷莲华,等.细胞分子病理生理学[M].河南:郑州大学出版社,2002. 267
8. Veikkola T,Karkkainen M,Claesson Welsh,et al. Regulation of anglogenesis via vascular endothelial growth factor receptors[ J ]. Cancer Res,2000,60 (2): 203
9. Salceda S and Caro J. Hypoxia-inducible factor 1α(HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions:its stabilization by hypoxic depends upon redox-induced changes. J Biol Chem,1997, 272: 22642-22647
10. Cockman ME,Masson N,Mole DR,et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem,2000,275: 25733-25741
11. Richard DE,Berra E,Gothie E,et al. p42/p44 mitogen-activated protein kinases phosphorylate hypoxiainducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem,1999,274:32631-32637
12. Semenza GL. Expression of hypoxia inducible factor 1 alpha:mechanisms and consequence [J ]. Biochem Pharmacol,2000,59:47～53
13.左顺庆,王建军,郭家龙.缺氧诱导因子-1α与血管内皮生长因子-C在非小细胞肺癌中的表达及相关性.实用医学杂志,2009,25(1):59-61
14.朱德淳,刘禄成,黄海龙,等.缺氧诱导因子-1及血管内皮生长因子在膀胱癌中的表达及临床意义.中国老年学杂志,2009,29(2):477-478
15.周秋洁,钱群,陶琦,等. HIF-1α、VEGF在家族性息肉病中的表达及相关性研究.武汉大学学报(医学版),2009,30(2):263-268
16. L’Allemaln G. The hypoxia - inducible factor HIF as a new target incancer research[ J ]. Bull Cancer,2002,89 (3):257– 260
17. Tomimoto H,Yano S,Muguruma H,et al. Levels of soluble vascular endothelial growth factor receptor 1 are elevated in the exudative pleural effusions. J Med Invest,2007,54 (1-2):146-153
18.曾艳,刘启功,程燕子,等.血管内皮生长因子在心包积液病因诊断中的价值研究.内科急危重症杂志,2008,14(1):27-28
19. Bianco F,Basini G,Grasselli F. Angiogenic activity of swine,granulosacells:effects of hypoxia and vascular endothelial growth factor trapR IR2,a VEGF blocker [ J ]. Domest Anita Endocrinol,2005,28 (3):308
20. Goldbrunner RH,BendszusM,Wood J,et al. an inhibitor of vascular endothelial growth factor receptor tyrosine kinases,decreases glioma growth and vascularization[ J ]. Neurosurgery,2004,55(2):426