HIF-1α、VEGF、CD105在骨肉瘤中的表达及其与血管生成的关系
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摘要
目的探讨缺氧诱导因子-1α(HIF-1α),血管内皮生长因子(VEGF)和CD105在骨肉瘤中的表达及其与血管生成的关系。
方法采用免疫组织化学SP法检测HIF-1α,VEGF和CD105在36例骨肉瘤和10例骨软骨瘤中的表达,并计数CD105标记的微血管密度(MVD),用统计学软件SPSS18.0进行统计学分析。
结果1)骨肉瘤中HIF-1α蛋白的阳性表达率41.7%,HIF-1α在骨软骨瘤中未检测到表达。2)骨肉瘤中VEGF蛋白的阳性表达率为63.9%,VEGF在骨软骨瘤中未检测到表达。3)骨肉瘤MVD值显著高于骨软骨瘤MVD值(P<0.05)。4)骨肉瘤Ⅲ期(有转移组)HIF-1α蛋白阳性表达率与Ⅰ、Ⅱ期(无转移组)相比明显升高,有统计学显著性差异(P<0.05)。5)骨肉瘤Ⅲ期(有转移组)VEGF蛋白阳性表达率与Ⅰ、Ⅱ期(无转移组)相比明显升高,有统计学显著性差异(P<0.05)。6)在骨肉瘤外科分期中,Ⅲ期MVD值显著高于Ⅱ期MVD值,Ⅱ期MVD值显著高于Ⅰ期,有统计学显著性差异(P<0.05)。7)在骨肉瘤中,HIF-1α蛋白与VEGF蛋白的表达呈正相关(rs=0.737,P<0.01),HIF-1α蛋白表达与MVD呈正相关(rs=0.556,P<0.01),VEGF蛋白表达与MVD呈正相关(rs=0.778,P<0.01)。
结论
(1)HIF-1α和VEGF在骨肉瘤中高表达,有转移组骨肉瘤中HIF-1α、VEGF的表达均高于无转移组,和骨肉瘤的侵润转移密切相关。
(2)HIF-1α在骨软骨瘤中不表达,在骨肉瘤中高表达,有可能作为判断骨肿瘤良恶性的潜在标志物。
(3)骨肉瘤中HIF-1α蛋白的表达和VEGF蛋白表达呈正相关,HIF-1α蛋白阳性表达和MVD正相关,VEGF蛋白阳性表达和MVD正相关,提示在骨肉瘤中HIF-1α可能主要通过VEGF途径促进肿瘤血管生成,在骨肉瘤发展中起重要作用,抑制其表达可能成为抗肿瘤血管生成的新靶点。
Objective To investigate the hypoxia-inducible factor-la (HIF-1α), vascular endothelial growth factor (VEGF) and CD 105 expression in osteosarcoma and their relationship with angiogenesis.
Methods Immunohistochemical method (SP) was applied to detected the expressions of HIF-1α, VEGF and CD 105 were detected in 36 cases of human osteosarcoma specimen and 10 cases of osteochondroma. We counted microvessel density(MVD) calculated CD105,then used SPSS 18.0 statistics software for analysis.
Results 1)HIF-1αprotein expression rate was 41.7% in osteosarcoma, the expression of HIF-1αin osteochondroma was not detected.2) VEGF protein expression rate was 63.9% in Osteosarcoma, the expression of VEGF in osteochondroma was not detected.3)The MVD value of osteosarcoma were significantly higher than that of osteochondroma(P<0.05).4) the expression of osteosarcoma HIF-1αprotein inⅢperiod (metastasis group) was significantly higher than that inⅠ,Ⅱperiod (without metastasis) with statistically significant difference (P<0.05).5) the expression of osteosarcoma VEGF protein inⅢperiod (metastasis group) was significantly higher than that inⅠ,Ⅱperiod (without metastasis) with statistically significant difference (P<0.05).6) The MVD value of osteosarcoma in III period was significantly higher than that in II period(P<0.05).The MVD value of osteosarcoma inⅡperiod was significantly higher than that in I period (P<0.05).7) The expression of HIF-la protein and VEGF protein in osteosarcoma was positively correlated(rs=0.737, P<0.01). The expression of HIF-1αprotein and MVD value in osteosarcoma was positively correlated(rs =0.556, P<0.01). The expression of HIF-la protein and MVD value in osteosarcoma was positively correlated(rs=0.778, P<0.01).
Conclusions
(1)The proteins of HIF-1αand VEGF had a high expression in osteosarcoma, the expression of HIF-1α, VEGF in Osteosarcoma with metastasis were higher than those without metastasis, which might be involved into the infiltration and metastasis of osteosarcoma.
(2)HIF-la is not expressed in osteochondroma but highly expressed in osteosarcoma, it may be a a new marker to judge the potential of benign and malignant bone tumor.
(3)The expression of HIF-1αprotein was positively correlated with that of VEGF protein, the expression of HIF-la protein was positively correlated with MVD, the expression of VEGF protein was positively correlated with MVD, Which verificating HIF-la played an important role in the building of osteosarcomas blood vesse] by depending on the expression of VEGF. So it may be a new target for the inhibition of angiogenesis is by restraining the expression of HIF-1α.
方法采用免疫组织化学SP法检测HIF-1α,VEGF和CD105在36例骨肉瘤和10例骨软骨瘤中的表达,并计数CD105标记的微血管密度(MVD),用统计学软件SPSS18.0进行统计学分析。
结果1)骨肉瘤中HIF-1α蛋白的阳性表达率41.7%,HIF-1α在骨软骨瘤中未检测到表达。2)骨肉瘤中VEGF蛋白的阳性表达率为63.9%,VEGF在骨软骨瘤中未检测到表达。3)骨肉瘤MVD值显著高于骨软骨瘤MVD值(P<0.05)。4)骨肉瘤Ⅲ期(有转移组)HIF-1α蛋白阳性表达率与Ⅰ、Ⅱ期(无转移组)相比明显升高,有统计学显著性差异(P<0.05)。5)骨肉瘤Ⅲ期(有转移组)VEGF蛋白阳性表达率与Ⅰ、Ⅱ期(无转移组)相比明显升高,有统计学显著性差异(P<0.05)。6)在骨肉瘤外科分期中,Ⅲ期MVD值显著高于Ⅱ期MVD值,Ⅱ期MVD值显著高于Ⅰ期,有统计学显著性差异(P<0.05)。7)在骨肉瘤中,HIF-1α蛋白与VEGF蛋白的表达呈正相关(rs=0.737,P<0.01),HIF-1α蛋白表达与MVD呈正相关(rs=0.556,P<0.01),VEGF蛋白表达与MVD呈正相关(rs=0.778,P<0.01)。
结论
(1)HIF-1α和VEGF在骨肉瘤中高表达,有转移组骨肉瘤中HIF-1α、VEGF的表达均高于无转移组,和骨肉瘤的侵润转移密切相关。
(2)HIF-1α在骨软骨瘤中不表达,在骨肉瘤中高表达,有可能作为判断骨肿瘤良恶性的潜在标志物。
(3)骨肉瘤中HIF-1α蛋白的表达和VEGF蛋白表达呈正相关,HIF-1α蛋白阳性表达和MVD正相关,VEGF蛋白阳性表达和MVD正相关,提示在骨肉瘤中HIF-1α可能主要通过VEGF途径促进肿瘤血管生成,在骨肉瘤发展中起重要作用,抑制其表达可能成为抗肿瘤血管生成的新靶点。
Objective To investigate the hypoxia-inducible factor-la (HIF-1α), vascular endothelial growth factor (VEGF) and CD 105 expression in osteosarcoma and their relationship with angiogenesis.
Methods Immunohistochemical method (SP) was applied to detected the expressions of HIF-1α, VEGF and CD 105 were detected in 36 cases of human osteosarcoma specimen and 10 cases of osteochondroma. We counted microvessel density(MVD) calculated CD105,then used SPSS 18.0 statistics software for analysis.
Results 1)HIF-1αprotein expression rate was 41.7% in osteosarcoma, the expression of HIF-1αin osteochondroma was not detected.2) VEGF protein expression rate was 63.9% in Osteosarcoma, the expression of VEGF in osteochondroma was not detected.3)The MVD value of osteosarcoma were significantly higher than that of osteochondroma(P<0.05).4) the expression of osteosarcoma HIF-1αprotein inⅢperiod (metastasis group) was significantly higher than that inⅠ,Ⅱperiod (without metastasis) with statistically significant difference (P<0.05).5) the expression of osteosarcoma VEGF protein inⅢperiod (metastasis group) was significantly higher than that inⅠ,Ⅱperiod (without metastasis) with statistically significant difference (P<0.05).6) The MVD value of osteosarcoma in III period was significantly higher than that in II period(P<0.05).The MVD value of osteosarcoma inⅡperiod was significantly higher than that in I period (P<0.05).7) The expression of HIF-la protein and VEGF protein in osteosarcoma was positively correlated(rs=0.737, P<0.01). The expression of HIF-1αprotein and MVD value in osteosarcoma was positively correlated(rs =0.556, P<0.01). The expression of HIF-la protein and MVD value in osteosarcoma was positively correlated(rs=0.778, P<0.01).
Conclusions
(1)The proteins of HIF-1αand VEGF had a high expression in osteosarcoma, the expression of HIF-1α, VEGF in Osteosarcoma with metastasis were higher than those without metastasis, which might be involved into the infiltration and metastasis of osteosarcoma.
(2)HIF-la is not expressed in osteochondroma but highly expressed in osteosarcoma, it may be a a new marker to judge the potential of benign and malignant bone tumor.
(3)The expression of HIF-1αprotein was positively correlated with that of VEGF protein, the expression of HIF-la protein was positively correlated with MVD, the expression of VEGF protein was positively correlated with MVD, Which verificating HIF-la played an important role in the building of osteosarcomas blood vesse] by depending on the expression of VEGF. So it may be a new target for the inhibition of angiogenesis is by restraining the expression of HIF-1α.
引文
[1]Marx J. How Cells Endure Low Oxygen[J]. Science,2004,303(5663):1454-1456
[2]Semenza GL, Agani F, Booth G, et al. structural and functional analysis of hypoxia-inducible factor 1[J].Kidney Int.1997,51(2):553-555
[3]Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc Natl Acad Sci USA,1995,92:5510-5514
[4]Adams JM, Difazio LT, Rolandelli RH, et al. HIF-1:a key mediator in hypoxia[J]. Acta Physiologica Hungarica,2009,96(1):19-28
[5]Jang MS, Park JE, et al. Binding and regulation of hypoxia-inducible factor-1 by the inhibitory PAS proteins. BBRC,2005,337(1):209-215
[6]Chan DA, Sutphin PD, Denko NC, et al. Role of poly hydroxylation in oncogenically stabilized hypoxia-inducible factor-la[J]. Biol Chem,2002,277 (42):40112-40117
[7]Semenza GL. Targeting HIF-1 for cancer therapy[J]. Nat Rev Cancer,2003, 3(10):721-732
[8]Lee JW, Bae SH, Jeong J W, et al. Hypoxia-inducible factor(HIF-1)alpha:its protein stability and biological functions[J]. Exp Mol Med,2004,36(1):1-12
[9]Folkman J, Klagsburn M. Angiogenic factors[J]. Science,1987,235:442-447
[10]Kumar S, Ghellal A, Li C, et al. Breast carcinoma:vascular density determined using CD105 antibody correlates with tumor prognosis[J]. Cancer Res.1999, 59(4):856-861
[11]Hiroo Mizobuchi MD, et al. Hypoxia Markers in Human Osteosarcoma:An Exploratory Study[J]. Clin Orthop Relat Res.2008,466(9):2052-2059
[12]Chen WL, Feng HJ, Li HG. Expression and significance of hypoxemia-inducible factor-1alpha in osteosarcoma of the jaws[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2008,106(2):254-257
[13]Postiglione L, Di Domenico G, Caraglia M, et al. Differential expression and cytoplasm/membrane distribution of endoglin (CD 105) in human tumour cell lines:Implications in the modulation of cell proliferation[J]. Int J Oncol.2005, 26(5):1193-1201
[14]Zhong H, De Marzo AM, Laughner E, et al. Overexpresion of hypoxia-inducible factor 1 in common human cancer and their metastases[J]. Cancer Res.1999,59(22):5830-5835
[15]Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumor cell proliferation in human epidermoid lung carcinoma. Br J Cancer,1996, 73(7):931-934
[16]Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent prognostic indicator in early-stage breast carcinoma[J]. J Natl Cancer Inst.1992,84(24):1875-1887
[17]Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation [J]. Mol Cell Biol,1992,12(12):5447-5454
[18]Semenza GL, HIF-1 Mediator of physiological and pathophysiological response to hypoxia[J]. Appl Physiol.2000,2(88):1474-1480
[19]Salceda S, CaroJ. Hypoxia-inducible factor lalpha (HIF-lalpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions.Its stabilization by hypoxia depends on redox-induced changes[J]. J Biol Chem,1999, 272(36):22642-22647
[20]Semenza GL. Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology.2004,19:176-182
[21]Viger A, Dervan PB. Exploring the limits of benzimidazole DNA-binding oligomers for the hypoxia inducible factor(HIF) site. Bioorg Med Chem.2006, 14(24):8539-8549
[22]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1Γ and HIF-2Γ in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol,2000,157:411-421
[23]Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics[J]. Oncogene,2010,29(5):625-634
[24]樊利芳,刁路明,陈德基.缺氧诱导因子1与肿瘤.中华病理学杂志2002,31(2)：168-170
[25]Rohwer N, Lobitz S, Daskalow K, et al. HIF-la determines the metastatic potential of gastric cancer cells[J]. Br J Cancer.2009,100(5):772-781
[26]Talks KL, Turley H, et al. hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues,cancers,and tumor-associated macrophages[J]. Am J Pathol.2000,157(2):411-421
[27]龚玲玲,吴卉娟等.子宫颈癌组织中缺氧诱导因子1α蛋白的表达及其与血管生成的关系[J].中华妇产科杂志.2004,39(11)：779-780
[28]Birner P, Sehindl M, Obermair A, et al. Overexpresion of hypoxia-inducible factor 1 alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer[J]. Cancer Res.2000,60(17):4693-4696
[29]Dan Cao, Mei Hou, et al. Expression of HIF-1alpha and VEGF in colorectal cancer:association with clinical outcomes and prognostic implications[J]. BMC Cancer.2009,9:432
[30]Geng-Wen Huang,Lian-Yue Yang.Wei-Qun Lu. Expression of hypoxia-inducible factor la and vascular endothelial growth factor in hepatocellular carcinoma:Impact on neovascularization and survival[J]. World J Gastroenterol.2005,11(11):1705-1708
[31]Ferrara N, Henzel WJ. Pituitary Follicular cells secrete a novel heparin binding growth factor specific for vascular endothelial cells [J]. Biochem Biophys Res Commun.1989,161(2):851-859
[32]Pradeep CR, Sunila ES, Kuttan G. Expression of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptors in Tumor Angiogenesis and Malignancies[J]. Integr Cancer Ther.2005.4(4):315-321
[33]Adams J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer:comparison of plasma, serum, and tissue VEGF and micro vessel density and effects of tamoxifen[J]. Cancer Res.2000, 60:2989-2905
[34]Cascinu S, Staccioli MP, Gasparini G, et al. Expression of Vascular Endothelial Growth Factor Can Predict Event-free Survival in Stage II Colon Cancer[J]. Clin Cancer Res.2000,6(7):2803-2807
[35]Li C, Guo B, Wilson PB, et al. Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer[J]. Int J Cancer.2000.89(2):122-126
[36]Joanna W. Ho Ronnie T. Poon Chris K. Sun, et al. Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver[J]. World J Gastroenterol.2005, 11(2):176-181
[37]Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia:role of the HIF system. Nat M ed.2003,9(6):677-684
[38]Griffiths EA, Pritchard SA, et al. Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer.2005,41(18):2792-2805
[39]Yang QC, Zeng BF, Dong Y, et al. Overexpression of Hypoxia-inducible factor-1alpha in human osteosarcoma:correlation with clinicopathological parameters and survival outcome [J]. Jpn J Clin Oncol.2007,37(2):127-134
[40]Ding L, Chen X, Jing K, et al. Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter[J]. J Huazhong Univ Sci Technolog Med Sci.2006, 26(1):75-78
[41]Bryant CS, Munkarah AR, Kumar S, et al. Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1 alpha gene expression [J]. Arch Gynecol Obstet.2010 Feb 7
[42]Wellmann S, Buhrer C, Moderegger E, et al. Oxygen-regulated expression of the RNA-bingding proteins RBM3 and CIRP by a HIF-1-independent mechanism [J]. J Cell Sci.2004,117(Pt9):1785-1794
[43]赵宇,邱贵兴.骨肉瘤微血管密度与血管内皮生长因子表达的关系[J].中国医学科学院学报.2001.23(6)：619-622
[44]Mabjeesh NJ, Escuin DL, LaVallee TM, et al.2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF [J]. Cancer Cell. 2003,3(4):363-375
[45]Yang QC, Zeng BF, Shi ZM, et al. Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma[J]. J Exp Clin Cancer Res.2006,25(4):593-599
[46]Ratclife PJ,Pugh CW,Maxwell PH. Targeting tumors through the HIF system [J]. Nat Med,2000,6(12):1315-1316
[47]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription [J]. Nat Med.2000, 6(12):1335-1340
[1]Marx J.How Cells Endure Low Oxygen[J].Science,2004,303(5663):1454-1456
[2]Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia[J]. Angiogenesis,2008,11 (2):121-140
[3]Semenza GL,Wang GL.A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation[J]. Mol Cell Biol,1992,12(12):5447-5454
[4]Semenza GL,Agani F,Booth G,et al. structural and functional analysis of hypoxia-inducible factor 1[J]. Kidney Int.1997,51(2):553-555
[5]Wang GL,Jiang BH,Rue EA,et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc Natl Acad Sci USA,1995,92:5510-5514
[6]Adams JM,Difazio LT,Rolandelli RH,et al.HIF-1:a key mediator in hypoxia[J]. Acta Physiologica Hungarica,2009,96(1):19-28
[7]Hickey MM,Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors [J].Curr Top Dev Biol.2006,76:217-257
[8]Jang MS,Park JE,et al.Binding and regulation of hypoxia-inducible factor-1 by the inhibitory PAS proteins.BBRC,2005,337(1):209-215
[9]Aebersold DM,Burri P,Beer KT,et al. Expression of hypoxia-inducible faetor-la: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal caner[J]. Cancer Res.2001,61 (10):2911-2916
[10]Semenza GL.Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology.2004,19:176-182
[11]Pan Y,Mansfield KD,Bertozzi CC,et al.Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor Prolyl hydroxylase activity in vivo and in vitro[J].Mol Cell Biol.2007,27(3):912-925
[12]Salceda S,CaroJ.Hypoxia-inducible factor lalpha (HIF-lalpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions.Its stabilization by hypoxia depends on redox-induced changes[J].J Biol Chem,1999, 272(36):22642-22647
[13]Kallio PJ,Pongratz I,Gradin K,McGuire J,Poellinger L.Activation of hypoxia inducible factor-la:posttranscriptional regulation and conformational change by recruitment of thearnt transcription factor[J]. Proc Natl Acad Sci USA,1997, 94(11);5667-5672
[14]Bae SH,Jeong JW,et al.Sumoylation increases HIF-la stability and its transcriptional activity[J]. BBRC,2004,324(1):394-400
[15]Evans SM,Koch CJ.Prognostic significance of tumor oxygenation in humans[J]. Cancer Letters.2003,195(1):1-16
[16]Jiang BH,Senenza GL,et al.Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of 02 tension[J]. AJP-Cell Physiology,1996,271(4):C1172-C118
[17]Yong-Hong Shi,Wei-Gang Fang. Hypoxia-inducible factor-1 in tumour angiogenesis. World J ournal of Gastroenterology.2004,10(8):1082-1087
[18]Hammond EM,Giaccia AJ. Hypoxia-inducible factor-1 and p53: friends,acquaintances,or strangers?[J]. Clin Cancer Res.2006,12 (17):5007-5009
[19]Hon WC,Wilson MI,Harlos K,et al.Structural basis for the recognition of hydroxyproline in HIF-la by pVHL[J].Nature,2002,417 (6892):975-978
[20]彭再梅,山长婷,王惠芳.肺癌组织中VHL和HIF-1α表达及其临床意义[J].中南大学学报(医学版).2009,34(4)：331-334
[21]Zhong H,Chiles K,Feldser D,et al. Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal gowth factor/phosphatidylinositol3-kinase /PTEN/AKT/FRAP pathway in human prostate cancer cells:Implications for tumors angiogenesis and therapeutics [J]. Cancer Res.2000,60(6):1541-1545
[22]Jiang BH,Agani F,Passaniti A,et al. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1 involvement of HIF-1 in tumor progression[J]. Cancer Res,1997,57 (23):5328-5335
[23]Fukuda R,Hirota K,Fan F,et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1 mediated vascular endothelial growth factor expression, Which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells [J].J Biol Chem.2002,277(41):38205-38211
[24]Schumacker PT.Hypoxia-inducible factor-1 (HIF-1)[J]. Critical Care Medicine. 2005,33(12)423-425
[25]Daskalow K,Rohwer N, et al. Role of hypoxia-inducible transcription factor 1α for progression and chemosensitivity of murine hepatocellular carcinoma. Journal of Molecular Medicine.2010, Apr 12
[26]Baba Y,Nosho K, et al. HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers.Am J Pathol.2010,Apr 2
[27]Ding Z,Yang L,et al. Expression and significance of hypoxia-inducible factor-1 alpha and MDRl/P-glycoprotein in human colon carcinoma tissue and cells.J Cancer Res Clin Oncol.2010,Mar 9
[28]Brahimi-Horn MC,Pouyssegur J.Harnessing the hypoxia-inducible factor in cancer and ischemic disease[J].Biochem Pharmacol.2007,73(3):450-457
[29]Semenza GL.Targeting HIF-1 for cancer therapy [J].Nat Rev Cancer,2003, 3(10):721-732
[30]Lee JW,Bae SH,Jeong J W,et al.Hypoxia-inducible factor(HIF-1)alpha:its protein stability and biological functions[J].Exp Mol Med,2004,36(1):1-12
[31]Viger A,Dervan PB.Exploring the limits of benzimidazole DNA-binding oligomers for the hypoxia inducible factor(HIF) site.Bioorg Med Chem.2006, 14(24):8539-8549
[32]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1 and HIF-2 in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000;157:411-21
[33]Semenza GL.Defining the role of hypoxia-inducible factor 1 in cancer biologyand therapeutics[J]. Oncogene,2010,29(5):625-634
[34]Zhong H,De Marzo AM,Laughner E,et al. Overexpresion of hypoxia-inducible factor 1 in common human cancer and their metastases[J]. Cancer Res.1999, 59(22):5830-5835
[35]Rohwer N,Lobitz S,Daskalow K, et al. HIF-1α determines the metastatic potential of gastric cancer cells[J]. Br J Cancer.2009,100(5):772-781
[36]Talks KL,Turley H,et al.hypoxia-inducible factors HIF-1 alpha and HIF-2alpha in normal human tissues,cancers,and tumor-associated macrophages [J]. Am J Pathol.2000,157(2):411-421
[37]Hiroo Mizobuchi MD,et al.Hypoxia Markers in Human Osteosarcoma:An Exploratory Study [J]. Clin Orthop Relat Res.2008,466(9):2052-2059
[38]龚玲玲,吴卉娟等.子宫颈癌组织中缺氧诱导因子1α蛋白的表达及其与血管生成的关系[J].中华妇产科杂志.2004,39(11)：779-780
[39]Birner P,Sehindl M,Obermair A,et al. Overexpresion of hypoxia-inducible factor 1 alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer[J]. Cancer Res.2000,60(17):4693-4696
[40]Chaudary N,Hill RP. Hypoxia and metastasis in breast cancer[J]. Breast Dis. 2006-2007,26:55-64
[41]Dan Cao,Mei Hou,et al. Expression of HIF-1 alpha and VEGF in colorectal cancer:association with clinical outcomes and prognostic implications[J]. BMC Cancer.2009,9:432
[42]Geng-Wen Huang,Lian-Yue Yang,Wei-Qun Lu. Expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in hepatocellular carcinoma:Impact on neovascularization and survival[J]. World J Gastroenterol.2005, 11(11):1705-1708
[43]Aebersold DM, Burri P, Beer KT, et al. Expression of hypoxia-inducible factor-la:a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer[J]. Cancer Res.2001,61(7):2911-2916
[44]Koukourakis MI, Giatromanolaki A,Sivridis E, et al. Hypoxia-inducible factor(HIF1a and HIF-2a),angiogenesis,and chemoradiotherapy outome of squamous cell head-and-neck cancer[J]. Int J Radiat Oncol Biol Phys.2002, 53(5):1192-1202
[45]Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation[J]. Nature.2000,407(6801):242-248
[46]Pugh CW,Ratcliffe PJ. Regulation of angiogenesis by hypoxia:role of the HIF system. Nat M ed.2003, (6):677-684
[47]Aragones J,Schneider M,Van Geyte K,et al. Deficiency or inhibition of oxygen sensor Phdl induces hypoxia tolerance by reprogramming basal metabolism[J]. Nat Genet,2008,40(2):170-80
[48]Liang WC, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006,281(2):951-961
[49]Berra E, Pages G, Pouyssegur J. MAP kinases and hypoxia in the control of VEGF express[J]. Cancer and Metastasis Reviews,2000,19(1-2):139-145
[50]Lang KJ,Kappel A,Goodall GJ. Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia[J]. Mol Biol Cell.2002,13(5):1792-801
[51]Kim HJ,Chung H,Yoo YG,et al. Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha[J]. Mol Cancer Res.2007,5(4):321-329
[52]Plouet J, Moro F, Bertagnolli S, et al. Extracelluar cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect[J]. J Biol Chem.1997,272:13390-13396
[53]Harris AL. Hypoxia:a key regulatory factor in tumor growth. Nature Reviews Cancer.2002;2:38-47
[54]Griffiths EA, Pritchard SA, et al. Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer.2005,41(18):2792-2805
[55]Yang QC, Zeng BF, Dong Y, et al. Overexpression of Hypoxia-inducible factor-1alpha in human osteosarcoma:correlation with clinicopathological parameters and survival outcome [J]. Jpn J Clin Oncol.2007,37(2):127-134
[56]Zhong H,Agani F,Baccala AA,et al. Increased expression of hypoxia inducible factor-1 in rat and human prostate cancer [J]. Cancer Res.1998, 58(23):5280-5284
[57]Dorevic G, Matusan-llijas K, Babarovic E,et al. Hypoxia inducible factor-1 alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma[J]. J Exp Clin Cancer Res.2009,28(1):40-47
[58]Ding L,Chen X,Jing K,et al. Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter[J].J Huazhong Univ Sci Technolog Med Sci.2006,26(1):75-78
[59]Bryant CS, Munkarah AR, Kumar S,et al. Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1 alpha gene expression[J]. Arch Gynecol Obstet.2010 Feb 7
[60]Wellmann S, Buhrer C, Moderegger E, et al. Oxygen-regulated expression of the RNA-bingding proteins RBM3 and CIRP by a HIF-1-independent mechanism [J]. J Cell Sci.2004,117(Pt 9):1785-1794
[61]Cook-Johnson RJ, Demasi M, Cleland LG, et al. Endothelial cell COX-2 expression and activity in hypoxia[J]. Biochim Biophys Acta.2006, 1761(12):1443-1449
[62]Kaidi A, Qualtrough D, Williams AC, et al. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia[J]. Cancer Res,,2006,66:6683-6691
[63]Daneau G, Boidot R, Martinive P, et al. Identification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia:effect on angiogenesis and metastases[J]. Clin Cancer Res.2010, 16(2):410-419
[64]Mabjeesh NJ, Escuin DL, LaVallee TM, et al.2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF [J]. Cancer Cell. 2003,3(4):363-375
[65]Ricker JL,Chen Z,Yang XP,et al.2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma [J]. Clin Cancer Res.2004, 10(4):8665-8673
[66]Yang QC, Zeng BF, Shi ZM, et al. Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma[J]. J Exp Clin Cancer Res.2006,25(4):593-599
[67]Ratclife PJ,Pugh CW,Maxwell PH. Targeting tumors through the HIF system [J]. Nat Med,2000,6(12):1315-1316
[68]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription [J]. Nat Med.2000, 6(12):1335-1340
[69]Welsh S,Williams R,Kirkpatrick L,et al. Antitumor activity and pharrmacodynamic properties of Px-478, an inhibitor of hypoxia-inducible factor-1alpha [J]. Mol Cancer Ther.2004,3(3):233-244
[2]Semenza GL, Agani F, Booth G, et al. structural and functional analysis of hypoxia-inducible factor 1[J].Kidney Int.1997,51(2):553-555
[3]Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc Natl Acad Sci USA,1995,92:5510-5514
[4]Adams JM, Difazio LT, Rolandelli RH, et al. HIF-1:a key mediator in hypoxia[J]. Acta Physiologica Hungarica,2009,96(1):19-28
[5]Jang MS, Park JE, et al. Binding and regulation of hypoxia-inducible factor-1 by the inhibitory PAS proteins. BBRC,2005,337(1):209-215
[6]Chan DA, Sutphin PD, Denko NC, et al. Role of poly hydroxylation in oncogenically stabilized hypoxia-inducible factor-la[J]. Biol Chem,2002,277 (42):40112-40117
[7]Semenza GL. Targeting HIF-1 for cancer therapy[J]. Nat Rev Cancer,2003, 3(10):721-732
[8]Lee JW, Bae SH, Jeong J W, et al. Hypoxia-inducible factor(HIF-1)alpha:its protein stability and biological functions[J]. Exp Mol Med,2004,36(1):1-12
[9]Folkman J, Klagsburn M. Angiogenic factors[J]. Science,1987,235:442-447
[10]Kumar S, Ghellal A, Li C, et al. Breast carcinoma:vascular density determined using CD105 antibody correlates with tumor prognosis[J]. Cancer Res.1999, 59(4):856-861
[11]Hiroo Mizobuchi MD, et al. Hypoxia Markers in Human Osteosarcoma:An Exploratory Study[J]. Clin Orthop Relat Res.2008,466(9):2052-2059
[12]Chen WL, Feng HJ, Li HG. Expression and significance of hypoxemia-inducible factor-1alpha in osteosarcoma of the jaws[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2008,106(2):254-257
[13]Postiglione L, Di Domenico G, Caraglia M, et al. Differential expression and cytoplasm/membrane distribution of endoglin (CD 105) in human tumour cell lines:Implications in the modulation of cell proliferation[J]. Int J Oncol.2005, 26(5):1193-1201
[14]Zhong H, De Marzo AM, Laughner E, et al. Overexpresion of hypoxia-inducible factor 1 in common human cancer and their metastases[J]. Cancer Res.1999,59(22):5830-5835
[15]Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumor cell proliferation in human epidermoid lung carcinoma. Br J Cancer,1996, 73(7):931-934
[16]Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent prognostic indicator in early-stage breast carcinoma[J]. J Natl Cancer Inst.1992,84(24):1875-1887
[17]Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation [J]. Mol Cell Biol,1992,12(12):5447-5454
[18]Semenza GL, HIF-1 Mediator of physiological and pathophysiological response to hypoxia[J]. Appl Physiol.2000,2(88):1474-1480
[19]Salceda S, CaroJ. Hypoxia-inducible factor lalpha (HIF-lalpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions.Its stabilization by hypoxia depends on redox-induced changes[J]. J Biol Chem,1999, 272(36):22642-22647
[20]Semenza GL. Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology.2004,19:176-182
[21]Viger A, Dervan PB. Exploring the limits of benzimidazole DNA-binding oligomers for the hypoxia inducible factor(HIF) site. Bioorg Med Chem.2006, 14(24):8539-8549
[22]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1Γ and HIF-2Γ in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol,2000,157:411-421
[23]Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics[J]. Oncogene,2010,29(5):625-634
[24]樊利芳,刁路明,陈德基.缺氧诱导因子1与肿瘤.中华病理学杂志2002,31(2)：168-170
[25]Rohwer N, Lobitz S, Daskalow K, et al. HIF-la determines the metastatic potential of gastric cancer cells[J]. Br J Cancer.2009,100(5):772-781
[26]Talks KL, Turley H, et al. hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues,cancers,and tumor-associated macrophages[J]. Am J Pathol.2000,157(2):411-421
[27]龚玲玲,吴卉娟等.子宫颈癌组织中缺氧诱导因子1α蛋白的表达及其与血管生成的关系[J].中华妇产科杂志.2004,39(11)：779-780
[28]Birner P, Sehindl M, Obermair A, et al. Overexpresion of hypoxia-inducible factor 1 alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer[J]. Cancer Res.2000,60(17):4693-4696
[29]Dan Cao, Mei Hou, et al. Expression of HIF-1alpha and VEGF in colorectal cancer:association with clinical outcomes and prognostic implications[J]. BMC Cancer.2009,9:432
[30]Geng-Wen Huang,Lian-Yue Yang.Wei-Qun Lu. Expression of hypoxia-inducible factor la and vascular endothelial growth factor in hepatocellular carcinoma:Impact on neovascularization and survival[J]. World J Gastroenterol.2005,11(11):1705-1708
[31]Ferrara N, Henzel WJ. Pituitary Follicular cells secrete a novel heparin binding growth factor specific for vascular endothelial cells [J]. Biochem Biophys Res Commun.1989,161(2):851-859
[32]Pradeep CR, Sunila ES, Kuttan G. Expression of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptors in Tumor Angiogenesis and Malignancies[J]. Integr Cancer Ther.2005.4(4):315-321
[33]Adams J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer:comparison of plasma, serum, and tissue VEGF and micro vessel density and effects of tamoxifen[J]. Cancer Res.2000, 60:2989-2905
[34]Cascinu S, Staccioli MP, Gasparini G, et al. Expression of Vascular Endothelial Growth Factor Can Predict Event-free Survival in Stage II Colon Cancer[J]. Clin Cancer Res.2000,6(7):2803-2807
[35]Li C, Guo B, Wilson PB, et al. Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer[J]. Int J Cancer.2000.89(2):122-126
[36]Joanna W. Ho Ronnie T. Poon Chris K. Sun, et al. Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver[J]. World J Gastroenterol.2005, 11(2):176-181
[37]Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia:role of the HIF system. Nat M ed.2003,9(6):677-684
[38]Griffiths EA, Pritchard SA, et al. Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer.2005,41(18):2792-2805
[39]Yang QC, Zeng BF, Dong Y, et al. Overexpression of Hypoxia-inducible factor-1alpha in human osteosarcoma:correlation with clinicopathological parameters and survival outcome [J]. Jpn J Clin Oncol.2007,37(2):127-134
[40]Ding L, Chen X, Jing K, et al. Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter[J]. J Huazhong Univ Sci Technolog Med Sci.2006, 26(1):75-78
[41]Bryant CS, Munkarah AR, Kumar S, et al. Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1 alpha gene expression [J]. Arch Gynecol Obstet.2010 Feb 7
[42]Wellmann S, Buhrer C, Moderegger E, et al. Oxygen-regulated expression of the RNA-bingding proteins RBM3 and CIRP by a HIF-1-independent mechanism [J]. J Cell Sci.2004,117(Pt9):1785-1794
[43]赵宇,邱贵兴.骨肉瘤微血管密度与血管内皮生长因子表达的关系[J].中国医学科学院学报.2001.23(6)：619-622
[44]Mabjeesh NJ, Escuin DL, LaVallee TM, et al.2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF [J]. Cancer Cell. 2003,3(4):363-375
[45]Yang QC, Zeng BF, Shi ZM, et al. Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma[J]. J Exp Clin Cancer Res.2006,25(4):593-599
[46]Ratclife PJ,Pugh CW,Maxwell PH. Targeting tumors through the HIF system [J]. Nat Med,2000,6(12):1315-1316
[47]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription [J]. Nat Med.2000, 6(12):1335-1340
[1]Marx J.How Cells Endure Low Oxygen[J].Science,2004,303(5663):1454-1456
[2]Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia[J]. Angiogenesis,2008,11 (2):121-140
[3]Semenza GL,Wang GL.A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation[J]. Mol Cell Biol,1992,12(12):5447-5454
[4]Semenza GL,Agani F,Booth G,et al. structural and functional analysis of hypoxia-inducible factor 1[J]. Kidney Int.1997,51(2):553-555
[5]Wang GL,Jiang BH,Rue EA,et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc Natl Acad Sci USA,1995,92:5510-5514
[6]Adams JM,Difazio LT,Rolandelli RH,et al.HIF-1:a key mediator in hypoxia[J]. Acta Physiologica Hungarica,2009,96(1):19-28
[7]Hickey MM,Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors [J].Curr Top Dev Biol.2006,76:217-257
[8]Jang MS,Park JE,et al.Binding and regulation of hypoxia-inducible factor-1 by the inhibitory PAS proteins.BBRC,2005,337(1):209-215
[9]Aebersold DM,Burri P,Beer KT,et al. Expression of hypoxia-inducible faetor-la: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal caner[J]. Cancer Res.2001,61 (10):2911-2916
[10]Semenza GL.Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology.2004,19:176-182
[11]Pan Y,Mansfield KD,Bertozzi CC,et al.Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor Prolyl hydroxylase activity in vivo and in vitro[J].Mol Cell Biol.2007,27(3):912-925
[12]Salceda S,CaroJ.Hypoxia-inducible factor lalpha (HIF-lalpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions.Its stabilization by hypoxia depends on redox-induced changes[J].J Biol Chem,1999, 272(36):22642-22647
[13]Kallio PJ,Pongratz I,Gradin K,McGuire J,Poellinger L.Activation of hypoxia inducible factor-la:posttranscriptional regulation and conformational change by recruitment of thearnt transcription factor[J]. Proc Natl Acad Sci USA,1997, 94(11);5667-5672
[14]Bae SH,Jeong JW,et al.Sumoylation increases HIF-la stability and its transcriptional activity[J]. BBRC,2004,324(1):394-400
[15]Evans SM,Koch CJ.Prognostic significance of tumor oxygenation in humans[J]. Cancer Letters.2003,195(1):1-16
[16]Jiang BH,Senenza GL,et al.Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of 02 tension[J]. AJP-Cell Physiology,1996,271(4):C1172-C118
[17]Yong-Hong Shi,Wei-Gang Fang. Hypoxia-inducible factor-1 in tumour angiogenesis. World J ournal of Gastroenterology.2004,10(8):1082-1087
[18]Hammond EM,Giaccia AJ. Hypoxia-inducible factor-1 and p53: friends,acquaintances,or strangers?[J]. Clin Cancer Res.2006,12 (17):5007-5009
[19]Hon WC,Wilson MI,Harlos K,et al.Structural basis for the recognition of hydroxyproline in HIF-la by pVHL[J].Nature,2002,417 (6892):975-978
[20]彭再梅,山长婷,王惠芳.肺癌组织中VHL和HIF-1α表达及其临床意义[J].中南大学学报(医学版).2009,34(4)：331-334
[21]Zhong H,Chiles K,Feldser D,et al. Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal gowth factor/phosphatidylinositol3-kinase /PTEN/AKT/FRAP pathway in human prostate cancer cells:Implications for tumors angiogenesis and therapeutics [J]. Cancer Res.2000,60(6):1541-1545
[22]Jiang BH,Agani F,Passaniti A,et al. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1 involvement of HIF-1 in tumor progression[J]. Cancer Res,1997,57 (23):5328-5335
[23]Fukuda R,Hirota K,Fan F,et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1 mediated vascular endothelial growth factor expression, Which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells [J].J Biol Chem.2002,277(41):38205-38211
[24]Schumacker PT.Hypoxia-inducible factor-1 (HIF-1)[J]. Critical Care Medicine. 2005,33(12)423-425
[25]Daskalow K,Rohwer N, et al. Role of hypoxia-inducible transcription factor 1α for progression and chemosensitivity of murine hepatocellular carcinoma. Journal of Molecular Medicine.2010, Apr 12
[26]Baba Y,Nosho K, et al. HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers.Am J Pathol.2010,Apr 2
[27]Ding Z,Yang L,et al. Expression and significance of hypoxia-inducible factor-1 alpha and MDRl/P-glycoprotein in human colon carcinoma tissue and cells.J Cancer Res Clin Oncol.2010,Mar 9
[28]Brahimi-Horn MC,Pouyssegur J.Harnessing the hypoxia-inducible factor in cancer and ischemic disease[J].Biochem Pharmacol.2007,73(3):450-457
[29]Semenza GL.Targeting HIF-1 for cancer therapy [J].Nat Rev Cancer,2003, 3(10):721-732
[30]Lee JW,Bae SH,Jeong J W,et al.Hypoxia-inducible factor(HIF-1)alpha:its protein stability and biological functions[J].Exp Mol Med,2004,36(1):1-12
[31]Viger A,Dervan PB.Exploring the limits of benzimidazole DNA-binding oligomers for the hypoxia inducible factor(HIF) site.Bioorg Med Chem.2006, 14(24):8539-8549
[32]Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1 and HIF-2 in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000;157:411-21
[33]Semenza GL.Defining the role of hypoxia-inducible factor 1 in cancer biologyand therapeutics[J]. Oncogene,2010,29(5):625-634
[34]Zhong H,De Marzo AM,Laughner E,et al. Overexpresion of hypoxia-inducible factor 1 in common human cancer and their metastases[J]. Cancer Res.1999, 59(22):5830-5835
[35]Rohwer N,Lobitz S,Daskalow K, et al. HIF-1α determines the metastatic potential of gastric cancer cells[J]. Br J Cancer.2009,100(5):772-781
[36]Talks KL,Turley H,et al.hypoxia-inducible factors HIF-1 alpha and HIF-2alpha in normal human tissues,cancers,and tumor-associated macrophages [J]. Am J Pathol.2000,157(2):411-421
[37]Hiroo Mizobuchi MD,et al.Hypoxia Markers in Human Osteosarcoma:An Exploratory Study [J]. Clin Orthop Relat Res.2008,466(9):2052-2059
[38]龚玲玲,吴卉娟等.子宫颈癌组织中缺氧诱导因子1α蛋白的表达及其与血管生成的关系[J].中华妇产科杂志.2004,39(11)：779-780
[39]Birner P,Sehindl M,Obermair A,et al. Overexpresion of hypoxia-inducible factor 1 alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer[J]. Cancer Res.2000,60(17):4693-4696
[40]Chaudary N,Hill RP. Hypoxia and metastasis in breast cancer[J]. Breast Dis. 2006-2007,26:55-64
[41]Dan Cao,Mei Hou,et al. Expression of HIF-1 alpha and VEGF in colorectal cancer:association with clinical outcomes and prognostic implications[J]. BMC Cancer.2009,9:432
[42]Geng-Wen Huang,Lian-Yue Yang,Wei-Qun Lu. Expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in hepatocellular carcinoma:Impact on neovascularization and survival[J]. World J Gastroenterol.2005, 11(11):1705-1708
[43]Aebersold DM, Burri P, Beer KT, et al. Expression of hypoxia-inducible factor-la:a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer[J]. Cancer Res.2001,61(7):2911-2916
[44]Koukourakis MI, Giatromanolaki A,Sivridis E, et al. Hypoxia-inducible factor(HIF1a and HIF-2a),angiogenesis,and chemoradiotherapy outome of squamous cell head-and-neck cancer[J]. Int J Radiat Oncol Biol Phys.2002, 53(5):1192-1202
[45]Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation[J]. Nature.2000,407(6801):242-248
[46]Pugh CW,Ratcliffe PJ. Regulation of angiogenesis by hypoxia:role of the HIF system. Nat M ed.2003, (6):677-684
[47]Aragones J,Schneider M,Van Geyte K,et al. Deficiency or inhibition of oxygen sensor Phdl induces hypoxia tolerance by reprogramming basal metabolism[J]. Nat Genet,2008,40(2):170-80
[48]Liang WC, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006,281(2):951-961
[49]Berra E, Pages G, Pouyssegur J. MAP kinases and hypoxia in the control of VEGF express[J]. Cancer and Metastasis Reviews,2000,19(1-2):139-145
[50]Lang KJ,Kappel A,Goodall GJ. Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia[J]. Mol Biol Cell.2002,13(5):1792-801
[51]Kim HJ,Chung H,Yoo YG,et al. Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha[J]. Mol Cancer Res.2007,5(4):321-329
[52]Plouet J, Moro F, Bertagnolli S, et al. Extracelluar cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect[J]. J Biol Chem.1997,272:13390-13396
[53]Harris AL. Hypoxia:a key regulatory factor in tumor growth. Nature Reviews Cancer.2002;2:38-47
[54]Griffiths EA, Pritchard SA, et al. Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer.2005,41(18):2792-2805
[55]Yang QC, Zeng BF, Dong Y, et al. Overexpression of Hypoxia-inducible factor-1alpha in human osteosarcoma:correlation with clinicopathological parameters and survival outcome [J]. Jpn J Clin Oncol.2007,37(2):127-134
[56]Zhong H,Agani F,Baccala AA,et al. Increased expression of hypoxia inducible factor-1 in rat and human prostate cancer [J]. Cancer Res.1998, 58(23):5280-5284
[57]Dorevic G, Matusan-llijas K, Babarovic E,et al. Hypoxia inducible factor-1 alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma[J]. J Exp Clin Cancer Res.2009,28(1):40-47
[58]Ding L,Chen X,Jing K,et al. Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter[J].J Huazhong Univ Sci Technolog Med Sci.2006,26(1):75-78
[59]Bryant CS, Munkarah AR, Kumar S,et al. Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1 alpha gene expression[J]. Arch Gynecol Obstet.2010 Feb 7
[60]Wellmann S, Buhrer C, Moderegger E, et al. Oxygen-regulated expression of the RNA-bingding proteins RBM3 and CIRP by a HIF-1-independent mechanism [J]. J Cell Sci.2004,117(Pt 9):1785-1794
[61]Cook-Johnson RJ, Demasi M, Cleland LG, et al. Endothelial cell COX-2 expression and activity in hypoxia[J]. Biochim Biophys Acta.2006, 1761(12):1443-1449
[62]Kaidi A, Qualtrough D, Williams AC, et al. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia[J]. Cancer Res,,2006,66:6683-6691
[63]Daneau G, Boidot R, Martinive P, et al. Identification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia:effect on angiogenesis and metastases[J]. Clin Cancer Res.2010, 16(2):410-419
[64]Mabjeesh NJ, Escuin DL, LaVallee TM, et al.2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF [J]. Cancer Cell. 2003,3(4):363-375
[65]Ricker JL,Chen Z,Yang XP,et al.2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma [J]. Clin Cancer Res.2004, 10(4):8665-8673
[66]Yang QC, Zeng BF, Shi ZM, et al. Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma[J]. J Exp Clin Cancer Res.2006,25(4):593-599
[67]Ratclife PJ,Pugh CW,Maxwell PH. Targeting tumors through the HIF system [J]. Nat Med,2000,6(12):1315-1316
[68]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription [J]. Nat Med.2000, 6(12):1335-1340
[69]Welsh S,Williams R,Kirkpatrick L,et al. Antitumor activity and pharrmacodynamic properties of Px-478, an inhibitor of hypoxia-inducible factor-1alpha [J]. Mol Cancer Ther.2004,3(3):233-244