缺氧诱导因子-1a在尖锐湿疣发病中的作用及机制的研究
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摘要
第一部分HIF-1a在尖锐湿疣患者皮损中的表达及意义
目的研究HIF-la在尖锐湿疣(condyloma acuminatum, CA)患者皮损中mRNA和蛋白的表达,探讨其意义以及与CA复发的关系。
方法使用RT-PCR和免疫组化SP法分别检测30例CA患者皮损中HIF-lamRNA和蛋白的表达,另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中HIF-la蛋白的阳性表达率和阳性表达量均分别显著高于对照组；但HIF-lamRNA的阳性表达率和阳性表达量与对照组相比差异无统计学意义。CA患者中复发组HIF-la蛋白的阳性表达量显著高于未复发组。
结论CA组织中缺氧的微环境诱导HIF-1a蛋白的异常高表达,可能是CA发病过程中的一个重要因素；而HIF-lamRNA的水平则保持稳定。HIF-1a蛋白的异常高表达与CA患者的预后有关,可作为预测CA临床复发的指标之一。
第二部分HIF-1a促进CA细胞增殖的作用及机制研究
目的研究CA细胞的增殖活性及其与CA复发的关系以及GLUT-1在CA患者皮损中mRNA和蛋白的表达；探讨HIF-la促进CA细胞增殖的作用及机制。
方法使用RT-PCR方法检测30例CA患者皮损中GLUT-lmRNA的表达,免疫组化SP法检测30例CA患者皮损中PCNA和GLUT-1蛋白的表达。另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中PCNA的阳性表达率和PI值均分别显著高于对照组；其中复发组PCNA的阳性表达率和PI值均分别显著高于未复发组。CA患者皮损中GLUT-lmRNA和蛋白的阳性表达率及阳性表达量均分别显著高于对照组。CA患者中HIF-1a蛋白与GLUT-1、PCNA蛋白的表达均呈正相关；GLUT-1蛋白与PCNA蛋白的表达也呈正相关。
结论CA组织中的细胞增殖活性较正常水平升高,并与CA的预后有关。HIF-la可能通过与GLUT-1相应的HRE结合诱导GLUT-1的大量表达,改善CA细胞的能量代谢,导致CA细胞的过度增殖。
第三部分CA组织中MVD的测定及HIF-1α在CA组织血管生成中的作用研究
目的检测CA组织中的微血管密度及其与CA复发的关系；研究HIF-la在缺氧状态下促进CA组织血管形成的作用及机制。
方法使用RT-PCR方法检测30例CA患者皮损中VEGF. COX-2、iNOS的mRNA表达；免疫组化SP法检测30例CA患者皮损中CD34、VEGF、COX-2、iNOS蛋白的表达。另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中MVD值显著高于对照组；其中复发组MVD值显著高于未复发组。CA患者皮损中VEGFmRNA和蛋白的阳性表达率与对照组相比差异无统计学意义；但VEGFmRNA和蛋白的阳性表达量均分别显著高于对照组。CA患者皮损中COX-2.iNOS的mRNA和蛋白的阳性表达率及阳性表达量均分别显著高于对照组。CA患者中VEGF. COX-2、iNOS蛋白的表达与MVD均呈正相关；HIF-1a蛋白与VEGF. COX-2、iNOS蛋白的表达均呈正相关；VEGF蛋白与COX-2、iNOS蛋白的表达无相关。
结论CA组织中的血管生成能力较正常组织明显增强,并与CA的预后相关。HIF-la是CA组织血管生成的核心调控因子,其调节CA组织血管生成的机制包括两个途径：一是VEGF依赖途径:HIF-la与HRE结合诱导VEGF高表达,通过VEGF的作用促进血管生成。另一途径为VEGF非依赖途径:HIF-1a还可通过上调其它靶基因的表达而促进血管生成,如诱导COX-2. iNOS的高表达参与调控血管新生。
Part Ⅰ The expression of HIF-la in Condyloma Acuminatum and its Significance
Objective To study the expression of HIF-la in Condyloma Acuminatum(CA)tissues. Furthermore,to explore its significance and its association with the recurrence of CA patients.
Methods The mRNA and protein expression of HIF-la were detected by RT-PCR and immunohistochemistry respectively in30cases of CA and20normal foreskin tissues.
Results The positive rates and expression intensity of HIF-la protein were significantly higher in CA than those in normal controls respectively while the positive rates and expression intensity of HIF-la mRNA in CA tissues have no statistical significance compared with those in normal foreskin tissues.Moreover, the expression intensity of HIF-la protein was significantly higher in recurrent CA patients than that in non-recurrent CA patients.
Conclusions The hypoxia microenvironment may induce the high expression of HIF-la protein in CA tissues which might play an important role in the pathogenesis of CA while the HIF-la mRNA remains a stable level.The abnormal expression of HIF-la protein was correlated with the prognosis of CA patients and can be used as an index to forecast the recurrence of CA.
Part Ⅱ The promotion of CA cells proliferation by HIF-la and its mechanisms
Objective To investigate the proliferation activity of CA cells and its association with the recurrence of CA. The expression of GLUT-1was also detected in CA tissues to explore the role of HIF-1a in the promotion of CA cells proliferation and its mechanisms.
Methods The mRNA expression of GLUT-1was detected by RT-PCR and the protein expression of GLUT-1and PCNA was detected by immunohistochemistry in30cases of CA and20normal foreskin tissues.
Results The positive rates and the number of PI in CA tissues were significantly higher than those in normal controls respectively. Moreover, the positive rates and the number of PI were significantly higher in recurrent CA patients than those in non-recurrent CA patients. The positive rates and expression intensity of GLUT-1mRNA and protein were significantly higher in CA than those in normal controls respectively.The protein expression of HIF-la was both positively correlated with that of GLUT-1and PCNA in CA patients while the protein expression of GLUT-1was also positively correlated with that of PCNA.
Conclusions The proliferation activity of CA cells is higher than that of normal foreskin cells which is correlated with the prognosis of CA patients. HIF-1a might combine the HRE of GLUT-1to induce the over-expression of GLUT-1which results in the improvement of the energy metabolism leading to an over-proliferation of CA cells.
Part ⅢDetection of microvessel density and study of the role of HIF-la in the angiogenesis in CA tissues
Objective To detect the microvessel density(MVD) in CA tissues and its association with the recurrence of CA and to explore the role of HIF-la in the angiogenesis in CA tissues and its mechanisms.
Methods The mRNA expression of VEGF、COX-2、iNOS was detected by RT-PCR and the protein expression of VEGF、COX-2、iNOS and CD34was detected by immunohistochemistry in30cases of CA and20normal foreskin tissues.
Results The number of MVD in CA tissues was significantly higher than that in normal controls while the number of MVD in recurrent CA patients was significantly higher than that in non-recurrent CA patients.The positive rates of VEGF mRNA and protein in CA tissues have no statistical significance compared with those in normal foreskin tissues respectively but the expression intensity of VEGF mRNA and protein were significantly higher in CA than those in normal controls respectively.The positive rates and expression intensity of COX-2、 iNOS mRNA and protein were significantly higher in CA than those in normal controls respectively. All of the protein expression of VEGF、COX-2, iNOS were positively correlated with MVD in CA patients while the protein expression of HIF-la was positively correlated with that of VEGF、COX-2、iNOS respectively.Moreover,no correlation was found between the protein expression of VEGF and that of COX-2,nor is that of iNOS.
Conclusions The cability of angiogenesis in CA tissues was significantly higher than that in normal controls which is correlated with the prognosis of CA patients.HIF-1a is a central regulating factor in the course of angogenesis which can monitor the angiogenesis in CA tissues by two means:one is the VEGF-dependent route:HIF-la may combine the HRE of VEGF to induce the over-expression of VEGF so as to promote the angiogenesis.The other is the non-VEGF-dependent route:HIF-1a can up-regulate the expression of its target gene such as COX-2and iNOS to favor the angiogenesis
目的研究HIF-la在尖锐湿疣(condyloma acuminatum, CA)患者皮损中mRNA和蛋白的表达,探讨其意义以及与CA复发的关系。
方法使用RT-PCR和免疫组化SP法分别检测30例CA患者皮损中HIF-lamRNA和蛋白的表达,另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中HIF-la蛋白的阳性表达率和阳性表达量均分别显著高于对照组；但HIF-lamRNA的阳性表达率和阳性表达量与对照组相比差异无统计学意义。CA患者中复发组HIF-la蛋白的阳性表达量显著高于未复发组。
结论CA组织中缺氧的微环境诱导HIF-1a蛋白的异常高表达,可能是CA发病过程中的一个重要因素；而HIF-lamRNA的水平则保持稳定。HIF-1a蛋白的异常高表达与CA患者的预后有关,可作为预测CA临床复发的指标之一。
第二部分HIF-1a促进CA细胞增殖的作用及机制研究
目的研究CA细胞的增殖活性及其与CA复发的关系以及GLUT-1在CA患者皮损中mRNA和蛋白的表达；探讨HIF-la促进CA细胞增殖的作用及机制。
方法使用RT-PCR方法检测30例CA患者皮损中GLUT-lmRNA的表达,免疫组化SP法检测30例CA患者皮损中PCNA和GLUT-1蛋白的表达。另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中PCNA的阳性表达率和PI值均分别显著高于对照组；其中复发组PCNA的阳性表达率和PI值均分别显著高于未复发组。CA患者皮损中GLUT-lmRNA和蛋白的阳性表达率及阳性表达量均分别显著高于对照组。CA患者中HIF-1a蛋白与GLUT-1、PCNA蛋白的表达均呈正相关；GLUT-1蛋白与PCNA蛋白的表达也呈正相关。
结论CA组织中的细胞增殖活性较正常水平升高,并与CA的预后有关。HIF-la可能通过与GLUT-1相应的HRE结合诱导GLUT-1的大量表达,改善CA细胞的能量代谢,导致CA细胞的过度增殖。
第三部分CA组织中MVD的测定及HIF-1α在CA组织血管生成中的作用研究
目的检测CA组织中的微血管密度及其与CA复发的关系；研究HIF-la在缺氧状态下促进CA组织血管形成的作用及机制。
方法使用RT-PCR方法检测30例CA患者皮损中VEGF. COX-2、iNOS的mRNA表达；免疫组化SP法检测30例CA患者皮损中CD34、VEGF、COX-2、iNOS蛋白的表达。另取20例正常成年男性的包皮组织作为对照。
结果CA患者皮损中MVD值显著高于对照组；其中复发组MVD值显著高于未复发组。CA患者皮损中VEGFmRNA和蛋白的阳性表达率与对照组相比差异无统计学意义；但VEGFmRNA和蛋白的阳性表达量均分别显著高于对照组。CA患者皮损中COX-2.iNOS的mRNA和蛋白的阳性表达率及阳性表达量均分别显著高于对照组。CA患者中VEGF. COX-2、iNOS蛋白的表达与MVD均呈正相关；HIF-1a蛋白与VEGF. COX-2、iNOS蛋白的表达均呈正相关；VEGF蛋白与COX-2、iNOS蛋白的表达无相关。
结论CA组织中的血管生成能力较正常组织明显增强,并与CA的预后相关。HIF-la是CA组织血管生成的核心调控因子,其调节CA组织血管生成的机制包括两个途径：一是VEGF依赖途径:HIF-la与HRE结合诱导VEGF高表达,通过VEGF的作用促进血管生成。另一途径为VEGF非依赖途径:HIF-1a还可通过上调其它靶基因的表达而促进血管生成,如诱导COX-2. iNOS的高表达参与调控血管新生。
Part Ⅰ The expression of HIF-la in Condyloma Acuminatum and its Significance
Objective To study the expression of HIF-la in Condyloma Acuminatum(CA)tissues. Furthermore,to explore its significance and its association with the recurrence of CA patients.
Methods The mRNA and protein expression of HIF-la were detected by RT-PCR and immunohistochemistry respectively in30cases of CA and20normal foreskin tissues.
Results The positive rates and expression intensity of HIF-la protein were significantly higher in CA than those in normal controls respectively while the positive rates and expression intensity of HIF-la mRNA in CA tissues have no statistical significance compared with those in normal foreskin tissues.Moreover, the expression intensity of HIF-la protein was significantly higher in recurrent CA patients than that in non-recurrent CA patients.
Conclusions The hypoxia microenvironment may induce the high expression of HIF-la protein in CA tissues which might play an important role in the pathogenesis of CA while the HIF-la mRNA remains a stable level.The abnormal expression of HIF-la protein was correlated with the prognosis of CA patients and can be used as an index to forecast the recurrence of CA.
Part Ⅱ The promotion of CA cells proliferation by HIF-la and its mechanisms
Objective To investigate the proliferation activity of CA cells and its association with the recurrence of CA. The expression of GLUT-1was also detected in CA tissues to explore the role of HIF-1a in the promotion of CA cells proliferation and its mechanisms.
Methods The mRNA expression of GLUT-1was detected by RT-PCR and the protein expression of GLUT-1and PCNA was detected by immunohistochemistry in30cases of CA and20normal foreskin tissues.
Results The positive rates and the number of PI in CA tissues were significantly higher than those in normal controls respectively. Moreover, the positive rates and the number of PI were significantly higher in recurrent CA patients than those in non-recurrent CA patients. The positive rates and expression intensity of GLUT-1mRNA and protein were significantly higher in CA than those in normal controls respectively.The protein expression of HIF-la was both positively correlated with that of GLUT-1and PCNA in CA patients while the protein expression of GLUT-1was also positively correlated with that of PCNA.
Conclusions The proliferation activity of CA cells is higher than that of normal foreskin cells which is correlated with the prognosis of CA patients. HIF-1a might combine the HRE of GLUT-1to induce the over-expression of GLUT-1which results in the improvement of the energy metabolism leading to an over-proliferation of CA cells.
Part ⅢDetection of microvessel density and study of the role of HIF-la in the angiogenesis in CA tissues
Objective To detect the microvessel density(MVD) in CA tissues and its association with the recurrence of CA and to explore the role of HIF-la in the angiogenesis in CA tissues and its mechanisms.
Methods The mRNA expression of VEGF、COX-2、iNOS was detected by RT-PCR and the protein expression of VEGF、COX-2、iNOS and CD34was detected by immunohistochemistry in30cases of CA and20normal foreskin tissues.
Results The number of MVD in CA tissues was significantly higher than that in normal controls while the number of MVD in recurrent CA patients was significantly higher than that in non-recurrent CA patients.The positive rates of VEGF mRNA and protein in CA tissues have no statistical significance compared with those in normal foreskin tissues respectively but the expression intensity of VEGF mRNA and protein were significantly higher in CA than those in normal controls respectively.The positive rates and expression intensity of COX-2、 iNOS mRNA and protein were significantly higher in CA than those in normal controls respectively. All of the protein expression of VEGF、COX-2, iNOS were positively correlated with MVD in CA patients while the protein expression of HIF-la was positively correlated with that of VEGF、COX-2、iNOS respectively.Moreover,no correlation was found between the protein expression of VEGF and that of COX-2,nor is that of iNOS.
Conclusions The cability of angiogenesis in CA tissues was significantly higher than that in normal controls which is correlated with the prognosis of CA patients.HIF-1a is a central regulating factor in the course of angogenesis which can monitor the angiogenesis in CA tissues by two means:one is the VEGF-dependent route:HIF-la may combine the HRE of VEGF to induce the over-expression of VEGF so as to promote the angiogenesis.The other is the non-VEGF-dependent route:HIF-1a can up-regulate the expression of its target gene such as COX-2and iNOS to favor the angiogenesis
引文
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48.Liu LX,Lu H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor-1.Biochem Biophys Res Commun,2002,291(4):908-941.
49.Semenza GL.HIF-1 and mechanism of hypoxia sensing.Curr Opin Cell Biol,2001,(13):167-171.
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51.Gregg L.Semenza HIF-1 and tumor progression:pathophysiology and therapeutics.Trends Mol Med,2002,8(4):562-567.
52.Mazure NM,Brahim-i Horn MC,Pouyssegur J.Protein kinases and the hypoxia-inducible factor-l,two switches in angiogenesis.Curr Pharm Des,2003,9(7):531-541.
53.Linden T,Kat schinski DM,Eckhardt K,et al.The antimycotic c-iclopirox olamine induces HIF-lalpha stability, VEGF expression,and angiogenesis.FASEB J,2003,17(6):761-763.
54.Vincent KA,Feron O,Kelly RA.Harnessing the response to tissue hypoxia:HIF-1 alpha and therapeutic angiogenesis.Trends Cardiovasc Med,2002,12(8):362-367.
55.Lee JW,Bae SH,Jeong JW,et al.Hypoxia-inducible factor alpha(HIF-1):its protein stability and biological functions.Exp Mol Med,2004,36(1):1-12.
56.Semenza GL.O2-regulated gene expression:transcriptional control of cardiorespiratory physiology by HIF-1.J Appl Physiol,2004,96(3):1173-1177.
57.Bruick RK,Mcknighy SL.A conserved family of prolyl-4-hydroxylases that modify HIF.Science,2001,294(5545):1337-1340.
58.Mahon PC,Hirota K,Semenza GL,et al.HIF-l:a novel protein that interacts with HIF-la transcriptional activity.Genes Dev,2001,15(20):2675-2686.
59.Lando D,Peet DJ,Whelan DA,et al.Asparagine hydroxylation of the HIF transactivtion domain a hypoxic switch.Science,2002,295(5556):858-861.
60.Maxwell PH,Dachs GU,Gleadle JM,et al.Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci USA,1997,94(15):8104-8109.
61.Figueroa YG,Chan AK,Ibrahim R,et al.NF-JB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression.ExpHematol,2002,30(12):1419-1427.
62.Gradin K,McGuire J,Wenger RH,et al.Functional interference between hypoxia and dioxin signal transduction pathways:competition for recruitment of the Arnt transcription factor.Mol Cell Biol,1996,16(10):5221-5231.
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64.Semenza GL.HIF-la and tumor progression:pathophysiology and therapeutics.TrendaMolMed,2002,8(4Suppl):62-67.
65.温敏杰,朱光辉,翁杰辉.缺氧对人肝癌细胞中缺氧诱导因子1、己糖激酶Ⅱ表达及周期调控的实验研究[J].中华普通外科学杂志,2008,2(2)：109-112.
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69.Shyu KG,Hsu FL,WangMJ,et al.Hypoxia-inducible factor-1 alpha regulates lung adenocarcinoma cell invasion.Exp Cell Res,2007,313(6):1181-1191.
70.Krishnamachary B,Zagag D,Nagasawa H,et al.Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor null renal cell carcinoma mediated by TCF3,ZFHX1 and ZFHX1.Cancer Res,2006,66(5):2725-2731.
71.Greijer AE,Vander Wall E.The role of hypoxia inducible factor-1(HIF-1)in hypoxia induced apoptosis.Clin Pathol,2004,57(10):1009-1014.
72.Zhou J,Fandrey J,Schumann J,et al.NO and TNF-alpha released from activated macrophages stabilize HIF-1 alpha in resting tubular LLC-PK1 cells.Am J Physiol Cell Physiol,2003,284(2):439-446.
73.Yun Z,Maecker HL,Johnson RS.Ihibition of PPAR gamma-gene expression by the HIF-1-regulated gene DEC1/Stral3:a mechanism for regulation of adipogenesis by hypoxia.Dev Cell,2002,2(3):331-341.
74.Fajas L,Landsberg RL,Huss-Garcia Y,et al.E2Fs regulate adipocyte differentiation.Dev Cell,2002,3(1):39-49.
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76.Kakinuma Y,Miyauchi T,Yuki K,et al.Novelmo lecularmechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1alpha induced for impaired myocardial energy metabolism.Circu lation,2001,103(19):2387-2394.
77.Carmeliet P,Dor Y,Herbert JM,et al.Role of HIF-1 alpha in Hypoxia-mediated apoptosis,cell proliferation and tumour angiogenesis.Nature,1998,394(6692):485-490.
78.Guo K,Searfoss G,Krolikowski D,et al.Hypoxia induces the expression of the pro-apoptotic gene BNIP3.Cell D eath Differ,2001,8(4):367-376.
79.Meeson AP,Radford N,Shelton JM,et al.Adaptive mechanisms that preserve cardiac function in mice without myoglobin.Circ Res,2001,88(7):713-720.
80.Chen D,Li M,Luo J,et al.Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.J Biol Chem,2003,278(16):13595-13598.
81.Na X,Wu G,Ryan CK,et al.Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas.J Urol,2003,170(2pt1):588-592.
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83.Aebersold DM,Burri P,Beer KT,et al.Expression of hypoxia-inducible factor-lalpha:a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer.Cancer Res,2001,61:2911-2916.
84.Jubb AM,Pham TQ,Hanby AM,et al.Expression of vascular endothelial growth factor,hypoxia inducible factor 1 alpha and carbonic anhydraseIX in human tumours J Clin Patholl,2004,57:504-512.
85.Krieg M,Hass R,Brauch H,et al.Up-regulation of hyporia-inducible factors HIF-1 alpha and HIF-2 alpha under normoxic condition in renal carcinoma cells by von Hippe-1 Lindau tumor suppressor gene loss of function.Oncogene,2000,19(48):5435-5443.
86.Salnikow K,CostaM, FiggWD,et al.Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer.Cancer Res,2000,60(20):5630-5634.
87.Yeo EJ,Chun YS,Park JW.New anticancer strategies targeting HIF-1.Biochem Pharmacol,2004,68(6):1061-1069.
88.Podar K,Anderson KC.A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways.Cell Cycle,2010,9(9):1722-8.
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48.Liu LX,Lu H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor-1.Biochem Biophys Res Commun,2002,291(4):908-941.
49.Semenza GL.HIF-1 and mechanism of hypoxia sensing.Curr Opin Cell Biol,2001,(13):167-171.
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51.Gregg L.Semenza HIF-1 and tumor progression:pathophysiology and therapeutics.Trends Mol Med,2002,8(4):562-567.
52.Mazure NM,Brahim-i Horn MC,Pouyssegur J.Protein kinases and the hypoxia-inducible factor-l,two switches in angiogenesis.Curr Pharm Des,2003,9(7):531-541.
53.Linden T,Kat schinski DM,Eckhardt K,et al.The antimycotic c-iclopirox olamine induces HIF-lalpha stability, VEGF expression,and angiogenesis.FASEB J,2003,17(6):761-763.
54.Vincent KA,Feron O,Kelly RA.Harnessing the response to tissue hypoxia:HIF-1 alpha and therapeutic angiogenesis.Trends Cardiovasc Med,2002,12(8):362-367.
55.Lee JW,Bae SH,Jeong JW,et al.Hypoxia-inducible factor alpha(HIF-1):its protein stability and biological functions.Exp Mol Med,2004,36(1):1-12.
56.Semenza GL.O2-regulated gene expression:transcriptional control of cardiorespiratory physiology by HIF-1.J Appl Physiol,2004,96(3):1173-1177.
57.Bruick RK,Mcknighy SL.A conserved family of prolyl-4-hydroxylases that modify HIF.Science,2001,294(5545):1337-1340.
58.Mahon PC,Hirota K,Semenza GL,et al.HIF-l:a novel protein that interacts with HIF-la transcriptional activity.Genes Dev,2001,15(20):2675-2686.
59.Lando D,Peet DJ,Whelan DA,et al.Asparagine hydroxylation of the HIF transactivtion domain a hypoxic switch.Science,2002,295(5556):858-861.
60.Maxwell PH,Dachs GU,Gleadle JM,et al.Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci USA,1997,94(15):8104-8109.
61.Figueroa YG,Chan AK,Ibrahim R,et al.NF-JB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression.ExpHematol,2002,30(12):1419-1427.
62.Gradin K,McGuire J,Wenger RH,et al.Functional interference between hypoxia and dioxin signal transduction pathways:competition for recruitment of the Arnt transcription factor.Mol Cell Biol,1996,16(10):5221-5231.
63.Abdel-Aleem S,Stlouis J,Hughes G,et al.Metabolic changes in the normal and hypoxic neonatal myocardium. Ann NY Acad Sci,1999,874(4):254-256.
64.Semenza GL.HIF-la and tumor progression:pathophysiology and therapeutics.TrendaMolMed,2002,8(4Suppl):62-67.
65.温敏杰,朱光辉,翁杰辉.缺氧对人肝癌细胞中缺氧诱导因子1、己糖激酶Ⅱ表达及周期调控的实验研究[J].中华普通外科学杂志,2008,2(2)：109-112.
66.Jiang CQ,Fan LF,liu ZS,et al.Expression levels and significance of hypoxia inducible factor-1 alpha and vascular endothelial growth factor in human colorectal adenocarcinoma.Chin Med J,2004,117(10):1541-1546.
67. Lakemeier S,Reichelt JJ,Patzer T,et al.The association between retraction of the torn rotator cuff and increasing expression of hypoxia inducible factor 1α and vascular endothelial growth factor expression:an immunohistological study.BMC Musculoskelet Disord,2010,8(11):230-240.
68.Munoz UM,Neurath KM,Vumbaca F,et al.Hypoxia stimulates breast carcinoma cell invasion through MT1,MMP and MMP2 activation.Oncogene,2006,25(16):2379-2392.
69.Shyu KG,Hsu FL,WangMJ,et al.Hypoxia-inducible factor-1 alpha regulates lung adenocarcinoma cell invasion.Exp Cell Res,2007,313(6):1181-1191.
70.Krishnamachary B,Zagag D,Nagasawa H,et al.Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor null renal cell carcinoma mediated by TCF3,ZFHX1 and ZFHX1.Cancer Res,2006,66(5):2725-2731.
71.Greijer AE,Vander Wall E.The role of hypoxia inducible factor-1(HIF-1)in hypoxia induced apoptosis.Clin Pathol,2004,57(10):1009-1014.
72.Zhou J,Fandrey J,Schumann J,et al.NO and TNF-alpha released from activated macrophages stabilize HIF-1 alpha in resting tubular LLC-PK1 cells.Am J Physiol Cell Physiol,2003,284(2):439-446.
73.Yun Z,Maecker HL,Johnson RS.Ihibition of PPAR gamma-gene expression by the HIF-1-regulated gene DEC1/Stral3:a mechanism for regulation of adipogenesis by hypoxia.Dev Cell,2002,2(3):331-341.
74.Fajas L,Landsberg RL,Huss-Garcia Y,et al.E2Fs regulate adipocyte differentiation.Dev Cell,2002,3(1):39-49.
75.Lee SH,Wolf PL,Escudero R,et al.Early expression of angiogenesis factors in acute myocardialischemia and infarction.N Engl J Med,2000,342(9):626-633.
76.Kakinuma Y,Miyauchi T,Yuki K,et al.Novelmo lecularmechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1alpha induced for impaired myocardial energy metabolism.Circu lation,2001,103(19):2387-2394.
77.Carmeliet P,Dor Y,Herbert JM,et al.Role of HIF-1 alpha in Hypoxia-mediated apoptosis,cell proliferation and tumour angiogenesis.Nature,1998,394(6692):485-490.
78.Guo K,Searfoss G,Krolikowski D,et al.Hypoxia induces the expression of the pro-apoptotic gene BNIP3.Cell D eath Differ,2001,8(4):367-376.
79.Meeson AP,Radford N,Shelton JM,et al.Adaptive mechanisms that preserve cardiac function in mice without myoglobin.Circ Res,2001,88(7):713-720.
80.Chen D,Li M,Luo J,et al.Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.J Biol Chem,2003,278(16):13595-13598.
81.Na X,Wu G,Ryan CK,et al.Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas.J Urol,2003,170(2pt1):588-592.
82.Wiesener MS,Munchenhagen PM,Berger L,et al.Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1 alpha in clear renal carcinomas.Cancer Res,2001,61(13):5215-5222.
83.Aebersold DM,Burri P,Beer KT,et al.Expression of hypoxia-inducible factor-lalpha:a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer.Cancer Res,2001,61:2911-2916.
84.Jubb AM,Pham TQ,Hanby AM,et al.Expression of vascular endothelial growth factor,hypoxia inducible factor 1 alpha and carbonic anhydraseIX in human tumours J Clin Patholl,2004,57:504-512.
85.Krieg M,Hass R,Brauch H,et al.Up-regulation of hyporia-inducible factors HIF-1 alpha and HIF-2 alpha under normoxic condition in renal carcinoma cells by von Hippe-1 Lindau tumor suppressor gene loss of function.Oncogene,2000,19(48):5435-5443.
86.Salnikow K,CostaM, FiggWD,et al.Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer.Cancer Res,2000,60(20):5630-5634.
87.Yeo EJ,Chun YS,Park JW.New anticancer strategies targeting HIF-1.Biochem Pharmacol,2004,68(6):1061-1069.
88.Podar K,Anderson KC.A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways.Cell Cycle,2010,9(9):1722-8.