HIF-1a与VEGF在小脑血管网织细胞瘤中的表达
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摘要
血管网织细胞瘤,也叫血管母细胞瘤(Hemangioblastoma, HB),是一种起源于中胚叶残余组织,发生在中枢神经系统的肿瘤,约占颅内肿瘤的0.9%～2.1%,为良性肿瘤,一般不具有侵袭性。小脑、脊髓、脑干是其好发部位,病变位于小脑者约占95%,它常散在或伴随VHL疾病发生。目前,手术切除是治疗的主要方法。小脑HB主要由血管组成,血供非常丰富,增加了手术的风险和死亡率,而且位置靠近脑干和第四脑室,尤其是肿瘤的部位位于手术禁区时,就不能采取手术的方法,亟待一种新的治疗方法。因为小脑HB相比于其它脑肿瘤最突出的特征就是高度血管化,所以针对小脑HB的发生和发展过程中肿瘤血管的新生的治疗成为一种理想的治疗方法。
缺氧诱导因子-1α(Hypoxia-inducible factor-1α, HIF-1α)是近年来发现的在体内缺氧条件下发挥主要调控作用的一种转录因子,在多种肿瘤细胞中均有表达。目前,已知体内促进血管新生最重要的因子为血管内皮细胞生长因子(Vascular Endothelial Growth Factor,VEGF),它能够直接刺激内皮细胞分裂增殖,是高度特异的血管内皮细胞有丝分裂素,参与许多生理及病理过程,可促进血管内皮细胞增生、迁移及增加血管通透性。近年来对HIF-1α和VEGF在肿瘤的发生和发展中的作用成为研究的热点,并且研究证明HIF-1α能够促进VEGF等基因的表达,使肿瘤血管出现增生改变,在肿瘤血管新生的过程中起核心调控作用。
目的:本文通过免疫组化法和RT-PCR法对小脑HB组织中HIF-1α与VEGF基因蛋白及mRNA水平表达的检测,探索HIF-1α与VEGF在小脑HB中的表达及相关性,为小脑HB发生和发展的分子机制研究提供实验数据。
方法:
1病例资料采集:收集2001年至2006年间,河北医科大学第二医院神经外科手术切除,且病历资料保存完好的小脑HB组织石蜡包埋标本30例,且所有患者临床资料完整,所有患者术前均未经过放、化疗。另取我院神经外科10例后颅窝减压术患者的正常小脑组织作为对照。新鲜冷冻标本5例,均来自2005年至2006年我院神经外科手术过程中所取的小脑HB组织,并及时经液氮冷冻后保存于-80℃冰柜,并取1例行后颅窝减压术患者正常小脑组织冷冻保存作为对照。
2免疫组织化学染色法检测小脑HB组织中HIF-1α与VEGF在蛋白水平的表达:免疫组化步骤按试剂盒说明进行操作。判定标准:光学显微镜下观察10个高倍镜(10×40倍)视野阳性细胞所占比例,计算阳性细胞率。无阳性细胞或阳性细胞数<1%为阴性(-),阳性细胞数1%～10%为阳性(+),11%～50%为中度阳性(++),>50%为强阳性(+++)。
3 RT-PCR法检测小脑HB组织中HIF-1α与VEGF mRNA水平的表达:从冻存的正常小脑组织和小脑HB标本中,用TRIzol法提取细胞总RNA,经RT-PCR反应,并分别对HIF-1α与VEGF目的基因片段进行扩增后,经1.5%琼脂糖凝胶电泳,紫外灯下观察后用LabWork系统对各条带进行扫描测定光密度值,对所得半定量数据进行统计分析。
4统计学分析:分类数据变量资料的比较采用Fisher确切概率法,相关分析采用Spearman等级相关分析。0.4≤r<0.7表示中度相关,r≥0.7表示高度相关。计量资料用均数±标准差(x±S)表示。
结果:
1 HIF-1α蛋白在小脑HB组织中的表达情况:正常人小脑组织标本仅见1例HIF-1α阳性表达,小脑HB中28例HIF-1α阳性表达,HIF-1α在小脑HB和正常小脑中表达的阳性的率为93.3%和10%,两者差异具有统计学意义(P<0.01)。
2 VEGF蛋白在小脑HB组织中的表达情况:正常人小脑组织仅见1例VEGF阳性表达,小脑HB中29例VEGF阳性表达,VEGF在小脑HB和正常小脑中表达的阳性率为96.6%和10%,两者差异具有统计学意义(P<0.01)。
3 HIF-1αmRNA在小脑HB组织中的表达情况:正常人小脑组织未见HIF-1αmRNA表达,所有的小脑HB组织中都检测到HIF-1αmRNA表达。在小脑HB和正常小脑组织中表达的阳性率为100%和0%。
4 VEGF mRNA在小脑HB组织中的表达情况:正常人小脑组织未见VEGF mRNA表达,所有的小脑HB组织中都检测到VEGF mRNA表达。在小脑HB和正常小脑组织中表达的阳性率为100%和0%。
5小脑HB中HIF-1α与VEGF在蛋白水平的表达是正相关(r=0.903)。
结论:
1小脑HB中HIF-1α蛋白和HIF-1αmRNA表达都明显增高。
2小脑HB中VEGF蛋白和VEGF mRNA表达都明显增高。
3小脑HB中HIF-1α与VEGF的表达具有相关性。HIF-1α可能通过促进VEGF的表达,在小脑HB的发生和发展过程中发挥重要作用。
4 HIF-1α与VEGF有望成为小脑HB治疗中很有意义的治疗目标或预后指标。
Hemangioblastoma (HB) is a sort of central nervous system (CNS) tumor, which is traceable from mesoblast remnant tissue. Hemangioblastoma is benign tumor, which generally has no character of invasion. They account for 0.9% to 2.1% of all intracranial tumors, and the cerebellum, spinal cord, and brainstem are the most frequently affected sites. Hemangioblastoma may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Now, the main therapeutic measure is exairesis. Cerebellar hemangioblastoma is composed of blood vessel, and its blood supply is extremely abundant. All of these increase difficulty and death rate of the operation. And, when the affected site adjoins brainstem and fourth ventricle of cerebrum. Especially when the tumor position located operation-restricted zone, we have to give up the operation. We hope find a new therapy. Most distinguished characteristic of cerebellar hemangioblastoma, which is compared to other brain tumors, is that cerebellar hemangioblastoma was highly vascularized. So, the therapy, which aim directly at tumor angiogenesis during the process of generation and development of cerebellar hemangioblastoma may be an ideal therapy.
Recently, Hypoxia-inducible factor-1α(HIF-1α) was discovered as a major transcription factor, which has regulatory function in hypoxia in vivo. Vascular Endothelial Growth Factor (VEGF) is the most important factor in vivo, which can promote angiogenesis. It can directly stimulate the division growth of endothelial cell. And VEGF is most specific mitogen of vascular endothelial cell, which participate in many of physiology and pathology process. It cannot only promotes the proliferation and migration of vascular endothelial cell, but also increases vasopermeability. For the past few years, the effect of HIF-1αand VEGF become a hot topic in the occurrence and development of tumor, and the research demonstrate that HIF-1αcan promote the expression of such as VEGF gene etc, then tumor vessel appear the change of hyperplasia. HIF-1αis the central regulator of tumor angiogenesis.
Objective: In this topic, we use immunohistochemical stain and RT-PCR to detect the expression of HIF-1αgene in cerebellar hemangioblastoma both in protein level and mRNA level. We want to search for the expression of HIF-1αand VEGF and their associativity in cerebellar hemangioblastoma. We hope to provide experimental data for the research of molecular mechanism of the occurrence and development of cerebellar hemangioblastoma.
Methods:
1 The 30 paraffin-embedded specimen of cerebellar Hemangioblastoma were collected from the department of neurosurgery at the second hospital of Hebei Medcial University from 2001 to 2006, and all of patient’s clinical data are complete. All of patients had not suffered from radiotherapy and chemotherapy before they operated. And we obtain normal cerebellar tissues from 10 patients, on who was performed posterior fossa decompression (PFD) at our institution from 2005 to 2006. The 10 normal cerebellar tissues were served as controls. We obtain 5 cases freezed fresh specimens during the operative process from the department of neurosurgery at the second hospital of Hebei Medcial University from 2005 to 2006, when we obtain specimens; we immerge specimens into liquid nitrogen at once, then, preserve it in -80oC refrigerator. We obtain normal cerebellar tissues from 1 patient, on who was performed posterior fossa decompression (PFD) at our institution. The 1 normal cerebellar tissues was frozen and served as controls.
2 We use immunohistochemistry technique to detect the expresseion of protein level of HIF-1αand VEGF. We execute the procedure according to illustration of kit. HIF-1αprotein and VEGF protein were classified as follows: we observe proportion of positive cell in the field of vision of 10 of high power lens (10×40) by optical microscope, then we calculate the positive cell ratio. No positive cell or positive cell less than 1% classified negative (-), 1～10% positive cell classified positive (+), 11%～50% positive cell classified middle positive (++), more than 50% positive cell classified strong positive (+++).
3 We use RT-PCR technique to detect the expressed of HIF-1αmRNA and VEGF mRNA. Total RNA was isolated from harvested cells by Trizol. The obtained target gene fragment of HIF-1αand VEGF were amplified through RT-PCR reaction. The products were analyzed by 1.5% agarose gel electrophoresis followed by staining with ethidium bromide (EB). Then we observe and take photos in the viltalight lamp. We adopt LabWork system to scan each band and carry out semiquantitative analysis. Fisher exact propability and Spearman rank correlation were used for statistics.
Results:
1 Expression of HIF-1αprotein in cerebellar hemangioblastoma tissues: 1 sample of normal cerebellar tissues has HIF-1αto express. 28 samples of cerebellar Hemangioblastoma tissues have HIF-1αto express. The positive rate of HIF-1αwas 93.3% in cerebellar Hemangioblastoma, 10% in normal cerebellar (p<0.01).
2 Expression of VEGF protein in cerebellar hemangioblastoma tissues: 1 sample of normal cerebellar tissues has VEGF to express. 29 samples of cerebellar hemangioblastoma tissues have VEGF to express. The positive rate of VEGF was 96.6% in hemangioblastoma, 10% in normal cerebellum (P < 0.01).
3 Expression of HIF-1αmRNA in cerebellar hemangioblastoma tissues: none of samples of normal cerebellar tissues have HIF-1αmRNA to express. 5 samples of cerebellar hemangioblastoma tissues have HIF-1αmRNA to express. The positive rate of HIF-1αwas 100% in cerebellar Hemangioblastoma, 0% in normal cerebellar.
4 Expression of VEGF mRNA in cerebellar hemangioblastoma: none of samples of normal cerebellar tissues have VEGF mRNA to express. 5 samples of cerebellar hemangioblastoma tissues have VEGF mRNA to express. The positive rate of VEGF mRNA was 100% in cerebellar hemangioblastoma, 0% in normal cerebellar tissues.
5 The correlation of HIF-1αand VEGF in protein level in cerebellar hemangioblastoma is positive correlation (r=0.903).
Conclusions:
1 Expression of HIF-1αprotein and HIF-1αmRNA in cerebellar hemangioblastoma increase obviously.
2 Expression of VEGF protein and VEGF mRNA in cerebellar hemangioblastoma increase obviously.
3 Expression of HIF-1αand VEGF in cerebellar hemangioblastoma are correlative. HIF-1αmay act as an important role during the process of generation and development of cerebellar Hemangioblastoma through promoting the expression of VEGF.
4 HIF-1αand VEGF may become a therapeutic target or prognostic indicator in cerebellar hemangioblastoma.
缺氧诱导因子-1α(Hypoxia-inducible factor-1α, HIF-1α)是近年来发现的在体内缺氧条件下发挥主要调控作用的一种转录因子,在多种肿瘤细胞中均有表达。目前,已知体内促进血管新生最重要的因子为血管内皮细胞生长因子(Vascular Endothelial Growth Factor,VEGF),它能够直接刺激内皮细胞分裂增殖,是高度特异的血管内皮细胞有丝分裂素,参与许多生理及病理过程,可促进血管内皮细胞增生、迁移及增加血管通透性。近年来对HIF-1α和VEGF在肿瘤的发生和发展中的作用成为研究的热点,并且研究证明HIF-1α能够促进VEGF等基因的表达,使肿瘤血管出现增生改变,在肿瘤血管新生的过程中起核心调控作用。
目的:本文通过免疫组化法和RT-PCR法对小脑HB组织中HIF-1α与VEGF基因蛋白及mRNA水平表达的检测,探索HIF-1α与VEGF在小脑HB中的表达及相关性,为小脑HB发生和发展的分子机制研究提供实验数据。
方法:
1病例资料采集:收集2001年至2006年间,河北医科大学第二医院神经外科手术切除,且病历资料保存完好的小脑HB组织石蜡包埋标本30例,且所有患者临床资料完整,所有患者术前均未经过放、化疗。另取我院神经外科10例后颅窝减压术患者的正常小脑组织作为对照。新鲜冷冻标本5例,均来自2005年至2006年我院神经外科手术过程中所取的小脑HB组织,并及时经液氮冷冻后保存于-80℃冰柜,并取1例行后颅窝减压术患者正常小脑组织冷冻保存作为对照。
2免疫组织化学染色法检测小脑HB组织中HIF-1α与VEGF在蛋白水平的表达:免疫组化步骤按试剂盒说明进行操作。判定标准:光学显微镜下观察10个高倍镜(10×40倍)视野阳性细胞所占比例,计算阳性细胞率。无阳性细胞或阳性细胞数<1%为阴性(-),阳性细胞数1%～10%为阳性(+),11%～50%为中度阳性(++),>50%为强阳性(+++)。
3 RT-PCR法检测小脑HB组织中HIF-1α与VEGF mRNA水平的表达:从冻存的正常小脑组织和小脑HB标本中,用TRIzol法提取细胞总RNA,经RT-PCR反应,并分别对HIF-1α与VEGF目的基因片段进行扩增后,经1.5%琼脂糖凝胶电泳,紫外灯下观察后用LabWork系统对各条带进行扫描测定光密度值,对所得半定量数据进行统计分析。
4统计学分析:分类数据变量资料的比较采用Fisher确切概率法,相关分析采用Spearman等级相关分析。0.4≤r<0.7表示中度相关,r≥0.7表示高度相关。计量资料用均数±标准差(x±S)表示。
结果:
1 HIF-1α蛋白在小脑HB组织中的表达情况:正常人小脑组织标本仅见1例HIF-1α阳性表达,小脑HB中28例HIF-1α阳性表达,HIF-1α在小脑HB和正常小脑中表达的阳性的率为93.3%和10%,两者差异具有统计学意义(P<0.01)。
2 VEGF蛋白在小脑HB组织中的表达情况:正常人小脑组织仅见1例VEGF阳性表达,小脑HB中29例VEGF阳性表达,VEGF在小脑HB和正常小脑中表达的阳性率为96.6%和10%,两者差异具有统计学意义(P<0.01)。
3 HIF-1αmRNA在小脑HB组织中的表达情况:正常人小脑组织未见HIF-1αmRNA表达,所有的小脑HB组织中都检测到HIF-1αmRNA表达。在小脑HB和正常小脑组织中表达的阳性率为100%和0%。
4 VEGF mRNA在小脑HB组织中的表达情况:正常人小脑组织未见VEGF mRNA表达,所有的小脑HB组织中都检测到VEGF mRNA表达。在小脑HB和正常小脑组织中表达的阳性率为100%和0%。
5小脑HB中HIF-1α与VEGF在蛋白水平的表达是正相关(r=0.903)。
结论:
1小脑HB中HIF-1α蛋白和HIF-1αmRNA表达都明显增高。
2小脑HB中VEGF蛋白和VEGF mRNA表达都明显增高。
3小脑HB中HIF-1α与VEGF的表达具有相关性。HIF-1α可能通过促进VEGF的表达,在小脑HB的发生和发展过程中发挥重要作用。
4 HIF-1α与VEGF有望成为小脑HB治疗中很有意义的治疗目标或预后指标。
Hemangioblastoma (HB) is a sort of central nervous system (CNS) tumor, which is traceable from mesoblast remnant tissue. Hemangioblastoma is benign tumor, which generally has no character of invasion. They account for 0.9% to 2.1% of all intracranial tumors, and the cerebellum, spinal cord, and brainstem are the most frequently affected sites. Hemangioblastoma may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Now, the main therapeutic measure is exairesis. Cerebellar hemangioblastoma is composed of blood vessel, and its blood supply is extremely abundant. All of these increase difficulty and death rate of the operation. And, when the affected site adjoins brainstem and fourth ventricle of cerebrum. Especially when the tumor position located operation-restricted zone, we have to give up the operation. We hope find a new therapy. Most distinguished characteristic of cerebellar hemangioblastoma, which is compared to other brain tumors, is that cerebellar hemangioblastoma was highly vascularized. So, the therapy, which aim directly at tumor angiogenesis during the process of generation and development of cerebellar hemangioblastoma may be an ideal therapy.
Recently, Hypoxia-inducible factor-1α(HIF-1α) was discovered as a major transcription factor, which has regulatory function in hypoxia in vivo. Vascular Endothelial Growth Factor (VEGF) is the most important factor in vivo, which can promote angiogenesis. It can directly stimulate the division growth of endothelial cell. And VEGF is most specific mitogen of vascular endothelial cell, which participate in many of physiology and pathology process. It cannot only promotes the proliferation and migration of vascular endothelial cell, but also increases vasopermeability. For the past few years, the effect of HIF-1αand VEGF become a hot topic in the occurrence and development of tumor, and the research demonstrate that HIF-1αcan promote the expression of such as VEGF gene etc, then tumor vessel appear the change of hyperplasia. HIF-1αis the central regulator of tumor angiogenesis.
Objective: In this topic, we use immunohistochemical stain and RT-PCR to detect the expression of HIF-1αgene in cerebellar hemangioblastoma both in protein level and mRNA level. We want to search for the expression of HIF-1αand VEGF and their associativity in cerebellar hemangioblastoma. We hope to provide experimental data for the research of molecular mechanism of the occurrence and development of cerebellar hemangioblastoma.
Methods:
1 The 30 paraffin-embedded specimen of cerebellar Hemangioblastoma were collected from the department of neurosurgery at the second hospital of Hebei Medcial University from 2001 to 2006, and all of patient’s clinical data are complete. All of patients had not suffered from radiotherapy and chemotherapy before they operated. And we obtain normal cerebellar tissues from 10 patients, on who was performed posterior fossa decompression (PFD) at our institution from 2005 to 2006. The 10 normal cerebellar tissues were served as controls. We obtain 5 cases freezed fresh specimens during the operative process from the department of neurosurgery at the second hospital of Hebei Medcial University from 2005 to 2006, when we obtain specimens; we immerge specimens into liquid nitrogen at once, then, preserve it in -80oC refrigerator. We obtain normal cerebellar tissues from 1 patient, on who was performed posterior fossa decompression (PFD) at our institution. The 1 normal cerebellar tissues was frozen and served as controls.
2 We use immunohistochemistry technique to detect the expresseion of protein level of HIF-1αand VEGF. We execute the procedure according to illustration of kit. HIF-1αprotein and VEGF protein were classified as follows: we observe proportion of positive cell in the field of vision of 10 of high power lens (10×40) by optical microscope, then we calculate the positive cell ratio. No positive cell or positive cell less than 1% classified negative (-), 1～10% positive cell classified positive (+), 11%～50% positive cell classified middle positive (++), more than 50% positive cell classified strong positive (+++).
3 We use RT-PCR technique to detect the expressed of HIF-1αmRNA and VEGF mRNA. Total RNA was isolated from harvested cells by Trizol. The obtained target gene fragment of HIF-1αand VEGF were amplified through RT-PCR reaction. The products were analyzed by 1.5% agarose gel electrophoresis followed by staining with ethidium bromide (EB). Then we observe and take photos in the viltalight lamp. We adopt LabWork system to scan each band and carry out semiquantitative analysis. Fisher exact propability and Spearman rank correlation were used for statistics.
Results:
1 Expression of HIF-1αprotein in cerebellar hemangioblastoma tissues: 1 sample of normal cerebellar tissues has HIF-1αto express. 28 samples of cerebellar Hemangioblastoma tissues have HIF-1αto express. The positive rate of HIF-1αwas 93.3% in cerebellar Hemangioblastoma, 10% in normal cerebellar (p<0.01).
2 Expression of VEGF protein in cerebellar hemangioblastoma tissues: 1 sample of normal cerebellar tissues has VEGF to express. 29 samples of cerebellar hemangioblastoma tissues have VEGF to express. The positive rate of VEGF was 96.6% in hemangioblastoma, 10% in normal cerebellum (P < 0.01).
3 Expression of HIF-1αmRNA in cerebellar hemangioblastoma tissues: none of samples of normal cerebellar tissues have HIF-1αmRNA to express. 5 samples of cerebellar hemangioblastoma tissues have HIF-1αmRNA to express. The positive rate of HIF-1αwas 100% in cerebellar Hemangioblastoma, 0% in normal cerebellar.
4 Expression of VEGF mRNA in cerebellar hemangioblastoma: none of samples of normal cerebellar tissues have VEGF mRNA to express. 5 samples of cerebellar hemangioblastoma tissues have VEGF mRNA to express. The positive rate of VEGF mRNA was 100% in cerebellar hemangioblastoma, 0% in normal cerebellar tissues.
5 The correlation of HIF-1αand VEGF in protein level in cerebellar hemangioblastoma is positive correlation (r=0.903).
Conclusions:
1 Expression of HIF-1αprotein and HIF-1αmRNA in cerebellar hemangioblastoma increase obviously.
2 Expression of VEGF protein and VEGF mRNA in cerebellar hemangioblastoma increase obviously.
3 Expression of HIF-1αand VEGF in cerebellar hemangioblastoma are correlative. HIF-1αmay act as an important role during the process of generation and development of cerebellar Hemangioblastoma through promoting the expression of VEGF.
4 HIF-1αand VEGF may become a therapeutic target or prognostic indicator in cerebellar hemangioblastoma.
引文
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17 Wizigmann-Voos S, Plate KH.Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol. 1996, 11(4): 1049-61
18 Siemeister G, Schirner M, Weindel K, et al. Two independ- ent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res. 1999, 59(13): 3185-91
19 Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004, 22(24): 4991-5004
20 Wizigmann-Voos S, Breier G, Risau W, et al. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995, 55(6): 1358-64
21 李爱冰, 袁先厚, 陈新军.VEGF、bFGF 在血管网织细胞瘤中的表达. 中国临床神经外科杂志. 2000, 5(4): 229-231
22 Chen Y, Tachibana O, Hasegawa M, et al. Absence of tight junctions between microvascular endothelial cells in human cerebellar hemangioblastoma. Neurosurgery. 2006, 59(3): 660-70
23 Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991, 266(18): 11947-11954
24 Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci USA. 1998, 95(26): 15809-15814
1 Catapano D, Muscarella LA, Guarnieri V, et al. Hemangio- blastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery. 2005, 56(6): 1215-21
2 Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 2000, 35(2): 71-103
3 Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001, 13(2): 167-71
4 Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia byHIF-1. Blood. 2005, 105(2): 659-69
5 Zagzag D, Krishnamachary B, Yee H, et al. Stromal cell-derivedfactor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005, 65(14): 6178-88
6 Hellwig-Bürgel T, Stiehl DP, Wagner AE, et al. Hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res. 2005, 25(6): 297-310
7 Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001, 93(4): 309-14
8 Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999, 59(22): 5830-5
9 Jones A, Fujiyama C, Blanche C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin Cancer Res. 2001, 7(5): 1263-72
10 Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003, 3(10): 721-32
11 Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 2000,88(11): 2606-18
12 Krieg M, Marti HH, Plate KH, et al. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood. 1998, 92(9): 3388-93
13 李林繁, 李德泽, 麦洁文. 小脑血管网织细胞瘤中缺氧诱导因子-1a表达水平的改变海南医学院学报. 2005, 11(2): 95-97
14 Huang H, Held-Feindt J, Buhl R, et al. Expression of VEGF and its receptors in different brain tumors. Neurol Res. 2005, 27(4): 371-7
15 Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000, 50(1-2): 109-20
16 Patton KT, Satcher RL Jr, Laskin WB. Apillary hemangioblastoma of soft tissue: report of a case and review of the literature. Hum Pathol. 2005, 36(10): 1135-9
17 Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004, 22(24): 4991-5004
18 Wizigmann-Voos S, Plate KH. Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol. 1996, 11(4): 1049-1061
19 Beckner ME, Sasatomi E, Swalsky PA, et al. Loss of heterozygosity reveals non-VHL allelic loss in hemangio-blastomas at 22q13. Hum Pathol. 2004, 35(9): 1105-11
20 Chen Y, Tachibana O, Hasegawa M, et al. Absence of tight junctions between microvascular endothelial cells in human cerebellar hemangioblastoma. Neurosurgery. 2006, 59(3): 660-70
21 Wizigmann-Voos S, Breier G, Risau W, et al. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangio- blastomas. Cancer Res. 1995, 55(6): 1358-64
22 李爱冰, 袁先厚, 陈新军. VEGF、bFGF 在血管网织细胞瘤中的表达. 中国临床神经外科杂志. 2000, 5(4): 229-231
23 Morii K, Tanaka R, Washiyama K, et al. Expression of vascular endothelial growth factor in capillary hemangio-blastoma. Biochem Biophys Res Commun. 1993, 194(2): 749-55
24 Vaquero J, Zurita M, Coca S, et al. Expression of vascular endothelial growth factor in cerebellar hemangioblastomas does not correlate with tumor angiogenesis. Cancer Lett. 1998, 132(1-2): 213-7
2 Catapano D, Muscarella LA, Guarnieri V, et al. Hemangioblastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery. 2005, 56(6): 1215-21
3 Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 2000, 35(2): 71-103
4 Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001, 13(2): 167-71
5 Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005, 105(2): 659-69
6 Zagzag D, Krishnamachary B, Yee H, et al. Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005, 65(14): 6178-88
7 Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001, 93(4): 309-14
8 Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999, 59(22): 5830-5
9 Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 2000, 88(11): 2606-18
10 Krieg M, Marti HH, Plate KH, et al. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood. 1998, 92(9): 3388-93
11 Clifford SC, Cockman ME, Smallwood AC, et al. Contrasting effects on HIF-1αlpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet. 2001, 10(10): 1029-38
12 Lonergan KM, Iliopoulos O, Ohh M, et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. 1998, 18(2): 732-41
13 Kallio PJ, Wilson WJ, O'Brien S, et al. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem. 1999, 274(10): 6519-25
14 李林繁, 李德泽, 麦洁文. 小脑血管网织细胞瘤中缺氧诱导因子-1a 表达水平的改变海南医学院学报. 2005, 11(2): 95-97
15 Huang H, Held-Feindt J, Buhl R, et al. Expression of VEGF and its receptors in different brain tumors Neurol Res. 2005, 27(4): 371-7
16 Achein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000, 50(1-2): 109-20
17 Wizigmann-Voos S, Plate KH.Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol. 1996, 11(4): 1049-61
18 Siemeister G, Schirner M, Weindel K, et al. Two independ- ent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res. 1999, 59(13): 3185-91
19 Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004, 22(24): 4991-5004
20 Wizigmann-Voos S, Breier G, Risau W, et al. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995, 55(6): 1358-64
21 李爱冰, 袁先厚, 陈新军.VEGF、bFGF 在血管网织细胞瘤中的表达. 中国临床神经外科杂志. 2000, 5(4): 229-231
22 Chen Y, Tachibana O, Hasegawa M, et al. Absence of tight junctions between microvascular endothelial cells in human cerebellar hemangioblastoma. Neurosurgery. 2006, 59(3): 660-70
23 Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991, 266(18): 11947-11954
24 Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci USA. 1998, 95(26): 15809-15814
1 Catapano D, Muscarella LA, Guarnieri V, et al. Hemangio- blastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery. 2005, 56(6): 1215-21
2 Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 2000, 35(2): 71-103
3 Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001, 13(2): 167-71
4 Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia byHIF-1. Blood. 2005, 105(2): 659-69
5 Zagzag D, Krishnamachary B, Yee H, et al. Stromal cell-derivedfactor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005, 65(14): 6178-88
6 Hellwig-Bürgel T, Stiehl DP, Wagner AE, et al. Hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res. 2005, 25(6): 297-310
7 Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001, 93(4): 309-14
8 Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999, 59(22): 5830-5
9 Jones A, Fujiyama C, Blanche C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin Cancer Res. 2001, 7(5): 1263-72
10 Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003, 3(10): 721-32
11 Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 2000,88(11): 2606-18
12 Krieg M, Marti HH, Plate KH, et al. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood. 1998, 92(9): 3388-93
13 李林繁, 李德泽, 麦洁文. 小脑血管网织细胞瘤中缺氧诱导因子-1a表达水平的改变海南医学院学报. 2005, 11(2): 95-97
14 Huang H, Held-Feindt J, Buhl R, et al. Expression of VEGF and its receptors in different brain tumors. Neurol Res. 2005, 27(4): 371-7
15 Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000, 50(1-2): 109-20
16 Patton KT, Satcher RL Jr, Laskin WB. Apillary hemangioblastoma of soft tissue: report of a case and review of the literature. Hum Pathol. 2005, 36(10): 1135-9
17 Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004, 22(24): 4991-5004
18 Wizigmann-Voos S, Plate KH. Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol. 1996, 11(4): 1049-1061
19 Beckner ME, Sasatomi E, Swalsky PA, et al. Loss of heterozygosity reveals non-VHL allelic loss in hemangio-blastomas at 22q13. Hum Pathol. 2004, 35(9): 1105-11
20 Chen Y, Tachibana O, Hasegawa M, et al. Absence of tight junctions between microvascular endothelial cells in human cerebellar hemangioblastoma. Neurosurgery. 2006, 59(3): 660-70
21 Wizigmann-Voos S, Breier G, Risau W, et al. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangio- blastomas. Cancer Res. 1995, 55(6): 1358-64
22 李爱冰, 袁先厚, 陈新军. VEGF、bFGF 在血管网织细胞瘤中的表达. 中国临床神经外科杂志. 2000, 5(4): 229-231
23 Morii K, Tanaka R, Washiyama K, et al. Expression of vascular endothelial growth factor in capillary hemangio-blastoma. Biochem Biophys Res Commun. 1993, 194(2): 749-55
24 Vaquero J, Zurita M, Coca S, et al. Expression of vascular endothelial growth factor in cerebellar hemangioblastomas does not correlate with tumor angiogenesis. Cancer Lett. 1998, 132(1-2): 213-7