HIF-1α与P-gp、Topo-Ⅱα在乳腺癌中的表达及意义
摘要
背景和目的:乳腺癌是妇女最常见的恶性肿瘤之一,近年来在我国,特别是大城市内的发病率仍呈直线上升趋势。乳腺癌已被视为全身性疾病,化疗是治疗乳腺癌的重要手段之一,但化疗耐药的出现,导致患者无病生存期缩短,所以探讨有关乳腺癌耐药相关基因,指导规范化治疗尤为重要。肿瘤细胞微环境的改变与肿瘤多药耐药的关系成为目前研究的新热点。肿瘤细胞微环境改变中最重要的是细胞的缺血缺氧,由于缺氧诱导因子-l(hypoxia-inducible factor-1, HIF-1)在细胞缺氧改变中占有重要中心地位,因此作为其活性亚单位的HIF-1α与肿瘤细胞多药耐药的关系备受关注。P-糖蛋白(permeability- glucoprotein, P-gp)过表达是肿瘤多药耐药(multidrug resistance, MDR)产生的一个主要原因,拓扑异构酶Ⅱα(topoisomeraseⅡα, Topo-Ⅱα)是多种抗肿瘤药物如蒽环类药物的靶分子,其表达降低将影响肿瘤对化疗的敏感性。
本研究采用免疫组织化学方法检测HIF-1α、P-gp与Topo-Ⅱα在乳腺癌组织中的表达,分析其表达与患者临床病理特征及三者之间的相关关系,探讨缺氧对乳腺癌发生、发展以及化疗耐药的影响,希望对乳腺癌患者的治疗及预后提供可靠的参考指标,以及有助于实现逆转肿瘤耐药和提高化疗效果。
方法:选取秦皇岛市第一医院2000年9月~2003年12月接受手术治疗的乳腺癌患者的组织石蜡标本59例,采用免疫组织化学SP法对乳腺癌组织HIF-1α、P-gp与Topo-Ⅱα的表达进行检测,并结合完整的临床资料,采用SPSS14.0软件系统进行分析,应用χ2检验等分析三者与临床病理特征的关系,以p<0.05为有统计学意义。
结果:1 HIF-1α、P-gp与Topo-Ⅱα在59例乳腺癌组织中的阳性表达率分别为:61.01%(36/59)、40.68%(24/59)和49.15%(29/59),而在15例癌旁正常乳腺组织中均为阴性表达,HIF-1α、P-gp与Topo-Ⅱα在乳腺癌组织中的表达均明显高于正常乳腺组织,差异具有统计学意义(p<0.05)。
2 HIF-1α、P-gp与Topo-Ⅱα的表达与乳腺癌不同的临床病理特征之间的关系:
HIF-1α在T≤2cm、2cm5cm组中的阳性表达率分别为30.77%(4/13)、65.71%(23/35)和81.82%(9/11),各组差异均具有统计学意义(P<0.05);随着乳腺癌组织T分期的增加HIF-1α的阳性表达率增高,具有线性趋势(P<0.05)。HIF-1α在组织学Ⅰ、Ⅱ和Ⅲ级组中的阳性表达率分别为22.22%(2/9)、58.62%(17/29)和80.95%(17/21),各组间差异均具有统计学意义(P<0.05);随着乳腺癌组织学分级的增加HIF-1α的阳性表达率增高,具有线性趋势(P<0.05)。HIF-1α在有淋巴结转移组中的阳性表达率明显高于其在无淋巴结转移组中的阳性表达率(76.47%VS40.00%),差异具有统计学意义(P<0.05)。HIF-1α在病理分期0~Ⅰ、Ⅱ和Ⅲ期组中的阳性表达率分别为58.33%(7/12)、61.11%(22/36)和63.64%(7/11),三组间差异无统计学意义(P >0.05);在不同年龄、病理类型及月经状态组中HIF-1α阳性表达率的差异无统计学意义(P >0.05)。
P-gp在有淋巴结转移组中的阳性表达率明显高于其在无淋巴结转移组中的阳性表达率(52.94%VS24.00%),差异具有统计学意义(P<0.05);在不同年龄、肿块大小、组织学分级、病理分期、病理类型及月经状态组中P-gp阳性表达率的差异均无统计学意义(P >0.05)。
在不同年龄、肿块大小、组织学分级、淋巴结转移情况、病理分期、病理类型及月经状态组中Topo-Ⅱα阳性表达率的差异均无统计学意义(P >0.05)。
3乳腺癌中HIF-1α与P-gp表达的相关性
HIF-1α阳性组的P-gp阳性表达率为55.56%(20/36),HIF-1α阴性组的P-gp阴性表达率为82.61%(19/23),HIF-1α与P-gp表达呈正相关表达(r=0.38,P<0.05)。
4乳腺癌中HIF-1α与Topo-Ⅱα表达的相关性
HIF-1α阳性组的Topo-Ⅱα阳性表达率为55.56% (20/36),HIF-1α阴性组的P-gp阴性表达率为60.87%(14/23),HIF-1α与Topo-Ⅱα表达无相关性(r=0.16,P >0.05)。
结论:1 HIF-1α表达与乳腺癌肿块大小、组织学分级和淋巴结转移与否呈正相关,HIF-1α过表达提示乳腺癌具有更高的侵袭性。
2 P-gp的表达与乳腺癌淋巴结转移与否呈正相关,可能是乳腺癌复发、转移的一个高危因素。
3 Topo-Ⅱα在乳腺癌组织中过表达,而在正常乳腺组织中呈阴性表达,且与临床病理特征之间无相关性,提示它可能是一个独立的影响耐药的因素。
4 HIF-1α与P-gp在乳腺癌中的表达呈正相关,提示其可能与乳腺癌多药耐药相关,可以为揭示耐药机制提供新的思路。
5 HIF-1α与Topo-Ⅱα在乳腺癌中的表达无相关性。
Background and Objective: Breast cancer is the most common malignant disease of women. Recently, the mortality of breast cancer is sharp rising in China, especially in big citys. Breast cancer has already been regarded as a systemic disease, and chemotherapy is one of the important therapeutic approaches to treat breast cancer. But the disease free survival (DFS) of patients has been induced by the appearance of drug resistant, so it is important to probe the breast cancer resistant related gene and guide the standard therapeutics. The relationship between the changes of cell microenvironment and multidrug resistance (MDR) becomes a new hot spot. The most important change of cell microenvironment is the ischemia and hypoxia. Since hypoxia-inducible factor-1 (HIF-1) plays an important role in cell microenvironment changes,it is very interesting to investigate the relationship between MDR and HIF-1α—the active subunit of HIF-1. The over expression of permeability-glycoprotein (P-gp) plays a more important role in MDR, The DNA topoisomerase-Ⅱ(Topo-Ⅱ) is the effective target of many anti-tumor medicine including anthracycline, and it is often associated with drug resistance when its level decrease.
This study was designed to evaluate the expression of HIF-1αand P-gp, Topo-Ⅱαin breast cancer by immunohistochemistry and investigate the relationships between their expressions and the clinicopathological characteristics, and we also analysed the association among their expressions,which may reveal the role of hypoxia in the pathogenesis and progression of breast cancer. Thus we would find a promising target for therapy and a potentially useful factor for prognostic detection in breast cancer,which would retroconverse tumor drug resistance and improve the effect of chemotherapy.
Methods: We collected 59 breast cancer samples which were resected by surgery and confirmed by pathology in the First Hospital of Qin Huangdao from September, 2000 to December, 2003. We detected the expression of HIF-1α, P-gp and Topo-Ⅱαusing immunohistochemieal SP methods to investigate the relationship between them,as well as the correlate with clinicopathological characteristics in human breast cancer. Statistical methodsχ2 test was performed by SPSS software version 14.0.
Results: 1 Expression of HIF-1α, P-gp and Topo-Ⅱαin breast cancer: The positive rates of the expression of HIF-1α, P-gp and Topo-Ⅱαin 59 cases were 61.01%、40.68% and 49.15% respectively. These proteins were all negative in 15 normal breast tissues. And there were significant differences between breast cancer tissues and normal tissues (P<0.05).
2 The relationship of the expression of HIF-1α, P-gp and Topo-Ⅱαand the clinicopathological characteristics:
Expression of HIF-1αwas positively related to tumor size, histological gradesand and lymph node matastasis, and had linear trend with tumor size and histological grades (P<0.05). And it was not correlated with patients’age, pTNM stages, histological types and menstruation status (P>0.05).
The positive rate of the expression of P-gp in lymph node matastasis group (52.94%) was higher than that in no lymph node matastasis group (24.00%), the difference had statistical significance (P<0.05). The expression of P-gp had significantly positive correlation with lymph node matastasis (P<0.05), and no correlation with age, tumor size, histological grades, pTNM stages, histological types and menstruation status (P>0.05).
There was no correlation between the expression of Topo-Ⅱαand any of the clinicopathological characteristics mentioned as above, such as age,tumor size, histological grades, et al (P>0.05).
3 The relationship between expression of HIF-1αand P-gp: The positive expression rate of P-gp was 55.56%(20/36) in the group of HIF-1αpositive. The negative expression rate of P-gp was 82.61%(19/23) in the group of HIF-1αnegative. Expression of P-gp was positively correlated with HIF-1α(r=0.38, P<0.05).
4 The relationship between expression of HIF-1αand Topo-Ⅱα: There was no correlation between the expression of Topo-Ⅱαand HIF-1α(r=0.16, P >0.05).
Conclusions: 1 The expression of HIF-1αis positively related to tumor size, histological gradesand and lymph node matastasis, its over expression shows that the invasion of breast cancer is even higher.
2 The expression of P-gp has significantly positive correlation with lymph node matastasis, it may be a high risk factor for recurrence and matastasis of breast cancer.
3 Topo-Ⅱαis over expressed in breast cancer tissues, and is negative in normal tissues, it may be a particular factor of drug resistance.
4 The expression of HIF-1αis positively correlated with P-gp, and HIF-1αmay play an important role in multidrug resistance, which may provide a novel application strategy gene targeted therapy of breast cancer.
5 There is no correlation between the expression of HIF-1αand Topo-Ⅱαin breast cancer.
本研究采用免疫组织化学方法检测HIF-1α、P-gp与Topo-Ⅱα在乳腺癌组织中的表达,分析其表达与患者临床病理特征及三者之间的相关关系,探讨缺氧对乳腺癌发生、发展以及化疗耐药的影响,希望对乳腺癌患者的治疗及预后提供可靠的参考指标,以及有助于实现逆转肿瘤耐药和提高化疗效果。
方法:选取秦皇岛市第一医院2000年9月~2003年12月接受手术治疗的乳腺癌患者的组织石蜡标本59例,采用免疫组织化学SP法对乳腺癌组织HIF-1α、P-gp与Topo-Ⅱα的表达进行检测,并结合完整的临床资料,采用SPSS14.0软件系统进行分析,应用χ2检验等分析三者与临床病理特征的关系,以p<0.05为有统计学意义。
结果:1 HIF-1α、P-gp与Topo-Ⅱα在59例乳腺癌组织中的阳性表达率分别为:61.01%(36/59)、40.68%(24/59)和49.15%(29/59),而在15例癌旁正常乳腺组织中均为阴性表达,HIF-1α、P-gp与Topo-Ⅱα在乳腺癌组织中的表达均明显高于正常乳腺组织,差异具有统计学意义(p<0.05)。
2 HIF-1α、P-gp与Topo-Ⅱα的表达与乳腺癌不同的临床病理特征之间的关系:
HIF-1α在T≤2cm、2cm
P-gp在有淋巴结转移组中的阳性表达率明显高于其在无淋巴结转移组中的阳性表达率(52.94%VS24.00%),差异具有统计学意义(P<0.05);在不同年龄、肿块大小、组织学分级、病理分期、病理类型及月经状态组中P-gp阳性表达率的差异均无统计学意义(P >0.05)。
在不同年龄、肿块大小、组织学分级、淋巴结转移情况、病理分期、病理类型及月经状态组中Topo-Ⅱα阳性表达率的差异均无统计学意义(P >0.05)。
3乳腺癌中HIF-1α与P-gp表达的相关性
HIF-1α阳性组的P-gp阳性表达率为55.56%(20/36),HIF-1α阴性组的P-gp阴性表达率为82.61%(19/23),HIF-1α与P-gp表达呈正相关表达(r=0.38,P<0.05)。
4乳腺癌中HIF-1α与Topo-Ⅱα表达的相关性
HIF-1α阳性组的Topo-Ⅱα阳性表达率为55.56% (20/36),HIF-1α阴性组的P-gp阴性表达率为60.87%(14/23),HIF-1α与Topo-Ⅱα表达无相关性(r=0.16,P >0.05)。
结论:1 HIF-1α表达与乳腺癌肿块大小、组织学分级和淋巴结转移与否呈正相关,HIF-1α过表达提示乳腺癌具有更高的侵袭性。
2 P-gp的表达与乳腺癌淋巴结转移与否呈正相关,可能是乳腺癌复发、转移的一个高危因素。
3 Topo-Ⅱα在乳腺癌组织中过表达,而在正常乳腺组织中呈阴性表达,且与临床病理特征之间无相关性,提示它可能是一个独立的影响耐药的因素。
4 HIF-1α与P-gp在乳腺癌中的表达呈正相关,提示其可能与乳腺癌多药耐药相关,可以为揭示耐药机制提供新的思路。
5 HIF-1α与Topo-Ⅱα在乳腺癌中的表达无相关性。
Background and Objective: Breast cancer is the most common malignant disease of women. Recently, the mortality of breast cancer is sharp rising in China, especially in big citys. Breast cancer has already been regarded as a systemic disease, and chemotherapy is one of the important therapeutic approaches to treat breast cancer. But the disease free survival (DFS) of patients has been induced by the appearance of drug resistant, so it is important to probe the breast cancer resistant related gene and guide the standard therapeutics. The relationship between the changes of cell microenvironment and multidrug resistance (MDR) becomes a new hot spot. The most important change of cell microenvironment is the ischemia and hypoxia. Since hypoxia-inducible factor-1 (HIF-1) plays an important role in cell microenvironment changes,it is very interesting to investigate the relationship between MDR and HIF-1α—the active subunit of HIF-1. The over expression of permeability-glycoprotein (P-gp) plays a more important role in MDR, The DNA topoisomerase-Ⅱ(Topo-Ⅱ) is the effective target of many anti-tumor medicine including anthracycline, and it is often associated with drug resistance when its level decrease.
This study was designed to evaluate the expression of HIF-1αand P-gp, Topo-Ⅱαin breast cancer by immunohistochemistry and investigate the relationships between their expressions and the clinicopathological characteristics, and we also analysed the association among their expressions,which may reveal the role of hypoxia in the pathogenesis and progression of breast cancer. Thus we would find a promising target for therapy and a potentially useful factor for prognostic detection in breast cancer,which would retroconverse tumor drug resistance and improve the effect of chemotherapy.
Methods: We collected 59 breast cancer samples which were resected by surgery and confirmed by pathology in the First Hospital of Qin Huangdao from September, 2000 to December, 2003. We detected the expression of HIF-1α, P-gp and Topo-Ⅱαusing immunohistochemieal SP methods to investigate the relationship between them,as well as the correlate with clinicopathological characteristics in human breast cancer. Statistical methodsχ2 test was performed by SPSS software version 14.0.
Results: 1 Expression of HIF-1α, P-gp and Topo-Ⅱαin breast cancer: The positive rates of the expression of HIF-1α, P-gp and Topo-Ⅱαin 59 cases were 61.01%、40.68% and 49.15% respectively. These proteins were all negative in 15 normal breast tissues. And there were significant differences between breast cancer tissues and normal tissues (P<0.05).
2 The relationship of the expression of HIF-1α, P-gp and Topo-Ⅱαand the clinicopathological characteristics:
Expression of HIF-1αwas positively related to tumor size, histological gradesand and lymph node matastasis, and had linear trend with tumor size and histological grades (P<0.05). And it was not correlated with patients’age, pTNM stages, histological types and menstruation status (P>0.05).
The positive rate of the expression of P-gp in lymph node matastasis group (52.94%) was higher than that in no lymph node matastasis group (24.00%), the difference had statistical significance (P<0.05). The expression of P-gp had significantly positive correlation with lymph node matastasis (P<0.05), and no correlation with age, tumor size, histological grades, pTNM stages, histological types and menstruation status (P>0.05).
There was no correlation between the expression of Topo-Ⅱαand any of the clinicopathological characteristics mentioned as above, such as age,tumor size, histological grades, et al (P>0.05).
3 The relationship between expression of HIF-1αand P-gp: The positive expression rate of P-gp was 55.56%(20/36) in the group of HIF-1αpositive. The negative expression rate of P-gp was 82.61%(19/23) in the group of HIF-1αnegative. Expression of P-gp was positively correlated with HIF-1α(r=0.38, P<0.05).
4 The relationship between expression of HIF-1αand Topo-Ⅱα: There was no correlation between the expression of Topo-Ⅱαand HIF-1α(r=0.16, P >0.05).
Conclusions: 1 The expression of HIF-1αis positively related to tumor size, histological gradesand and lymph node matastasis, its over expression shows that the invasion of breast cancer is even higher.
2 The expression of P-gp has significantly positive correlation with lymph node matastasis, it may be a high risk factor for recurrence and matastasis of breast cancer.
3 Topo-Ⅱαis over expressed in breast cancer tissues, and is negative in normal tissues, it may be a particular factor of drug resistance.
4 The expression of HIF-1αis positively correlated with P-gp, and HIF-1αmay play an important role in multidrug resistance, which may provide a novel application strategy gene targeted therapy of breast cancer.
5 There is no correlation between the expression of HIF-1αand Topo-Ⅱαin breast cancer.
引文
1沈镇宙,邵志敏.现代乳腺肿瘤学进展[M].上海科技文献出版社,2002:4
2 Semenza GL. HIF-1: mediator of physiological and pathophy-siological resposes to hypoxia[J].Appl Physiol, 2000,88(4):1474-1480
3 Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF1) alpha: it’s protein stability and biological functions [J]. Exp Mol Med,2004,36(1):1-12
4 Semenza GL. Targeting HIF-1 for cancer therapy[J].Nat Rev Cancer,2003,3(10):721-732
5 Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1 alpha in Hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis[J]. Nature,1998,394(6692):485-490
6桂贤,刘会敏.肿瘤多药耐药发生机制的研究进展[J].上海医学,2005,28(2):161-164
7 Lu CD, Altieri DC, Tanigawa N. Expression of a novel anti-apoptosis gene, surviving, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinoma. Cancer Res,1998,1808-1812
8 Zhong H, De Marzo A M, Laughner E. Over expression of HIF-la in common human cancers and their metastases[J]. Cancer Res, 1999,59 (22): 5830-5835
9 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. Mol Cell Biol,1992,12(12): 5447-5454
10 Semenza GL. Signal transduction to hypoxia-inducible factor[J]. Biochem Pharmaco,l 2002, 64(5-6): 993-998
11 Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation[J]. J B ioch in Biophys Acta,2003, 1619(2): 113-124
12 Zhong H, Semenza GL, Simons JW, et al. UP-reguliltion of hypoxia inducible factor-1 alpha is an early event in carcinogenesis [J].Cancercer Detect Prev,2004,28(l):88-93
13 Schindl M, Schoppmann SF, Samonigg H, et al. Overexpression of hypoxia-inducible factor 1 alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer[J].Clin Cancer Res,2002,8 (6):1831-1837
14 Yoshimura H, Dhar DK, Kohno H, et al. Prognostic impactof hypoxia-inducible factors 1 alpha and 2 alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression[J].Clin Cancer Res,2004,10(24):8554-8641
15 Marxsen JH, Schmitt O, Metzen E, et al. Vascuar endothelial growth factor gene expression in the human breast cancer cell lineMX-1 is controlled by O2 availability in vitro and in vivo[J].Ann Anat,2001,183:243-249
16樊利芳等.肺癌组织中缺氧诱导因子-1α的表达及其凋亡和增殖的关系.癌症,2002,21(3):254-258
17王蕴,姜洁.HIF-1,MRP和P-gp在上皮性卵巢癌中的表达及其临床意义.济宁医学院学报,2008,31(1):26-30
18夏曙,于世英,袁响林,等.乏氧对肺腺癌A549细胞p-糖蛋白和多药耐药相关蛋白表达的影响.中华医学杂志,2004,84(8):663-666
19 Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance [J].J Natl Cancer Inst,1997,89(13):917-931
20徐光辉,叶胜龙,郑义同,等.人乳腺癌中3种耐药基因产物的表达及其与预后的相关性[J].复旦学报(医学版),2005,32(1):33-35
21周建伟.乳腺癌组织中多药耐药基因的表达及其临床意义.江西医药,2008,43(11):1157-1159
22李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症,2001,20(8):866-868
23 Komdeur R, Molenaar WM, Zwart N, et al. Multidrug resistance proteins in primary and metastatic soft-tissue sarcomas: down-regulation of P-glycoprotein during metastatic progression[J].Anticancer Res.2004,24(1):291 -295
24 Hellemans P, van Dam PA, Geyskens M, et al. Immunohistochemical study of topoisomeraseⅡ-alpha expression in primary ductal carcinoma of the breast [J].J Clin Pathol,1995,48(2):147-150
25孙丽梅,王鲁建,宋敏,等.乳腺癌中耐药蛋白P-gp、GST-π、Topo-Ⅱ的表达[J].中国组织化学与细胞化学杂志,2006,15(2):169-172
26 Sandri MI, Hochhauser D, Ayton P, et al. Differential expression of the topoisomeraseⅡalpha and beta genes in human breast cancers[J].Br J Cancer,1996,73(12):1518 -1524
27樊峰,吴伟国,何影娟.乳腺癌中多药耐药基因产物的表达及临床意义.实用临床医药杂志,2006,10(1):44
28 Tusnady G E, Bakos E, Varadi A, et al. Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporter [J].FEBS Lett,1997,402(1):1-3
29 Dantzig AH, Shepard RL, Pratt SE, et al. Evaluation of the binding of the tricyclic isoxazole photoaffinity label LY475776 to multidrug resistance associated protein 1(MRP1) orthologs and several ATP-binding cassette (ABC) drug transporters [J].Bio Chem Pharmacol.2004,67(6):1111-1121
30 Cardoso F, Durbecq V, Larsimont D, et al. Correlation between complete response to anthracyline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer[J].Int J Oncol,2004,24 (1):201-209
31 Knoop AS, Knudsen H, Balslev, et al. Retrospective analysis of topoisomeraseⅡa amplifications and deletions as predictive markers in primary breast cancer Patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group.J Clin Oncol.2006,24(6):1015
32 Tanner M, Isola J, Wiklund T, et al. TopoisomeraseⅡalpha Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline- Based Adjuvant Chemotherapy in HER-2/neu-Amplified Breast Cancer: Results From the Randomized Scandinavian Breast Group Trial 9401. J Clin Oncol.2006 May 8:[Epub ahead of print]
33 Durbecq V, Paesmans M, Cardoso F, et al. Topoisomerase-Ⅱalpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther. 2004,3(10):1207-1214
34陈晓耕,林招贤,林孟波,等.缺氧诱导因子-1α在胃癌中的表达与临床病理、P53及P糖蛋白(P-gp)的关系[J].中国癌症杂志,2006,16(10):813-816
35 Comerford KM, Wallace TJ, Karhausen J, et al. Hypoxia-inducible factor-1 dependent regulation of the multidrug resistance (MDR1) gene[J].Cancer Res,2002, 62(12):3387-3394
36 Song X, Liu X, Chi W, et al. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-l alpha gene[J].Cancer Chemother Pharmacol, 2006,58(6):776-784
37 Ogiso Y, Tomida A, Lei S, et al. Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. Cancer Res,2000,60(9):2429-2434
38 Peters KB, Brown JM. Tirapazamine: A hypoxia-activated topoisomeraseⅡpoison. Cancer Res,2002,62(18):5248- 5253
39刘丽丽,战雪梅,孙崇伟.HIF-1α和TopoⅡ在子宫内膜癌中的表达及意义[J].山东医学高等专科学校学报2008,30(2):81-83
40刘志坤,黄雄,谢文彪.贫血对胃癌患者术后化疗耐药的影响[J].社区医学杂志2007,5(3):45-47
1 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. Mol Cell Biol,1992,12(12):5447 -5454
2 Jiang BH, Rue E, Wang GL, et al. Dimerization, DNA binding, and transactivation properties of hypoxia inducible faetor1 [J]. J Biol Chem,1996,271(30):17771 -17778
3 Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor l levels vary exponentially over a physiologically relevant range of O2 tension [J].Am J Physiol,1996,271 (41):C1172-C1180
4 Ao N, Ding M, Zheng JZ, et al. Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species[J].Bio Chem,2002, 277(35):31963-31971
5 Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor 1(HIF-1) alpha: its protein stability and biology functions [J]. Exp Mol Med,2004,36(5):1-12
6 Zelzer E, Levy Y, Kahana C, et al. Insulin inducestranscription of target genes through the hypoxia-inducible factor HIF-lα/ARNT [J].EMBO J,1998,17:5085-5094
7 Richard DE, Berra E, Gothie E, et a1.P42/P44 mitogen- activated protein kinases phosphorylate hypoxia-inducible factor lα(HIF-lα) and enhance the transcriptional activity of HIF-1[J].J Biol Chem,l999,274:32631-32637
8 Ruas JL, Poellinger L, Pereira T. Functional analysis of hypoxia-inducible factor-1αmediated transactivation identification of amino acid residues critical for trans- criptional activation and/or interaction with CREB-binding protein [J]. Biol Chem,2002,277(41):38723-38730
9 Mircea I, Keiichi K, Haifeng Yang, et al. HIF-1αtargeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing[J].Science,2001,292(5516):464- 468
10 Sonja AD, Maria MY, Roberto NP, et a1.Structural basis for HIF-1α/CBP recognition in the cellular hypoxic response [J].Natl. Acad. Sci. USA,2002,99(8):5271-5276
11 Mahon PC, Hirota K, Semenza GL, et al. FIH-l: a novel protein that interacts with HIF-1 alpha and VHL tomediate repression of HIF-1 transcriptional activity[J].Genes Dev, 2001,15(20):2675-2686
12 Alrarez-Tejado M, Alfranea A, Aragones J, et al. Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt Pathways in the activation of hypoxia-inducible factors by low oxygen tension [J].J Biol Chem,2002,277(16):13508-13517
13 Anastasiadis AG, Ghafar MA, Salomon L, et al. Human hormone-refractory prostate cancers can harbor mutations in the 02-dePendent degradation domain of hypoxia inducible factor-lα(HIF-1α). J Clin Cancer Res Oncol.2002,128 (7):358-362
14 Maxwell PH, Wiesener MS, Chang G-W, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis[J].Nature,1999,399(6733): 271-275
15 Zhong H, De Marzo A M, Laughner E. Over expression of HIF-la in common human cancers and their metastases [J]. Cancer Res,1999,59 (22):5830-5835
16 Jiang BH, Agani F, Passaniti A, et al. V-SRC induces expression of hypoxia-inducible factor l(HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase I: Involvement of HIF-1 in tumor progression[J].Cancer Res,1997,57(23):5328-5335
17 Comerford KM, Wallace TJ, Karhausen J, et al. Hypoxia-inducible factor-1 dependent regulation of the multidrug resistance (MDR1) gene[J].Cancer Res,2002,62 (12):3387-3394
18 Semenza GL. Signal transduction to hypoxia-inducible factor[J]. Biochem Pharmaco,2002, 64(5-6):993-998
19 Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation[J]. J B ioch in BiophysActa,2003,1619(2):113-124
20 Zhong H, Semenza GL, Simons JW, et al. UP-reguliltion of hypoxia inducible factor-1 alpha is an early event in carcinogenesis [J].Cancercer Detect Prev,2004,28(l):88-93.
21 Jiang HY, Feng YJ.Relationship of hypoxia-inducible factor-1 alpha expression and vascular endothelial growth factor in SKOV-3 ovarian cancer model[J].Zhong hua Fu Chan Ke Za Zhi,2004,39(11):767-770
22 Jiang CQ, Fan LF, Liu ZS . Expression levels and significance of hypoxia inducible factor-1 alpha and vascular endothelial growth factor in human colorectal adenocarcinoma [J].Chin Med,J,2004,117(10):1541-1546
23 Wei HY, Chen LB, Wang CY, et a1.Correlation of mRNA expression of hypoxia inducible factor-1 alpha to biological features of pancreastic cancer[J].Chin, J Cancer,2005,24 (2):184-188
24 Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science,1989,86:1306-1310
25 Connolly DT, Heuveiman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endouthelial cell growth and angiogenesis [J].J Clin Invest,1989,84:1470- 1478
26 Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor expression at the deepest factor expression at the deepest invasive site of advanced colorectalcarcinoma[J]. Oncology,2003,64:61-73
27 Duff SE, Li C, Jeziorska M, et al. vascular growth factor and lymphangiogenesis[J].Physiol Rew,2002,82:673-700
28江晓丰,董强刚,冯文贤等.缺氧诱导人肺癌细胞株表达血管内皮生长因子.肺癌,2000,l20(6):423-427
29 Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance[J]. J Biol Chem,2003,278(22):19575 -19578
30 Wang Y, Pakunlu RI, Tsao W, et a1.Bimodal effect of hypoxia in cancer:the role of hypoxia inducible factor in apoptosis[J].Mol Pharm,2004,1(2):156-165
31 Suzuki H, Tomida A, Tsuruo T, et a1.Dephosphorylated hypoxia-inducible factor 1αas a mediator of p53 dependent apoptosis during hypoxia[J].Oncogene,2001,20(41):5779- 5788
32 Chen D, Li M, Luo J, et al. Direct interactions between HIF-1 and MDM2 modulate P53 function [J]. J Biol Chem, 2003,278(16):13595-13598
33 Schmid T, Zhou J, KohlR, et al. P300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1)[J]. Bio chem J,2004,380(3):289-295
34 Semenza GL. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res,2001, 49(5): 614-617
35 Bruick RK, ExPression of the gene encoding the proa- poptotic Nip3 Protein is induced by hypoxia[J].Proc NatlAcad Sci USA,2000,97(16):9082-9087
36 Kim JY, Ahn HJ, Ryu JH, et al. BH3-only protein noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor l alpha [J].J Exp Med,2004,199(l):113-124
37 Lee MJ, Kim JY, Suk K, et al. Identification of the hypoxia- inducible factor 1 alpha-responsive HGTD-P gene as a mediator in mitochondrial apoptotic Pathway[J]. Mol Cell Biol,2004,24(9):3918-3127
38 Zaman K, Ryu H, Hall D, et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-l and ATF-l/CREB and increased expression of glycolytic enzymes, p21(wafl/cipl), and erythropoietin[J].J Neurosci,1999,19(22):9821-9830
39 Erler JT, Cawthorne CJ, Williams KJ, et al. Hypoxia- mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor l-dependent and-independent mechanisms and contributes to drug resistance[J].Mol Cell Biol,2004,(7):2875-2889
40 Brune B. Nitric oxide NO apoptosis or turning it on?[J].Cell Death Differ,2003,10(8):864-869
41 Wang Y, Minko TA.Novel cancer therapy: combined liposomal hypoxia inducible factor 1 alpha antisense oligo- nucleotides and an anti-cancer drug[J].Bio chem Pharm, 2004,68(10):2031-2042
42 Bos R, Zhong H, Hanradan FC, et al. Levels of hypoxiainducible factor1 alpha during breast carcinogenesis[J]. Nat Cancer Inst Monogr,2001,93:309-314
43代志军,高洁,王西京,等.乳腺导管增生癌变过程中HIF-1a的表达变化及意义[J].中国肿瘤临床与康复,2007,14 (1):20-22
44高勇强,谢文彪,谷依学,等.乳腺癌中HIF-la, PCNA及Bcl-2的表达分析[J].南华大学学报,2006,34(2):200-202
45 Pore N, Jiang Z, Gupta A, et al. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia- inducible factor(HIF)-1-independent and HIF-1-dependent mechanisms [J]. Cancer Research,2006,66:3197-3204
46 Mayerhofer M, Valent P, Sperr WR, et al. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1 alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin[J].Blood,2002,100: 3767-3775
47 Koukourakis,M.I.,Simopoulos,C.,Polychronidis,A.,et al.The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: Dichotomus effect predictable by the HIFI alpha/VEGF pretreatment status?[J].Anticancer Research, 2003,23:1673-1680
2 Semenza GL. HIF-1: mediator of physiological and pathophy-siological resposes to hypoxia[J].Appl Physiol, 2000,88(4):1474-1480
3 Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF1) alpha: it’s protein stability and biological functions [J]. Exp Mol Med,2004,36(1):1-12
4 Semenza GL. Targeting HIF-1 for cancer therapy[J].Nat Rev Cancer,2003,3(10):721-732
5 Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1 alpha in Hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis[J]. Nature,1998,394(6692):485-490
6桂贤,刘会敏.肿瘤多药耐药发生机制的研究进展[J].上海医学,2005,28(2):161-164
7 Lu CD, Altieri DC, Tanigawa N. Expression of a novel anti-apoptosis gene, surviving, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinoma. Cancer Res,1998,1808-1812
8 Zhong H, De Marzo A M, Laughner E. Over expression of HIF-la in common human cancers and their metastases[J]. Cancer Res, 1999,59 (22): 5830-5835
9 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. Mol Cell Biol,1992,12(12): 5447-5454
10 Semenza GL. Signal transduction to hypoxia-inducible factor[J]. Biochem Pharmaco,l 2002, 64(5-6): 993-998
11 Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation[J]. J B ioch in Biophys Acta,2003, 1619(2): 113-124
12 Zhong H, Semenza GL, Simons JW, et al. UP-reguliltion of hypoxia inducible factor-1 alpha is an early event in carcinogenesis [J].Cancercer Detect Prev,2004,28(l):88-93
13 Schindl M, Schoppmann SF, Samonigg H, et al. Overexpression of hypoxia-inducible factor 1 alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer[J].Clin Cancer Res,2002,8 (6):1831-1837
14 Yoshimura H, Dhar DK, Kohno H, et al. Prognostic impactof hypoxia-inducible factors 1 alpha and 2 alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression[J].Clin Cancer Res,2004,10(24):8554-8641
15 Marxsen JH, Schmitt O, Metzen E, et al. Vascuar endothelial growth factor gene expression in the human breast cancer cell lineMX-1 is controlled by O2 availability in vitro and in vivo[J].Ann Anat,2001,183:243-249
16樊利芳等.肺癌组织中缺氧诱导因子-1α的表达及其凋亡和增殖的关系.癌症,2002,21(3):254-258
17王蕴,姜洁.HIF-1,MRP和P-gp在上皮性卵巢癌中的表达及其临床意义.济宁医学院学报,2008,31(1):26-30
18夏曙,于世英,袁响林,等.乏氧对肺腺癌A549细胞p-糖蛋白和多药耐药相关蛋白表达的影响.中华医学杂志,2004,84(8):663-666
19 Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance [J].J Natl Cancer Inst,1997,89(13):917-931
20徐光辉,叶胜龙,郑义同,等.人乳腺癌中3种耐药基因产物的表达及其与预后的相关性[J].复旦学报(医学版),2005,32(1):33-35
21周建伟.乳腺癌组织中多药耐药基因的表达及其临床意义.江西医药,2008,43(11):1157-1159
22李杰,许良中,吴炅.三种耐药基因蛋白表达在乳腺癌中的临床意义[J].癌症,2001,20(8):866-868
23 Komdeur R, Molenaar WM, Zwart N, et al. Multidrug resistance proteins in primary and metastatic soft-tissue sarcomas: down-regulation of P-glycoprotein during metastatic progression[J].Anticancer Res.2004,24(1):291 -295
24 Hellemans P, van Dam PA, Geyskens M, et al. Immunohistochemical study of topoisomeraseⅡ-alpha expression in primary ductal carcinoma of the breast [J].J Clin Pathol,1995,48(2):147-150
25孙丽梅,王鲁建,宋敏,等.乳腺癌中耐药蛋白P-gp、GST-π、Topo-Ⅱ的表达[J].中国组织化学与细胞化学杂志,2006,15(2):169-172
26 Sandri MI, Hochhauser D, Ayton P, et al. Differential expression of the topoisomeraseⅡalpha and beta genes in human breast cancers[J].Br J Cancer,1996,73(12):1518 -1524
27樊峰,吴伟国,何影娟.乳腺癌中多药耐药基因产物的表达及临床意义.实用临床医药杂志,2006,10(1):44
28 Tusnady G E, Bakos E, Varadi A, et al. Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporter [J].FEBS Lett,1997,402(1):1-3
29 Dantzig AH, Shepard RL, Pratt SE, et al. Evaluation of the binding of the tricyclic isoxazole photoaffinity label LY475776 to multidrug resistance associated protein 1(MRP1) orthologs and several ATP-binding cassette (ABC) drug transporters [J].Bio Chem Pharmacol.2004,67(6):1111-1121
30 Cardoso F, Durbecq V, Larsimont D, et al. Correlation between complete response to anthracyline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer[J].Int J Oncol,2004,24 (1):201-209
31 Knoop AS, Knudsen H, Balslev, et al. Retrospective analysis of topoisomeraseⅡa amplifications and deletions as predictive markers in primary breast cancer Patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group.J Clin Oncol.2006,24(6):1015
32 Tanner M, Isola J, Wiklund T, et al. TopoisomeraseⅡalpha Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline- Based Adjuvant Chemotherapy in HER-2/neu-Amplified Breast Cancer: Results From the Randomized Scandinavian Breast Group Trial 9401. J Clin Oncol.2006 May 8:[Epub ahead of print]
33 Durbecq V, Paesmans M, Cardoso F, et al. Topoisomerase-Ⅱalpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther. 2004,3(10):1207-1214
34陈晓耕,林招贤,林孟波,等.缺氧诱导因子-1α在胃癌中的表达与临床病理、P53及P糖蛋白(P-gp)的关系[J].中国癌症杂志,2006,16(10):813-816
35 Comerford KM, Wallace TJ, Karhausen J, et al. Hypoxia-inducible factor-1 dependent regulation of the multidrug resistance (MDR1) gene[J].Cancer Res,2002, 62(12):3387-3394
36 Song X, Liu X, Chi W, et al. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-l alpha gene[J].Cancer Chemother Pharmacol, 2006,58(6):776-784
37 Ogiso Y, Tomida A, Lei S, et al. Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. Cancer Res,2000,60(9):2429-2434
38 Peters KB, Brown JM. Tirapazamine: A hypoxia-activated topoisomeraseⅡpoison. Cancer Res,2002,62(18):5248- 5253
39刘丽丽,战雪梅,孙崇伟.HIF-1α和TopoⅡ在子宫内膜癌中的表达及意义[J].山东医学高等专科学校学报2008,30(2):81-83
40刘志坤,黄雄,谢文彪.贫血对胃癌患者术后化疗耐药的影响[J].社区医学杂志2007,5(3):45-47
1 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. Mol Cell Biol,1992,12(12):5447 -5454
2 Jiang BH, Rue E, Wang GL, et al. Dimerization, DNA binding, and transactivation properties of hypoxia inducible faetor1 [J]. J Biol Chem,1996,271(30):17771 -17778
3 Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor l levels vary exponentially over a physiologically relevant range of O2 tension [J].Am J Physiol,1996,271 (41):C1172-C1180
4 Ao N, Ding M, Zheng JZ, et al. Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species[J].Bio Chem,2002, 277(35):31963-31971
5 Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor 1(HIF-1) alpha: its protein stability and biology functions [J]. Exp Mol Med,2004,36(5):1-12
6 Zelzer E, Levy Y, Kahana C, et al. Insulin inducestranscription of target genes through the hypoxia-inducible factor HIF-lα/ARNT [J].EMBO J,1998,17:5085-5094
7 Richard DE, Berra E, Gothie E, et a1.P42/P44 mitogen- activated protein kinases phosphorylate hypoxia-inducible factor lα(HIF-lα) and enhance the transcriptional activity of HIF-1[J].J Biol Chem,l999,274:32631-32637
8 Ruas JL, Poellinger L, Pereira T. Functional analysis of hypoxia-inducible factor-1αmediated transactivation identification of amino acid residues critical for trans- criptional activation and/or interaction with CREB-binding protein [J]. Biol Chem,2002,277(41):38723-38730
9 Mircea I, Keiichi K, Haifeng Yang, et al. HIF-1αtargeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing[J].Science,2001,292(5516):464- 468
10 Sonja AD, Maria MY, Roberto NP, et a1.Structural basis for HIF-1α/CBP recognition in the cellular hypoxic response [J].Natl. Acad. Sci. USA,2002,99(8):5271-5276
11 Mahon PC, Hirota K, Semenza GL, et al. FIH-l: a novel protein that interacts with HIF-1 alpha and VHL tomediate repression of HIF-1 transcriptional activity[J].Genes Dev, 2001,15(20):2675-2686
12 Alrarez-Tejado M, Alfranea A, Aragones J, et al. Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt Pathways in the activation of hypoxia-inducible factors by low oxygen tension [J].J Biol Chem,2002,277(16):13508-13517
13 Anastasiadis AG, Ghafar MA, Salomon L, et al. Human hormone-refractory prostate cancers can harbor mutations in the 02-dePendent degradation domain of hypoxia inducible factor-lα(HIF-1α). J Clin Cancer Res Oncol.2002,128 (7):358-362
14 Maxwell PH, Wiesener MS, Chang G-W, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis[J].Nature,1999,399(6733): 271-275
15 Zhong H, De Marzo A M, Laughner E. Over expression of HIF-la in common human cancers and their metastases [J]. Cancer Res,1999,59 (22):5830-5835
16 Jiang BH, Agani F, Passaniti A, et al. V-SRC induces expression of hypoxia-inducible factor l(HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase I: Involvement of HIF-1 in tumor progression[J].Cancer Res,1997,57(23):5328-5335
17 Comerford KM, Wallace TJ, Karhausen J, et al. Hypoxia-inducible factor-1 dependent regulation of the multidrug resistance (MDR1) gene[J].Cancer Res,2002,62 (12):3387-3394
18 Semenza GL. Signal transduction to hypoxia-inducible factor[J]. Biochem Pharmaco,2002, 64(5-6):993-998
19 Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation[J]. J B ioch in BiophysActa,2003,1619(2):113-124
20 Zhong H, Semenza GL, Simons JW, et al. UP-reguliltion of hypoxia inducible factor-1 alpha is an early event in carcinogenesis [J].Cancercer Detect Prev,2004,28(l):88-93.
21 Jiang HY, Feng YJ.Relationship of hypoxia-inducible factor-1 alpha expression and vascular endothelial growth factor in SKOV-3 ovarian cancer model[J].Zhong hua Fu Chan Ke Za Zhi,2004,39(11):767-770
22 Jiang CQ, Fan LF, Liu ZS . Expression levels and significance of hypoxia inducible factor-1 alpha and vascular endothelial growth factor in human colorectal adenocarcinoma [J].Chin Med,J,2004,117(10):1541-1546
23 Wei HY, Chen LB, Wang CY, et a1.Correlation of mRNA expression of hypoxia inducible factor-1 alpha to biological features of pancreastic cancer[J].Chin, J Cancer,2005,24 (2):184-188
24 Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science,1989,86:1306-1310
25 Connolly DT, Heuveiman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endouthelial cell growth and angiogenesis [J].J Clin Invest,1989,84:1470- 1478
26 Kaio E, Tanaka S, Kitadai Y, et al. Clinical significance of angiogenic factor expression at the deepest factor expression at the deepest invasive site of advanced colorectalcarcinoma[J]. Oncology,2003,64:61-73
27 Duff SE, Li C, Jeziorska M, et al. vascular growth factor and lymphangiogenesis[J].Physiol Rew,2002,82:673-700
28江晓丰,董强刚,冯文贤等.缺氧诱导人肺癌细胞株表达血管内皮生长因子.肺癌,2000,l20(6):423-427
29 Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance[J]. J Biol Chem,2003,278(22):19575 -19578
30 Wang Y, Pakunlu RI, Tsao W, et a1.Bimodal effect of hypoxia in cancer:the role of hypoxia inducible factor in apoptosis[J].Mol Pharm,2004,1(2):156-165
31 Suzuki H, Tomida A, Tsuruo T, et a1.Dephosphorylated hypoxia-inducible factor 1αas a mediator of p53 dependent apoptosis during hypoxia[J].Oncogene,2001,20(41):5779- 5788
32 Chen D, Li M, Luo J, et al. Direct interactions between HIF-1 and MDM2 modulate P53 function [J]. J Biol Chem, 2003,278(16):13595-13598
33 Schmid T, Zhou J, KohlR, et al. P300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1)[J]. Bio chem J,2004,380(3):289-295
34 Semenza GL. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res,2001, 49(5): 614-617
35 Bruick RK, ExPression of the gene encoding the proa- poptotic Nip3 Protein is induced by hypoxia[J].Proc NatlAcad Sci USA,2000,97(16):9082-9087
36 Kim JY, Ahn HJ, Ryu JH, et al. BH3-only protein noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor l alpha [J].J Exp Med,2004,199(l):113-124
37 Lee MJ, Kim JY, Suk K, et al. Identification of the hypoxia- inducible factor 1 alpha-responsive HGTD-P gene as a mediator in mitochondrial apoptotic Pathway[J]. Mol Cell Biol,2004,24(9):3918-3127
38 Zaman K, Ryu H, Hall D, et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-l and ATF-l/CREB and increased expression of glycolytic enzymes, p21(wafl/cipl), and erythropoietin[J].J Neurosci,1999,19(22):9821-9830
39 Erler JT, Cawthorne CJ, Williams KJ, et al. Hypoxia- mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor l-dependent and-independent mechanisms and contributes to drug resistance[J].Mol Cell Biol,2004,(7):2875-2889
40 Brune B. Nitric oxide NO apoptosis or turning it on?[J].Cell Death Differ,2003,10(8):864-869
41 Wang Y, Minko TA.Novel cancer therapy: combined liposomal hypoxia inducible factor 1 alpha antisense oligo- nucleotides and an anti-cancer drug[J].Bio chem Pharm, 2004,68(10):2031-2042
42 Bos R, Zhong H, Hanradan FC, et al. Levels of hypoxiainducible factor1 alpha during breast carcinogenesis[J]. Nat Cancer Inst Monogr,2001,93:309-314
43代志军,高洁,王西京,等.乳腺导管增生癌变过程中HIF-1a的表达变化及意义[J].中国肿瘤临床与康复,2007,14 (1):20-22
44高勇强,谢文彪,谷依学,等.乳腺癌中HIF-la, PCNA及Bcl-2的表达分析[J].南华大学学报,2006,34(2):200-202
45 Pore N, Jiang Z, Gupta A, et al. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia- inducible factor(HIF)-1-independent and HIF-1-dependent mechanisms [J]. Cancer Research,2006,66:3197-3204
46 Mayerhofer M, Valent P, Sperr WR, et al. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1 alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin[J].Blood,2002,100: 3767-3775
47 Koukourakis,M.I.,Simopoulos,C.,Polychronidis,A.,et al.The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: Dichotomus effect predictable by the HIFI alpha/VEGF pretreatment status?[J].Anticancer Research, 2003,23:1673-1680