NDRG2、AKT2及其磷酸化蛋白在脑胶质瘤中的表达及相关性的研究
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摘要
研究背景脑胶质瘤是神经系统最常见的肿瘤,可以来源于多种神经外胚层间质细胞,甚至实质细胞,发病率高,且以恶性者多见,传统手术难以根除,常随复发其恶性度不断增高,导致大量患者致残、丧生,危害极大。单纯放射疗法、化学疗法的疗效也远不能令人满意。随着肿瘤是基因疾病概念的深化,新发展起来的基因治疗肿瘤的技术给克服这类疾病带来了希望。
NDRG2 (N-myc downstream regulated gene 2)基因是我的导师邓艳春教授于1999年首先发现的新的在正常脑组织和脑胶质瘤中差异表达的基因,在后者低表达或者无表达,而在前者高表达。系列研究表明,该基因还在多种组织的恶性肿瘤中低表达,而在相应的正常组织中高表达。应用重组NDRG2蛋白对肿瘤细胞系进行干预或者在恶性肿瘤细胞系内转染该基因,发现这些细胞系恶性表型明显下降。因此将该基因列为抑癌候选基因,并对其抑癌作用机制进行系列研究,以期开发其临床应用价值。
NDRG2功能的发挥可能是通过其蛋白表达产物在不同的信号转导通路中扮演不同的角色而实现的。PI3K-AKT通路在脑胶质瘤的发生和发展中常常异常激活,促进其进一步向恶性演变。国外在研究胰岛素信号通路时,发现NDRG2是AKT的底物,受其磷酸化作用的调节。由于NDRG2在各种组织内广泛表达,提示其可能发挥多重和重要的功能,这些功能的发挥也可能是由不同或者相同的信号转导通路参与的。因此,为了初步探索在脑胶质瘤中NDRG2与蛋白激酶AKT的关系,我们设计了如下实验。
实验方法:
1.收取临床脑胶质瘤手术切除组织标本24例,按WHO病理分级为Ⅱ、Ⅲ、Ⅳ级各8例,低温速冻保存。分别提取总蛋白,BCA法测定其浓度。培养胶质瘤细胞系U87和U251,应用浓度为10uM的PI3K抑制剂LY294002处理细胞1小时,抑制内源PI3K活性,蛋白提取方法同前。
2.采用蛋白半定量的Western-blotting方法测定相同含量总蛋白中的NDRG2蛋白、AKT2蛋白、332位丝氨酸磷酸化的NDRG2蛋白(P-NDRG2-SER332)、348位苏氨酸磷酸化的NDRG2蛋白(P-NDRG2-THR348)、474位丝氨酸磷酸化的AKT2蛋白(P-AKT2-SER474)的含量,统计分析不同病理级别的标本中各种蛋白含量变化及之间的关系。
3.在胶质瘤细胞系U87和U251中,仍采用Western-blotting方法测定上述蛋白在应用LY294002抑制PI3K-AKT通路的磷酸化前后的变化情况并进行分析。
实验结果
1. Western-blot检测到在Ⅱ、Ⅲ、Ⅳ级胶质瘤标本中,随着胶质瘤病理分级的升高,NDRG2蛋白的表达量下降,级别之间的差异具有统计学意义,P<0.05。AKT2蛋白在各个胶质瘤标本中均有表达, 474位丝氨酸磷酸化的AKT2蛋白(P-AKT2-SER474)在58%的胶质瘤标本中表达;332位丝氨酸磷酸化的NDRG2蛋白(P-NDRG2-SER332)和348位苏氨酸磷酸化的NDRG2蛋白(P-NDRG2-THR348)在Ⅱ、Ⅲ、Ⅳ级胶质瘤标本中含量不等,均是在Ⅲ级胶质瘤中表达量最高。
2.在多数高表达P-AKT2-SER474的标本中,P-NDRG2-SER332和P-NDRG2-THR348低表达或无表达;反之,在低表达或无表达P-AKT2-SER474的标本中,P-NDRG2-SER332和P-NDRG2-THR348均高表达。
3.在U87和U251细胞系中,NDRG2蛋白的表达量在PI3K磷酸化抑制后均有所减低。P-NDRG2-SER332蛋白和P-NDRG2-THR348蛋白的表达量在两个细胞系PI3K磷酸化抑制后也均有所减低。在U87和U251细胞系中,AKT2蛋白均有表达,P-AKT2-SER474蛋白在U87细胞系中表达,抑制后有所降低;而在U251细胞系中无论抑制前后均无表达。
结论
1. NDRG2蛋白在不同病理级别的胶质瘤中表达有差异,随着病理级别的升高,其含量明显下降(P<0.05),支持其为抑癌基因。
2.在胶质瘤中,NDRG2的磷酸化不依赖于AKT2的磷酸化,并且和AKT2蛋白的磷酸化可能存在竞争关系。
3. NDRG2是PI3K下游信号分子之一,除了AKT2外,尚有其他PI3K下游激酶分子可以磷酸化NDRG2。
Background Human gliomas are the most common primary central nervous system neoplasm. The vast majority of these tumors developing from glial cells and the minority from neuron cells are collectively called gliomas. The patient's prognosis was still not satisfactory with poor effect of traditional treats,such as surgical operation, radiotherapy and chemotherapy. Gene therapy has been thought of as a promising method to treat gliomas nowadays for higher understanding that tumors are gene related diseases .
NDRG2 (N-myc downstream regulated gene 2)is a novel gene found firstly by my teacher professor Deng Yanchun in 1999 and its expression level is decreased apparently in gliomas than in normal tissues. A series of researches have showed that the level of NDRG2 was lower in all kinds of tumors than in their counterpart normal tissues. Interfering some tumor cell lines with recombinant protein of NDRG2 or transfection of tumor cell lines with NDRG2 could inhibited proliferation and progression of these cells. So we regard NDRG2 as a candidate tumor suppressor gene,and are going to study its mechanisem of being downregulated and inhibiting tumors,wishing that it may be a tool to help curing tumors.
Extensive expression of NDRG2 in all kinds of tissues implies its important meaning.NDRG2 may function by acting a role in some signal transduction path. PI3K-AKT signaling pathway is often activated in gliomas and encourages tumors’malignant progression.It has reported that NDRG2 is a substrate of AKT and is phosphorylated by AKT in rats’skeletal muscle cells when investigating insulin signaling pathway, so we design this experiment to investigate the expression level of NDRG2 and AKT2 protein and their phosphoralated forms in different pathology grades gliomas and to study the quantitive changes of these proteins through PI3K activity inhibition in both U87 and U251 cell lines in order to get more information available to more research of action mechanism of NDRG2.
Methods
1.Every 8 samples belonging toⅡ,Ⅲ,Ⅳpathology grade gliomas were collected and total protein was extracted from them respectively.BCA method was applied to test concentration of total protein.At the same time,glioma cell lines U87 and U251 were cultured,and 10uM LY294002, a PI3K signaling pathway inhibitor, was used to inhibit the activity of PI3K for 1 hour.Total protein was extracted from two cell lines before and after the inhibition with the same ways.
2. Western blot analysis was applied to detect the expression level of NDRG2 and AKT2 protein and their phosphoralated forms in all of tissue samples. At last,all data was analyzed statistically.
3. The level of five kinds of proteins was still detected in U87 and U251 cell lines before and after the inhibition and analyzed.
Result
1.The level of NDRG2 protein decreased apparently in gliomas with the increasing of grades and the variance was significant statistically ( P<0.05 ) .The AKT2 protein is expressed in all samples ,while the AKT2 phosphorylated at Ser474 site (P-AKT2-SER474) is only expressed in 58% gliomas samples.The levels of the NDRG2 phosphorylated at Ser332 (P-NDRG2-SER332) and the NDRG2 phosphorylated at thr348 (P-NDRG2-THR348) were different in gliomas from every grade and the levels of two kinds of protein in gradeⅢwere both the highest of the three grades.
2. Both P-NDRG2-SER332 protein and P-NDRG2-THR348 protein highly expressed in the glioma samples in which P-AKT2-SER474 lowly or didn’t express,while both proteins lowly or didn’t express in the glioma samples in which P-AKT2-SER474 highly expressed.
3. After phosphorylation inhibition of PI3K,the level of NDRG2 protein, P-NDRG2-SER332 protein and P-NDRG2-THR348 protein decreased in both U87 cell line and U251 cell line.AKT2 protein expressed in both cell lines whenever before or after PI3K activity inhibition,but P-AKT2-SER474 expressed only in U87 cell line,and its level decreased after inhibion of PI3K activity.
Conclusion
1.The expression level of NDRG2 in gliomas correlates with the pathology grades of gliomas,which supports NDRG2 may a tumor suppressor gene.
2.In gliomas,the phosphorylation of NDRG2 doesn’t depend on the phosphorylation of the AKT2,and the competitive relation between the phosphorylation of NDRG2 and that of AKT2 maybe exist.
3.NDRG2 protein is a probable molecule in PI3K signaling pathway,but other molecules in downstream of PI3K must phosphorylate it except for AKT2.
NDRG2 (N-myc downstream regulated gene 2)基因是我的导师邓艳春教授于1999年首先发现的新的在正常脑组织和脑胶质瘤中差异表达的基因,在后者低表达或者无表达,而在前者高表达。系列研究表明,该基因还在多种组织的恶性肿瘤中低表达,而在相应的正常组织中高表达。应用重组NDRG2蛋白对肿瘤细胞系进行干预或者在恶性肿瘤细胞系内转染该基因,发现这些细胞系恶性表型明显下降。因此将该基因列为抑癌候选基因,并对其抑癌作用机制进行系列研究,以期开发其临床应用价值。
NDRG2功能的发挥可能是通过其蛋白表达产物在不同的信号转导通路中扮演不同的角色而实现的。PI3K-AKT通路在脑胶质瘤的发生和发展中常常异常激活,促进其进一步向恶性演变。国外在研究胰岛素信号通路时,发现NDRG2是AKT的底物,受其磷酸化作用的调节。由于NDRG2在各种组织内广泛表达,提示其可能发挥多重和重要的功能,这些功能的发挥也可能是由不同或者相同的信号转导通路参与的。因此,为了初步探索在脑胶质瘤中NDRG2与蛋白激酶AKT的关系,我们设计了如下实验。
实验方法:
1.收取临床脑胶质瘤手术切除组织标本24例,按WHO病理分级为Ⅱ、Ⅲ、Ⅳ级各8例,低温速冻保存。分别提取总蛋白,BCA法测定其浓度。培养胶质瘤细胞系U87和U251,应用浓度为10uM的PI3K抑制剂LY294002处理细胞1小时,抑制内源PI3K活性,蛋白提取方法同前。
2.采用蛋白半定量的Western-blotting方法测定相同含量总蛋白中的NDRG2蛋白、AKT2蛋白、332位丝氨酸磷酸化的NDRG2蛋白(P-NDRG2-SER332)、348位苏氨酸磷酸化的NDRG2蛋白(P-NDRG2-THR348)、474位丝氨酸磷酸化的AKT2蛋白(P-AKT2-SER474)的含量,统计分析不同病理级别的标本中各种蛋白含量变化及之间的关系。
3.在胶质瘤细胞系U87和U251中,仍采用Western-blotting方法测定上述蛋白在应用LY294002抑制PI3K-AKT通路的磷酸化前后的变化情况并进行分析。
实验结果
1. Western-blot检测到在Ⅱ、Ⅲ、Ⅳ级胶质瘤标本中,随着胶质瘤病理分级的升高,NDRG2蛋白的表达量下降,级别之间的差异具有统计学意义,P<0.05。AKT2蛋白在各个胶质瘤标本中均有表达, 474位丝氨酸磷酸化的AKT2蛋白(P-AKT2-SER474)在58%的胶质瘤标本中表达;332位丝氨酸磷酸化的NDRG2蛋白(P-NDRG2-SER332)和348位苏氨酸磷酸化的NDRG2蛋白(P-NDRG2-THR348)在Ⅱ、Ⅲ、Ⅳ级胶质瘤标本中含量不等,均是在Ⅲ级胶质瘤中表达量最高。
2.在多数高表达P-AKT2-SER474的标本中,P-NDRG2-SER332和P-NDRG2-THR348低表达或无表达;反之,在低表达或无表达P-AKT2-SER474的标本中,P-NDRG2-SER332和P-NDRG2-THR348均高表达。
3.在U87和U251细胞系中,NDRG2蛋白的表达量在PI3K磷酸化抑制后均有所减低。P-NDRG2-SER332蛋白和P-NDRG2-THR348蛋白的表达量在两个细胞系PI3K磷酸化抑制后也均有所减低。在U87和U251细胞系中,AKT2蛋白均有表达,P-AKT2-SER474蛋白在U87细胞系中表达,抑制后有所降低;而在U251细胞系中无论抑制前后均无表达。
结论
1. NDRG2蛋白在不同病理级别的胶质瘤中表达有差异,随着病理级别的升高,其含量明显下降(P<0.05),支持其为抑癌基因。
2.在胶质瘤中,NDRG2的磷酸化不依赖于AKT2的磷酸化,并且和AKT2蛋白的磷酸化可能存在竞争关系。
3. NDRG2是PI3K下游信号分子之一,除了AKT2外,尚有其他PI3K下游激酶分子可以磷酸化NDRG2。
Background Human gliomas are the most common primary central nervous system neoplasm. The vast majority of these tumors developing from glial cells and the minority from neuron cells are collectively called gliomas. The patient's prognosis was still not satisfactory with poor effect of traditional treats,such as surgical operation, radiotherapy and chemotherapy. Gene therapy has been thought of as a promising method to treat gliomas nowadays for higher understanding that tumors are gene related diseases .
NDRG2 (N-myc downstream regulated gene 2)is a novel gene found firstly by my teacher professor Deng Yanchun in 1999 and its expression level is decreased apparently in gliomas than in normal tissues. A series of researches have showed that the level of NDRG2 was lower in all kinds of tumors than in their counterpart normal tissues. Interfering some tumor cell lines with recombinant protein of NDRG2 or transfection of tumor cell lines with NDRG2 could inhibited proliferation and progression of these cells. So we regard NDRG2 as a candidate tumor suppressor gene,and are going to study its mechanisem of being downregulated and inhibiting tumors,wishing that it may be a tool to help curing tumors.
Extensive expression of NDRG2 in all kinds of tissues implies its important meaning.NDRG2 may function by acting a role in some signal transduction path. PI3K-AKT signaling pathway is often activated in gliomas and encourages tumors’malignant progression.It has reported that NDRG2 is a substrate of AKT and is phosphorylated by AKT in rats’skeletal muscle cells when investigating insulin signaling pathway, so we design this experiment to investigate the expression level of NDRG2 and AKT2 protein and their phosphoralated forms in different pathology grades gliomas and to study the quantitive changes of these proteins through PI3K activity inhibition in both U87 and U251 cell lines in order to get more information available to more research of action mechanism of NDRG2.
Methods
1.Every 8 samples belonging toⅡ,Ⅲ,Ⅳpathology grade gliomas were collected and total protein was extracted from them respectively.BCA method was applied to test concentration of total protein.At the same time,glioma cell lines U87 and U251 were cultured,and 10uM LY294002, a PI3K signaling pathway inhibitor, was used to inhibit the activity of PI3K for 1 hour.Total protein was extracted from two cell lines before and after the inhibition with the same ways.
2. Western blot analysis was applied to detect the expression level of NDRG2 and AKT2 protein and their phosphoralated forms in all of tissue samples. At last,all data was analyzed statistically.
3. The level of five kinds of proteins was still detected in U87 and U251 cell lines before and after the inhibition and analyzed.
Result
1.The level of NDRG2 protein decreased apparently in gliomas with the increasing of grades and the variance was significant statistically ( P<0.05 ) .The AKT2 protein is expressed in all samples ,while the AKT2 phosphorylated at Ser474 site (P-AKT2-SER474) is only expressed in 58% gliomas samples.The levels of the NDRG2 phosphorylated at Ser332 (P-NDRG2-SER332) and the NDRG2 phosphorylated at thr348 (P-NDRG2-THR348) were different in gliomas from every grade and the levels of two kinds of protein in gradeⅢwere both the highest of the three grades.
2. Both P-NDRG2-SER332 protein and P-NDRG2-THR348 protein highly expressed in the glioma samples in which P-AKT2-SER474 lowly or didn’t express,while both proteins lowly or didn’t express in the glioma samples in which P-AKT2-SER474 highly expressed.
3. After phosphorylation inhibition of PI3K,the level of NDRG2 protein, P-NDRG2-SER332 protein and P-NDRG2-THR348 protein decreased in both U87 cell line and U251 cell line.AKT2 protein expressed in both cell lines whenever before or after PI3K activity inhibition,but P-AKT2-SER474 expressed only in U87 cell line,and its level decreased after inhibion of PI3K activity.
Conclusion
1.The expression level of NDRG2 in gliomas correlates with the pathology grades of gliomas,which supports NDRG2 may a tumor suppressor gene.
2.In gliomas,the phosphorylation of NDRG2 doesn’t depend on the phosphorylation of the AKT2,and the competitive relation between the phosphorylation of NDRG2 and that of AKT2 maybe exist.
3.NDRG2 protein is a probable molecule in PI3K signaling pathway,but other molecules in downstream of PI3K must phosphorylate it except for AKT2.
引文
1.Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005 Jun;64(6):479-89.
2.Francois Berger, Emmanuel Gay, et al. Development of gliomas: potential role of asymmetrical cell division of neural stem cells. The Lancet Oncology, Volume 5, Issue 8, August 2004, 511-514.
3.Esther Hulleman and Kristian Helin.Molecular Mechanisms in Gliomagenesis. Advances in Cancer Research, Volume 94, 2005, Pages 1-27.
4.Chengkai Dai, Yelena Lyustikman, et al. The Characteristics of Astrocytomas and Oligodendrogliomas Are Caused by Two Distinct and Interchangeable Signaling Formats. Neoplasia. 2005 April; 7(4): 397–406.
5.Cavenee WK, Furnari FB, Nagane M, et al. Diffusely infiltrating astrocytomas. In: Keilhues P, Cavenee WK(eds). Pathology & Genetics: Tumors of the Nervous System. Lyon: IARC Press, 2000, pp 9–51.
6.Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA. Malignant glioma: genetics and biology of a grave matter. Genes Devel 2001;15:1311–33.
7.Gresner SM, Liberski PP. Significance and prospects of study on molecular alterations in oligodendrogliomas. Neurol Neurochir Pol. 2007 Jul-Aug;41(4):333-9.
8.Cai DX, Banerjee R, et al.Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications.J Neuropathol Exp Neurol 2001;60:628–36.
9.Nauman P, Czernicki Z. The molecular basis of glia-derived tumours of the brain. Part I .Neurol Neurochir Pol. 2002 May-Jun;36(3):553-64.
10.Eoli M, Silvani A, et al. Molecular markers of gliomas: a clinical approach. Neurol Res. 2006 Jul;28(5):538-41.
11.Eckert A, Kloor M, Microsatellite instability in pediatric and adult high-grade gliomas. Brain Pathol. 2007 Apr;17(2):146-50.
12.Martinez R, Roggendorf W, et al. Cytogenetic and molecular genetic analyses of giant cell glioblastoma multiforme reveal distinct profiles in giant cell and non-giant cell subpopulations. Cancer Genet Cytogenet. 2007 May;175(1):26-34.
13.Banelli B, Casciano I, Romani M. Methylation-independent silencing of the p73 gene in neuroblastoma. Oncogene. 2000 Sep 14;19(39):4553-6.
14.Lindsey JC, Lusher ME, et al.Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma. Br J Cancer. 2007 Jul 16;97(2):267-74. Epub 2007 Jun 19.
15.Eriks A. Lusis, Mark A. Watson,et al.Integrative Genomic Analysis Identifies NDRG2 as a Candidate Tumor Suppressor Gene Frequently Inactivated in Clinically Aggressive Meningioma. Cancer Res. 2005, 65: (16). August 15, 7121-26
16.Wiencke JK, Zheng S, et al.Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol. 2007 Jul;9(3):271-9. Epub 2007 May 15.
17.Alonso MM, Gomez-Manzano C, et al.Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res. 2007 Dec 15;67(24):11499-504.
18.Gorlia T, van den Bent MJ, et al. Nomograms for predicting survival ofpatients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol. 2008 Jan;9(1):29-38. Epub 2007 Dec 21.
19.Patel R, Shervington L, Lea R, Shervington A. Epigenetic silencing of telomerase and a non-alkylating agent as a novel therapeutic approach for glioma. Brain Res. 2008 Jan 10;1188:173-81. Epub 2007 Oct
20.Barsyte-Lovejoy D, Lau SK, et al. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006 May 15;66(10):5330-7.
21.Gensert JM, Baranova OV, Weinstein DE, Ratan RR.CD81, a cell cycle regulator, is a novel target for histone deacetylase inhibition in glioma cells. Neurobiol Dis. 2007 Jun;26(3):671-80. Epub 2007 Mar 28.
22.Lopez CA, Feng FY, et al.Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):214-20.
23.Entin-Meer M, Yang X, et al. In vivo efficacy of a novel histone deacetylase inhibitor in combination with radiation for the treatment of gliomas. Neuro Oncol. 2007 Apr;9(2):82-8. Epub 2007 Mar 8.
24.Entin-Meer M, Rephaeli A, et al.AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines. Cancer Lett. 2007 Aug 18;253(2):205-14. Epub 2007 Mar 7.
25.Colman H, Giannini C, et al. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006 May;30(5):657-64.
26.Martinez R, Schackert G. Epigenetic aberrations in malignant gliomas: an open door leading to better understanding and treatment. Epigenetics. 2007 Jul-Sep;2(3):147-50. Epub 2007 Sep 15.
27.Kil WJ, Cerna D, et al. In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide. Clin Cancer Res. 2008 Feb 1;14(3):931-8.
28.Huamin Wang, Hua Wang, et al. Analysis of the activation status of Akt, NFkB,and Stat3 in human diffuse gliomas. Laboratory Investigation (2004) 84, 941–951.
29.Datta SR ,Brunet A , Greenberg ME. Cellular survival : a play in three Akts[J ] . Genes Dev ,1999 ,13 (22) :2905-2927.
30.Maehama T , Dixon J E. The tumor suppressor , PTENP/MMAC1 , dephosphorylates the lipid second messenger , phosphatidylinositol 3 ,4 ,5-trisphosphate[J ] . J Biol Chem ,1998 ,273 (22) :13375-78.
31.Waite KA , Eng C. Protean PTEN : form and function[J ] . AmJ Hum Genet , 2002 , 70 (4) :829-844.
32.Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–1947.
33.Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997;57:4183–4186.
34.Sano T, Lin H, Chen X, et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res.
35.Shih AH,Dai C,Hu X,et al.Dose-dependent effects of platelet-derived growthfactor-B on glial tumorigenesis.Cancer Res.2004,64(14):4783-4789.
36.Hesselager G,Uhrbom L,Westermark B,et al.Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a mouse glioma model. Cancer Res.2003,63(15):4305-4309.
37.Luis Del Valle, Sahnila Enam, Adam Lassak, et al. Insulin-like Growth Factor I Receptor Activity in Human Medulloblastomas. Clinical Cancer Research. 1822 Vol. 8, 1822–1830, June 2002.
38.Wong AJ, Bigner SH, et al.Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA. 1987;84:6899–6903.
39. Fleming TP, Saxena A, et al.Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res. 1992;52:4550–4553.
40.Wong AJ, Ruppert JM, et al.Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA. 1992;89:2965–2969.
41.Morrison RS, Yamaguchi F, et al.Basic fibroblast growth factor and fibroblast growth factor receptor I are implicated in the growth of human astrocytomas. J Neuro-Oncol. 1994;18:207–216.
42.邓艳春,药立波,刘新平,等,人脑内ACP样结构域新基因的发现,生物化学与生物物理进展,2001;28(1):72-76
43.Nagase T, Ishikawa K, et al. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro,DNA Res, 1999; 6(1):63-70
44.李剑,刘新平,林树新,等。一种新的抑癌候选基因—NDRG2在人类正常组织及相应肿瘤组织中的表达,生物化学与生物物理进展,2002; 29(1):223-227
45.Qu X, Zhai Y, Wei H, et al.Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family, Mol Cell Biochem, 2002 ; 229(1-2):35-44
46.王立峰。应激刺激对NDRG2蛋白在细胞内定位的影响。[第四军医大学硕士论文,2003年P79-81]
47.Jing Zhang a, Junye Liu a, et al.The physical and functional interaction of NDRG2 with MSP58 in cells,Biochemical and Biophysical Research Communications ,2007; (352 ): 6–11
48.Deng Y, Yao L, et al. N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation, Int J Cancer, 2003 ;106(3):342-347
49.刘娜,刘新平,等,抑癌侯选基因NDRG2在乳腺肿瘤组织及乳腺癌细胞系中的表达分析,第四军医大学学报,2004;25(12):1065-1068
50.Hu XL, Liu XP, Deng YC et al. NDRG2 expression and mutation in human liver and pancreatic cancers, World J Gastroenterol, 2004;10(23):3518-3521
51.Reetta ?ss?m?ki, Maarit Sarlomo-Rikala, et al. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors, Genes Chromosomes Cancer, 2007;46(6):564-567
52.吴国强,刘新平等. NDRG2对肝癌细胞HepG2凋亡的诱导作用[J].细胞与分子免疫学杂志,2003,19(4):357-360.
53.Jian Zhang, Fuyang Li, et al.The repression of human differentiation related gene NDRG2 expression by MYC via MIZ-1 dependent interaction with theNDRG2 core promoter. J Biol Chem, 2006 ;281(51) :39159-39168
54.胡晓兰,药力波等. NDRG2在人胚胎组织中的表达分布特点. [J ].生理学报,2006,58(4):331-336.
55.候双兴,邓艳春等.NDRG2在人胎前脑发育期的表达特点. [J ]中华神经医学杂志,2006,5(2):109-112.
56.Hu XL, Liu XP, Deng YC, et al.Expression analysis of the NDRG2 gene in mouse embryonic and adult tissues. Cell Tissue Res. 2006 ;325(1):67-76
57.Zhang J,Wang JC, et al. High expression of bcl-x(L) in K562 cells and its role in the low sensitivity of K562 to realgar-induced apoptosis,Acta Haematol,2005;113(4):247-254
58.Choi SC, Kim KD, et al.Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells, FEBS Lett, 2003; 553(3): 413-418
59.Mitchelmore C, Buchmann-Moller S, et al.NDRG2: a novel Alzheimer's disease associated protein, Neurobiol Dis, 2004 ; 16(1):48-58
60.Takahashi K, Yamada M, et al.Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment, Int J Neuropsychopharmacol, 2005 ;8(3):381-389.
61.Kou Takahashi a,b, Misa Yamadaa, et al.Ndrg2 promotes neurite outgrowth of NGF-differentiated PC12 cells ,Neuroscience Letters, 2005;388 : 157–162
62.James G. Burchfield, Alecia J. Lennard,et al.Akt Mediates Insulin-stimulated Phosphorylation of Ndrg2[J]. The journal of Biological Chemistry,2004,279(18) :18623-32
63.Lang, F. and Cohen, P, Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms, Science STKE .2001; 108: 17
64.Firestone, G. L., Giampaolo, J. R. and O’Keeffe, B. A, Stimulus-dependent regulation of serum and glucocorticoid-induced protein kinase (SGK) transcription, sub-cellular location and enzymatic activity. Cell. Physiol. Biochem, 2003; 13: 1–12
65.James T. MURRAY, David G. CAMPBELL, et a1.Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3 [J].Biochem. J. 2004, 384, 477–488
66.Sheerazed Boulkrou, Michel Fay, et al.Characterization of Rat NDRG2 (N-Myc Downstream RegulatedGene 2), a Novel Early Mineralocorticoid-specific Induced Gene*,The Journal Of Biological Chemistry, 2002; 277(35): 31506–31515
67.Sheerazed Boulkroun Cathi Le Moellic et al.Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct,P.ugers Arch Eur J Physiol , 2005; 451: 388–394
68.Kalaydjieva, L.; Hallmayer, J. et.al, Gene mapping in Gypsies identifies a nove demyelinating neuropathy on chromosome 8q24, Nature Genet, 1996; 14: 214-217
69.Kurdistani SK, Arizti P, et al.Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage ,Cancer Res, 1998;58(19):4439-4444
70.Zhao W, Tang R,HuangY,Wang W, et al. Clong and expression pattern of the human NDRG3 gene, Biochem Biophys Acta,2001 ;1519(1-2):134-138
71.Zhou RH, Kokame K, et al.Characterization of the human NDRG gene family: a newly identified member,NDRG4, is specifically expressed in brain and heart,Genomics,2001;73(1):86-97
72.Xiao—Lan Hu ,l Xin—Ping Liu, et al.NDRG2 expression and mutation in human liver and pancreatic cancer[J]. W orld Journal of Gastroenterology, 2004,10(23):3518-21
73.张翊,陈杰,裴德宁等.重组人NDRG2蛋白对肿瘤细胞抑制作用研究[J].中国肿瘤生物治疗杂志,2004,11(3):204-207
74.Yanchun DENG, Libo YAO et al.N-Myc downstream-regulated gene 2(NDRG2)inhibits glioblastoma cell proliferation [J]. Int. J. Cancer,2003,106: 342–347
75.Choe G, Horvath S, et al. Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo [J]. Cancer Res. 2003 ,63(11):2742-6
76.Homma T, Fukushima T. Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol. 2006 Sep;65(9):846-54.
77.Okuda T,Kondoh H.Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/DRGI but show distinct tissue specificity and response to N—myc[J].Biochem Biophys Res Commun,1 999,266(1):208—215.
78.Zhou R H,Kokame K,Tsukamoto Y,et a1.Characterization of the human NDRG gene family:a newly identified member,NDRG4,is specifically expressed in brain and heart.Genomics,2001,73(1):86—97
79.张健,刘新平等. ndrg家族研究进展[J].生命科学,2003,15(4):203-206.
80.Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11598-603.
81.康春生,浦佩玉等.人脑胶质瘤AKT2表达与细胞增殖和侵袭性的关系[J].中华病理学杂志,2004,33(5):464-465
82.W?rntges S, Friedrich B, Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1. Pflugers Arch. 2002 ,443(4):617-24.
83.Tangir J, BonaféN, SGK1, a potential regulator of c-fms related breast cancer aggressiveness. [J].Proc Natl Acad Sci U S A. 2004,101(39):14057-62.
2.Francois Berger, Emmanuel Gay, et al. Development of gliomas: potential role of asymmetrical cell division of neural stem cells. The Lancet Oncology, Volume 5, Issue 8, August 2004, 511-514.
3.Esther Hulleman and Kristian Helin.Molecular Mechanisms in Gliomagenesis. Advances in Cancer Research, Volume 94, 2005, Pages 1-27.
4.Chengkai Dai, Yelena Lyustikman, et al. The Characteristics of Astrocytomas and Oligodendrogliomas Are Caused by Two Distinct and Interchangeable Signaling Formats. Neoplasia. 2005 April; 7(4): 397–406.
5.Cavenee WK, Furnari FB, Nagane M, et al. Diffusely infiltrating astrocytomas. In: Keilhues P, Cavenee WK(eds). Pathology & Genetics: Tumors of the Nervous System. Lyon: IARC Press, 2000, pp 9–51.
6.Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA. Malignant glioma: genetics and biology of a grave matter. Genes Devel 2001;15:1311–33.
7.Gresner SM, Liberski PP. Significance and prospects of study on molecular alterations in oligodendrogliomas. Neurol Neurochir Pol. 2007 Jul-Aug;41(4):333-9.
8.Cai DX, Banerjee R, et al.Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications.J Neuropathol Exp Neurol 2001;60:628–36.
9.Nauman P, Czernicki Z. The molecular basis of glia-derived tumours of the brain. Part I .Neurol Neurochir Pol. 2002 May-Jun;36(3):553-64.
10.Eoli M, Silvani A, et al. Molecular markers of gliomas: a clinical approach. Neurol Res. 2006 Jul;28(5):538-41.
11.Eckert A, Kloor M, Microsatellite instability in pediatric and adult high-grade gliomas. Brain Pathol. 2007 Apr;17(2):146-50.
12.Martinez R, Roggendorf W, et al. Cytogenetic and molecular genetic analyses of giant cell glioblastoma multiforme reveal distinct profiles in giant cell and non-giant cell subpopulations. Cancer Genet Cytogenet. 2007 May;175(1):26-34.
13.Banelli B, Casciano I, Romani M. Methylation-independent silencing of the p73 gene in neuroblastoma. Oncogene. 2000 Sep 14;19(39):4553-6.
14.Lindsey JC, Lusher ME, et al.Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma. Br J Cancer. 2007 Jul 16;97(2):267-74. Epub 2007 Jun 19.
15.Eriks A. Lusis, Mark A. Watson,et al.Integrative Genomic Analysis Identifies NDRG2 as a Candidate Tumor Suppressor Gene Frequently Inactivated in Clinically Aggressive Meningioma. Cancer Res. 2005, 65: (16). August 15, 7121-26
16.Wiencke JK, Zheng S, et al.Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol. 2007 Jul;9(3):271-9. Epub 2007 May 15.
17.Alonso MM, Gomez-Manzano C, et al.Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res. 2007 Dec 15;67(24):11499-504.
18.Gorlia T, van den Bent MJ, et al. Nomograms for predicting survival ofpatients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol. 2008 Jan;9(1):29-38. Epub 2007 Dec 21.
19.Patel R, Shervington L, Lea R, Shervington A. Epigenetic silencing of telomerase and a non-alkylating agent as a novel therapeutic approach for glioma. Brain Res. 2008 Jan 10;1188:173-81. Epub 2007 Oct
20.Barsyte-Lovejoy D, Lau SK, et al. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006 May 15;66(10):5330-7.
21.Gensert JM, Baranova OV, Weinstein DE, Ratan RR.CD81, a cell cycle regulator, is a novel target for histone deacetylase inhibition in glioma cells. Neurobiol Dis. 2007 Jun;26(3):671-80. Epub 2007 Mar 28.
22.Lopez CA, Feng FY, et al.Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):214-20.
23.Entin-Meer M, Yang X, et al. In vivo efficacy of a novel histone deacetylase inhibitor in combination with radiation for the treatment of gliomas. Neuro Oncol. 2007 Apr;9(2):82-8. Epub 2007 Mar 8.
24.Entin-Meer M, Rephaeli A, et al.AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines. Cancer Lett. 2007 Aug 18;253(2):205-14. Epub 2007 Mar 7.
25.Colman H, Giannini C, et al. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006 May;30(5):657-64.
26.Martinez R, Schackert G. Epigenetic aberrations in malignant gliomas: an open door leading to better understanding and treatment. Epigenetics. 2007 Jul-Sep;2(3):147-50. Epub 2007 Sep 15.
27.Kil WJ, Cerna D, et al. In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide. Clin Cancer Res. 2008 Feb 1;14(3):931-8.
28.Huamin Wang, Hua Wang, et al. Analysis of the activation status of Akt, NFkB,and Stat3 in human diffuse gliomas. Laboratory Investigation (2004) 84, 941–951.
29.Datta SR ,Brunet A , Greenberg ME. Cellular survival : a play in three Akts[J ] . Genes Dev ,1999 ,13 (22) :2905-2927.
30.Maehama T , Dixon J E. The tumor suppressor , PTENP/MMAC1 , dephosphorylates the lipid second messenger , phosphatidylinositol 3 ,4 ,5-trisphosphate[J ] . J Biol Chem ,1998 ,273 (22) :13375-78.
31.Waite KA , Eng C. Protean PTEN : form and function[J ] . AmJ Hum Genet , 2002 , 70 (4) :829-844.
32.Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–1947.
33.Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997;57:4183–4186.
34.Sano T, Lin H, Chen X, et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res.
35.Shih AH,Dai C,Hu X,et al.Dose-dependent effects of platelet-derived growthfactor-B on glial tumorigenesis.Cancer Res.2004,64(14):4783-4789.
36.Hesselager G,Uhrbom L,Westermark B,et al.Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a mouse glioma model. Cancer Res.2003,63(15):4305-4309.
37.Luis Del Valle, Sahnila Enam, Adam Lassak, et al. Insulin-like Growth Factor I Receptor Activity in Human Medulloblastomas. Clinical Cancer Research. 1822 Vol. 8, 1822–1830, June 2002.
38.Wong AJ, Bigner SH, et al.Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA. 1987;84:6899–6903.
39. Fleming TP, Saxena A, et al.Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res. 1992;52:4550–4553.
40.Wong AJ, Ruppert JM, et al.Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA. 1992;89:2965–2969.
41.Morrison RS, Yamaguchi F, et al.Basic fibroblast growth factor and fibroblast growth factor receptor I are implicated in the growth of human astrocytomas. J Neuro-Oncol. 1994;18:207–216.
42.邓艳春,药立波,刘新平,等,人脑内ACP样结构域新基因的发现,生物化学与生物物理进展,2001;28(1):72-76
43.Nagase T, Ishikawa K, et al. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro,DNA Res, 1999; 6(1):63-70
44.李剑,刘新平,林树新,等。一种新的抑癌候选基因—NDRG2在人类正常组织及相应肿瘤组织中的表达,生物化学与生物物理进展,2002; 29(1):223-227
45.Qu X, Zhai Y, Wei H, et al.Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family, Mol Cell Biochem, 2002 ; 229(1-2):35-44
46.王立峰。应激刺激对NDRG2蛋白在细胞内定位的影响。[第四军医大学硕士论文,2003年P79-81]
47.Jing Zhang a, Junye Liu a, et al.The physical and functional interaction of NDRG2 with MSP58 in cells,Biochemical and Biophysical Research Communications ,2007; (352 ): 6–11
48.Deng Y, Yao L, et al. N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation, Int J Cancer, 2003 ;106(3):342-347
49.刘娜,刘新平,等,抑癌侯选基因NDRG2在乳腺肿瘤组织及乳腺癌细胞系中的表达分析,第四军医大学学报,2004;25(12):1065-1068
50.Hu XL, Liu XP, Deng YC et al. NDRG2 expression and mutation in human liver and pancreatic cancers, World J Gastroenterol, 2004;10(23):3518-3521
51.Reetta ?ss?m?ki, Maarit Sarlomo-Rikala, et al. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors, Genes Chromosomes Cancer, 2007;46(6):564-567
52.吴国强,刘新平等. NDRG2对肝癌细胞HepG2凋亡的诱导作用[J].细胞与分子免疫学杂志,2003,19(4):357-360.
53.Jian Zhang, Fuyang Li, et al.The repression of human differentiation related gene NDRG2 expression by MYC via MIZ-1 dependent interaction with theNDRG2 core promoter. J Biol Chem, 2006 ;281(51) :39159-39168
54.胡晓兰,药力波等. NDRG2在人胚胎组织中的表达分布特点. [J ].生理学报,2006,58(4):331-336.
55.候双兴,邓艳春等.NDRG2在人胎前脑发育期的表达特点. [J ]中华神经医学杂志,2006,5(2):109-112.
56.Hu XL, Liu XP, Deng YC, et al.Expression analysis of the NDRG2 gene in mouse embryonic and adult tissues. Cell Tissue Res. 2006 ;325(1):67-76
57.Zhang J,Wang JC, et al. High expression of bcl-x(L) in K562 cells and its role in the low sensitivity of K562 to realgar-induced apoptosis,Acta Haematol,2005;113(4):247-254
58.Choi SC, Kim KD, et al.Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells, FEBS Lett, 2003; 553(3): 413-418
59.Mitchelmore C, Buchmann-Moller S, et al.NDRG2: a novel Alzheimer's disease associated protein, Neurobiol Dis, 2004 ; 16(1):48-58
60.Takahashi K, Yamada M, et al.Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment, Int J Neuropsychopharmacol, 2005 ;8(3):381-389.
61.Kou Takahashi a,b, Misa Yamadaa, et al.Ndrg2 promotes neurite outgrowth of NGF-differentiated PC12 cells ,Neuroscience Letters, 2005;388 : 157–162
62.James G. Burchfield, Alecia J. Lennard,et al.Akt Mediates Insulin-stimulated Phosphorylation of Ndrg2[J]. The journal of Biological Chemistry,2004,279(18) :18623-32
63.Lang, F. and Cohen, P, Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms, Science STKE .2001; 108: 17
64.Firestone, G. L., Giampaolo, J. R. and O’Keeffe, B. A, Stimulus-dependent regulation of serum and glucocorticoid-induced protein kinase (SGK) transcription, sub-cellular location and enzymatic activity. Cell. Physiol. Biochem, 2003; 13: 1–12
65.James T. MURRAY, David G. CAMPBELL, et a1.Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3 [J].Biochem. J. 2004, 384, 477–488
66.Sheerazed Boulkrou, Michel Fay, et al.Characterization of Rat NDRG2 (N-Myc Downstream RegulatedGene 2), a Novel Early Mineralocorticoid-specific Induced Gene*,The Journal Of Biological Chemistry, 2002; 277(35): 31506–31515
67.Sheerazed Boulkroun Cathi Le Moellic et al.Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct,P.ugers Arch Eur J Physiol , 2005; 451: 388–394
68.Kalaydjieva, L.; Hallmayer, J. et.al, Gene mapping in Gypsies identifies a nove demyelinating neuropathy on chromosome 8q24, Nature Genet, 1996; 14: 214-217
69.Kurdistani SK, Arizti P, et al.Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage ,Cancer Res, 1998;58(19):4439-4444
70.Zhao W, Tang R,HuangY,Wang W, et al. Clong and expression pattern of the human NDRG3 gene, Biochem Biophys Acta,2001 ;1519(1-2):134-138
71.Zhou RH, Kokame K, et al.Characterization of the human NDRG gene family: a newly identified member,NDRG4, is specifically expressed in brain and heart,Genomics,2001;73(1):86-97
72.Xiao—Lan Hu ,l Xin—Ping Liu, et al.NDRG2 expression and mutation in human liver and pancreatic cancer[J]. W orld Journal of Gastroenterology, 2004,10(23):3518-21
73.张翊,陈杰,裴德宁等.重组人NDRG2蛋白对肿瘤细胞抑制作用研究[J].中国肿瘤生物治疗杂志,2004,11(3):204-207
74.Yanchun DENG, Libo YAO et al.N-Myc downstream-regulated gene 2(NDRG2)inhibits glioblastoma cell proliferation [J]. Int. J. Cancer,2003,106: 342–347
75.Choe G, Horvath S, et al. Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo [J]. Cancer Res. 2003 ,63(11):2742-6
76.Homma T, Fukushima T. Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol. 2006 Sep;65(9):846-54.
77.Okuda T,Kondoh H.Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/DRGI but show distinct tissue specificity and response to N—myc[J].Biochem Biophys Res Commun,1 999,266(1):208—215.
78.Zhou R H,Kokame K,Tsukamoto Y,et a1.Characterization of the human NDRG gene family:a newly identified member,NDRG4,is specifically expressed in brain and heart.Genomics,2001,73(1):86—97
79.张健,刘新平等. ndrg家族研究进展[J].生命科学,2003,15(4):203-206.
80.Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11598-603.
81.康春生,浦佩玉等.人脑胶质瘤AKT2表达与细胞增殖和侵袭性的关系[J].中华病理学杂志,2004,33(5):464-465
82.W?rntges S, Friedrich B, Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1. Pflugers Arch. 2002 ,443(4):617-24.
83.Tangir J, BonaféN, SGK1, a potential regulator of c-fms related breast cancer aggressiveness. [J].Proc Natl Acad Sci U S A. 2004,101(39):14057-62.