Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of...Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of O6-methylguanine methyltransferase(MGMT)and/or lack of a DNA repair pathway in GBM cells.Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics.However,the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared.This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines.It also summarizes potential treatment options for TMZ resistant GBMs.展开更多
Background Invasion growth is the most characteristic biological phenotype of glioblastoma, but the molecular mechanism in glioma cell invasion is poorly understood. Recent data have showed that microRNA plays an esse...Background Invasion growth is the most characteristic biological phenotype of glioblastoma, but the molecular mechanism in glioma cell invasion is poorly understood. Recent data have showed that microRNA plays an essential role in tumor invasion. Our study aimed to explore the mechanism of miR-7 involved in the control of glioblastoma cell invasion. Methods Glioma cell invasion was evaluated by transwell and scratch assays after up-regulation of miR-7 using miR-7 mimics in U87 and U251 cells. Luciferase reporter assay was used to determine focal adhesion kinase （FAK） as a target of miR-7. The levels of miR-7, matrix metalloproteinases （MMP）-2 and MMP-9 mRNA were detected by PCR assay, and the levels of FAK, MMP-2, MMP-9, total and phosphorylation serine/threonine kinase （AKT）, and extracellular signal-regulated kinase （ERK） 1/2 were measured by Western blotting analysis. Results Over-expression of miR-7 inhibited the invasion and migration activity of U87 and U251 cells. And up-regulation of miR-7 reduced FAK protein expression, Further, luciferase reporter assay showed that miR-7 modulated FAK expression directly by binding 3＇UTR of FAK mRNA. In addition, miR-7 repressed p-ERK1/2 and p-AKT level, MMP-2 and MMP-9 expression. Finally, the inverse relationship between FAK and miR-7 expression was certificated in human glioma tissues. Conclusion To our knowledge, these data indicate for the first time that miR-7 directly regulates cell invasion by targeting FAK in glioblastoma and that miR-7 could be a potential therapeutic target for glioblastoma intervention.展开更多
Indoleamine 2,3-dioxygenase 1(IDO1)is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan(Trp)into downstream catabolites known as kynurenines.Coincidently,numerous studies have demonstr...Indoleamine 2,3-dioxygenase 1(IDO1)is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan(Trp)into downstream catabolites known as kynurenines.Coincidently,numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer.Preclinical studies have further introduced an interesting paradox:while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden,approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival.Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy,these data suggest that there is a more complex mechanism of action than previously appreciated.Similar to the dual faces of the astrological Gemini,we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism,as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects.The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration,but the lack of a universal prognostic significance among all cancer subtypes.Finally,ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients。展开更多
Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are i...Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases(MMPs) were found in glioblastoma(GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma(LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory dataavailable. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.展开更多
Background Recent studies have demonstrated the existence of a small fraction of cells with features of primitive neural progenitor cells and tumor-initiating function in brain tumors. These cells might represent prim...Background Recent studies have demonstrated the existence of a small fraction of cells with features of primitive neural progenitor cells and tumor-initiating function in brain tumors. These cells might represent primary therapeutic target for complete eradication of the tumors. This study aimed to determine the resistant phenotype of glioblastoma stem cells （GSCs） to temozolomide （TMZ） and to explore the possible molecular mechanisms underlying TMZ resistance. Methods Freshly resected glioblastoma specimen was collected and magnetic isolation of GSCs was carried out using the Miltenyi Biotec CD133 Cell Isolation kit. The cytotoxic effect of TMZ on CD133^＋ and CD133^- glioblastoma cells was determined by using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay. Autophagy-related proteins （Beclin-1, LC3 and Atg5） and cleaved caspase-3 （p17） were analyzed by Western blotting. Immunofluorescent staining was used to detect Atg5, glial fibrillary acidic protein （GFAP） and CD133 expression in glioblastoma cells. Statistical analysis was carried out using SPSS 10.0 software. For all tests, the level of statistical significance was set at P 〈0.05. Results CD133^＋ glioblastoma ceils exhibited neurosphere-like growth in vitro and high expression of CD133 stem cell marker. The growth-inhibiting rate in CD133- glioblastoma cells treated with 5 or 50 pmol/L TMZ was significantly higher than that in CD133^＋ glioblastoma cells （（14.36±3.75）% vs （2.54±1.36）% or （25.95±5.25）% vs （2.72±1.84）%, respectively, P 〈0.05）. Atg5, LC3-11 and Beclin-1 levels were significantly lower in CD133^＋ glioblastoma cells than those in autologous CD133^- cells after TMZ treatment （P 〈0.05）. Caspase-3 was mildly activated only in CD133^- glioblastoma cells after exposure to TMZ （P 〈0.05）. Immunofluorescent staining revealed elevated expression of Atg5 in GFAP^＋ cells following TMZ treatment. Conclusions The GSCs display strong capability of tumor�展开更多
Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistan...Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.展开更多
Background： The radiochemotherapy regimen concomitantly employing temozolomide （TMZ） chemotherapy and radiotherapy （RT） 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma （...Background： The radiochemotherapy regimen concomitantly employing temozolomide （TMZ） chemotherapy and radiotherapy （RT） 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma （GBM）. However, its median overall survival （OS） is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods： A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide （early TMZ group） or standard concomitant radiochemotherapy regimen （control group）. Overall response was assessed based on objective tumor assessments, administration ofcorticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event （AE）, and neurological condition were measured for 24 months of tbllow-up. The primary efficacy endpoint of this study was overall survival （OS）. The secondary endpoint was progression free survival （PFS）. Results： The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group （log-rank test P 0.021 ）. In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively （P 〈 0.05）. The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group （log-rank test P = 0.695）. AEs occurred in 29 （55.8%） and 31（73.8%） patients respectively in early and control groups, including nausea （15.4% vs. 33.3%）, vomiting （7.7% vs. 28.6%）, fever （7.7% vs. 11.9%）, and headache （3.8% vs. 23.8%）. Only 30.8% and 33.3% were drug-related, respectively. Conclusions： Addition of TMZ chemotherapy in the early break of the standard concomi展开更多
Background Everlasting cellular proliferation is the fundamental feature during gliomagenesis and Ki-67 is one of the classical proliferation markers in human glioblastoma multiforme （GBM）. However, the driver genes...Background Everlasting cellular proliferation is the fundamental feature during gliomagenesis and Ki-67 is one of the classical proliferation markers in human glioblastoma multiforme （GBM）. However, the driver genes or core pathways for cellular proliferation in GBM have not been elucidated systematically. Methods We evaluated by immunohistochemistry the prognostic value of Ki-67 expression in the clinical outcome of 156 Chinese patients with GBM and a total of 64 GBM samples were selected for further Agilent genome-wide microarray analysis. On the basis of the microarray data from Tiantan （n--64） and The Cancer Genome Atlas （TCGA） （n=202） database, differentially expressed genes between the GBM subgroups with high or low level of Ki-67 expression were identified using Significance Analysis of Microarrays （SAM）. Gene Ontology （GO） and KEGG Pathway analyses were then undertaken for the Ki-67 associated genes to identify the most significant biological processes and signaling pathways. Results We confirmed that Ki-67 was an independent prognostic indicator in the largest Chinese patient cohort of 156 GBM samples via immunohistochemical staining. Survival analysis of Ki-67 over-expression revealed a highly significant association with a worse clinical outcome （P=0.010 for progression-free survival; P=0.007 for overall survival）. Comparative and integrated analysis between -Iqantan and TCGA database identified a 247-gene ＂proliferation signature＂ （205 up-regulated and 42 down-regulated genes） that distinguished Ki-67 expression phenotypes. GO and KEGG Pathway analyses further indicated that Ki-67 expression phenotype was associated with distinct changes in gene expression associated with the regulation of cellular growth and proliferation. Conclusions Proliferation marker Ki-67 is an independent prognostic indicator in Chinese GBM patients. And Ki-67 associated proliferation signature identified through genome-wide microarray analysis may provide potential targets for anti-prolifer展开更多
基金These studies were supported from the Gittlen Foundation.
文摘Temozolomide(TMZ)is an oral alkylating agent used to treat glioblastoma multiforme(GBM)and astrocytomas.However,at least 50%of TMZ treated patients do not respond to TMZ.This is due primarily to the over-expression of O6-methylguanine methyltransferase(MGMT)and/or lack of a DNA repair pathway in GBM cells.Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics.However,the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared.This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines.It also summarizes potential treatment options for TMZ resistant GBMs.
基金This work was supported by grants from the National Natural Scientific Foundation of China （No. 81072078 and No. 30872657）, Jiangsu Province＇s Natural Science Foundation （No. BK2008475, No. 2009444 and No. 2010580）, the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, and Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Background Invasion growth is the most characteristic biological phenotype of glioblastoma, but the molecular mechanism in glioma cell invasion is poorly understood. Recent data have showed that microRNA plays an essential role in tumor invasion. Our study aimed to explore the mechanism of miR-7 involved in the control of glioblastoma cell invasion. Methods Glioma cell invasion was evaluated by transwell and scratch assays after up-regulation of miR-7 using miR-7 mimics in U87 and U251 cells. Luciferase reporter assay was used to determine focal adhesion kinase （FAK） as a target of miR-7. The levels of miR-7, matrix metalloproteinases （MMP）-2 and MMP-9 mRNA were detected by PCR assay, and the levels of FAK, MMP-2, MMP-9, total and phosphorylation serine/threonine kinase （AKT）, and extracellular signal-regulated kinase （ERK） 1/2 were measured by Western blotting analysis. Results Over-expression of miR-7 inhibited the invasion and migration activity of U87 and U251 cells. And up-regulation of miR-7 reduced FAK protein expression, Further, luciferase reporter assay showed that miR-7 modulated FAK expression directly by binding 3＇UTR of FAK mRNA. In addition, miR-7 repressed p-ERK1/2 and p-AKT level, MMP-2 and MMP-9 expression. Finally, the inverse relationship between FAK and miR-7 expression was certificated in human glioma tissues. Conclusion To our knowledge, these data indicate for the first time that miR-7 directly regulates cell invasion by targeting FAK in glioblastoma and that miR-7 could be a potential therapeutic target for glioblastoma intervention.
基金supported by NIH grants R00 NS082381(DAW)and R01 NS097851-01(DAW)the Cancer Research Institute—Clinic and Laboratory Integration Program(DAW)+1 种基金the Robert H.Lurie Comprehensive Cancer Center—Zell Scholar Program of the Zell Family Foundation Gift(DAW)the Northwestern Brain Tumor Institute.
文摘Indoleamine 2,3-dioxygenase 1(IDO1)is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan(Trp)into downstream catabolites known as kynurenines.Coincidently,numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer.Preclinical studies have further introduced an interesting paradox:while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden,approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival.Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy,these data suggest that there is a more complex mechanism of action than previously appreciated.Similar to the dual faces of the astrological Gemini,we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism,as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects.The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration,but the lack of a universal prognostic significance among all cancer subtypes.Finally,ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients。
基金Supported by Interdisziplinres Zentrum für Klinische Forschung der Universitt Würzburg,Project B25
文摘Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases(MMPs) were found in glioblastoma(GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma(LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory dataavailable. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.
基金This study was supported by a grant from National Natural Science Foundation of China （No. 30772551）.
文摘Background Recent studies have demonstrated the existence of a small fraction of cells with features of primitive neural progenitor cells and tumor-initiating function in brain tumors. These cells might represent primary therapeutic target for complete eradication of the tumors. This study aimed to determine the resistant phenotype of glioblastoma stem cells （GSCs） to temozolomide （TMZ） and to explore the possible molecular mechanisms underlying TMZ resistance. Methods Freshly resected glioblastoma specimen was collected and magnetic isolation of GSCs was carried out using the Miltenyi Biotec CD133 Cell Isolation kit. The cytotoxic effect of TMZ on CD133^＋ and CD133^- glioblastoma cells was determined by using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay. Autophagy-related proteins （Beclin-1, LC3 and Atg5） and cleaved caspase-3 （p17） were analyzed by Western blotting. Immunofluorescent staining was used to detect Atg5, glial fibrillary acidic protein （GFAP） and CD133 expression in glioblastoma cells. Statistical analysis was carried out using SPSS 10.0 software. For all tests, the level of statistical significance was set at P 〈0.05. Results CD133^＋ glioblastoma ceils exhibited neurosphere-like growth in vitro and high expression of CD133 stem cell marker. The growth-inhibiting rate in CD133- glioblastoma cells treated with 5 or 50 pmol/L TMZ was significantly higher than that in CD133^＋ glioblastoma cells （（14.36±3.75）% vs （2.54±1.36）% or （25.95±5.25）% vs （2.72±1.84）%, respectively, P 〈0.05）. Atg5, LC3-11 and Beclin-1 levels were significantly lower in CD133^＋ glioblastoma cells than those in autologous CD133^- cells after TMZ treatment （P 〈0.05）. Caspase-3 was mildly activated only in CD133^- glioblastoma cells after exposure to TMZ （P 〈0.05）. Immunofluorescent staining revealed elevated expression of Atg5 in GFAP^＋ cells following TMZ treatment. Conclusions The GSCs display strong capability of tumor�
文摘Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.
文摘Background： The radiochemotherapy regimen concomitantly employing temozolomide （TMZ） chemotherapy and radiotherapy （RT） 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma （GBM）. However, its median overall survival （OS） is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods： A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide （early TMZ group） or standard concomitant radiochemotherapy regimen （control group）. Overall response was assessed based on objective tumor assessments, administration ofcorticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event （AE）, and neurological condition were measured for 24 months of tbllow-up. The primary efficacy endpoint of this study was overall survival （OS）. The secondary endpoint was progression free survival （PFS）. Results： The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group （log-rank test P 0.021 ）. In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively （P 〈 0.05）. The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group （log-rank test P = 0.695）. AEs occurred in 29 （55.8%） and 31（73.8%） patients respectively in early and control groups, including nausea （15.4% vs. 33.3%）, vomiting （7.7% vs. 28.6%）, fever （7.7% vs. 11.9%）, and headache （3.8% vs. 23.8%）. Only 30.8% and 33.3% were drug-related, respectively. Conclusions： Addition of TMZ chemotherapy in the early break of the standard concomi
基金This work was supported by grants from National Key Project of Science and Technology Supporting Programs （No. 2007BAI05B08）, National Natural Science Foundation of China （No. 30772238 and 30730035）, Beijing Science and Technology Programs （Capital Clinical Application Research Project, No. D101100050010007）.
文摘Background Everlasting cellular proliferation is the fundamental feature during gliomagenesis and Ki-67 is one of the classical proliferation markers in human glioblastoma multiforme （GBM）. However, the driver genes or core pathways for cellular proliferation in GBM have not been elucidated systematically. Methods We evaluated by immunohistochemistry the prognostic value of Ki-67 expression in the clinical outcome of 156 Chinese patients with GBM and a total of 64 GBM samples were selected for further Agilent genome-wide microarray analysis. On the basis of the microarray data from Tiantan （n--64） and The Cancer Genome Atlas （TCGA） （n=202） database, differentially expressed genes between the GBM subgroups with high or low level of Ki-67 expression were identified using Significance Analysis of Microarrays （SAM）. Gene Ontology （GO） and KEGG Pathway analyses were then undertaken for the Ki-67 associated genes to identify the most significant biological processes and signaling pathways. Results We confirmed that Ki-67 was an independent prognostic indicator in the largest Chinese patient cohort of 156 GBM samples via immunohistochemical staining. Survival analysis of Ki-67 over-expression revealed a highly significant association with a worse clinical outcome （P=0.010 for progression-free survival; P=0.007 for overall survival）. Comparative and integrated analysis between -Iqantan and TCGA database identified a 247-gene ＂proliferation signature＂ （205 up-regulated and 42 down-regulated genes） that distinguished Ki-67 expression phenotypes. GO and KEGG Pathway analyses further indicated that Ki-67 expression phenotype was associated with distinct changes in gene expression associated with the regulation of cellular growth and proliferation. Conclusions Proliferation marker Ki-67 is an independent prognostic indicator in Chinese GBM patients. And Ki-67 associated proliferation signature identified through genome-wide microarray analysis may provide potential targets for anti-prolifer
