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ABSTRACT: To explore the expression pattern, prognostic value and functional role of stromal periostin (POSTN) in glioma patients, POSTN expression was measured using the Agilent Whole Human Genome Oligo Microarray in 220 frozen glioma tissues. We analyzed POSTN expression in 71 independent validated glioma samples using immuno-histochemistry. The expression levels of POSTN were relative to glioma grade progression and inversely correlated with overall survival in high-grade glioma patients (anaplastic gliomas and glioblastomas). Gene ontology (GO) analysis performed using DAVID showed that the gene sets related to cell migration and proliferation were significantly enriched in the cases with POSTN overexpression. Functional analyses in LN229 and U87 cells revealed that POSTN was involved in cell invasion and proliferation. MMP-9 was an effector of POSTN signaling in glioma cells. The expression of stromal protein POSTN is relative to glioma grade progression and confers a poor prognosis via promoting cellular invasion and proliferation in high-grade glioma patients.
International Journal of Oncology 03/2013; · 2.40 Impact Factor
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ABSTRACT: BACKGROUND: Meningioma is the second most common primary tumor of the central nervous system, and multiple genetic and environmental factors contribute to its etiology. Methylene tetrahydrofolate reductase (MTHFR) is a pivotal enzyme in folate metabolism. We conducted a case-control study to investigate the association of the MTHFR gene and meningioma in a Han population in northern China. METHODS: We genotyped two SNPs (C677T and A1298C) using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). In this study 317 meningioma patients were compared to 320 normal controls. Data were analyzed by SPSS 13.0 and HaploView software. RESULTS: We found a significant difference in the frequency distribution of 677CC and 677TT between cases and control groups; another SNP exhibited no differences in any genotype between the two cohorts. CONCLUSION: The results revealed that variations of the MTHFR gene were associated with meningioma; this finding indicates that the MTHFR gene potentially plays an important role in the pathogenesis of meningioma in the Northern Chinese Han population.
Gene 12/2012; · 2.34 Impact Factor
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Lingchao Chen,
Anling Zhang,
Yongli Li,
Kailiang Zhang,
Lei Han,
Wenzhong Du,
Wei Yan,
Ruiyan Li,
Yongzhi Wang,
Kun Wang,
Peiyu Pu,
Tao Jiang, Chuanlu Jiang,
Chunsheng Kang
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ABSTRACT: MicroRNAs are strongly implicated as affecting glioma, but their specific roles and functions have yet to be fully elucidated. In this study, we defined the expression and function of miR-24, which we found to be upregulated in glioma samples and glioma cells by qRT-PCR. Downregulation of miR-24 in glioma cell lines inhibited proliferation and invasion and induced apoptosis. Using computational and expression analysis, ST7L was identified as a candidate target of miR-24. A reporter assay with the 3'UTR of ST7L cloned downstream of a luciferase gene showed increased luciferase activity in the absence of miR-24, providing strong evidence that miR-24 is a direct regulator of ST7L. Furthermore, we observed that restoration of ST7L activity resulted in effects that were similar to those from transfecting a miR-24 inhibitor into glioma cells. Mechanistic investigation revealed that the deletion of miR-24 suppressed β-catenin/Tcf-4 transcription activity by targeting ST7L. In conclusion, our study demonstrates that miR-24 upregulation is common in glioma and that suppression of miR-24 expression inhibits cell proliferation and invasion, suggesting that miR-24 may act as an oncogene in glioma.
Cancer letters 11/2012; · 4.86 Impact Factor
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Wei Yan,
Wei Zhang,
Gan You,
Junxia Zhang,
Lei Han,
Zhaoshi Bao,
Yongzhi Wang,
Yanwei Liu, Chuanlu Jiang,
Chunsheng Kang,
Yongping You,
Tao Jiang
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ABSTRACT: Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to molecularly targeted therapy. However, prior studies attempting to classify glioma subtypes have given conflicting results. We aim to complement and validate the existing molecular classification system on a large number of samples from an East Asian population. A total of 225 samples from Chinese patients was selected for whole genome gene expression profiling. Consensus clustering was applied. Three major groups of gliomas were identified (referred to as G1, G2, and G3). The G1 subgroup correlates with a good clinical outcome, young age, and extremely high frequency of IDH1 mutations. Relative to the G1 subgroup, the G3 subgroup is correlated with a poorer clinical outcome, older age, and a very low rate of mutations in the IDH1 gene. Correlations of the G2 subgroup with respect to clinical outcome, age, and IDH1 mutation fall between the G1 and G3 subgroups. In addition, the G2 subtype was associated with a higher percentage of loss of 1p/19q when compared with G1 and G3 subtypes. Furthermore, our classification scheme was validated on 2 independent datasets derived from the cancer genome atlas (TCGA) and Rembrandt. With use of the TCGA classification system, proneural, neural, and mesenchymal, but not classical subtype, associated gene signatures were clearly defined. In summary, our results reveal that 3 main subtypes stably exist in Chinese patients with glioma. Our classification scheme may reflect the clinical and genetic alterations more clearly. Classical subtype-associated gene signature was not found in our dataset.
Neuro-Oncology 10/2012; · 5.72 Impact Factor
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Lingchao Chen,
Wei Zhang,
Wei Yan,
Lei Han,
Kailiang Zhang,
Zhendong Shi,
Junxia Zhang,
Yongzhi Wang,
Yongli Li,
Shizhu Yu,
Peiyu Pu, Chuanlu Jiang,
Tao Jiang,
Chunsheng Kang
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ABSTRACT: Notch pathway plays critical role in stem cell maintenance and angiogenesis, as well as cell fate decisions of cancer. However, concrete mechanisms of notch pathway regulation in glioma were not well known, especially mediated by microRNAs. In this study, we identified a brain-specific miRNA, miR-524-5p, which was associated with the pathological grade and overall survival of gliomas. Restorated expression of miR-524-5p in glioma suppressed cell proliferation and invasion both in vitro and in vivo. Using bioinformatics and biological approaches, we found that Jagged-1 and Hes-1, two key components of notch pathway, were direct targets of miR-524-5p. Knocking down of Jagged-1 or Hes-1 partially phenocopied miR-524-5p re-expression, whereas forced expression of Jagged-1 or Hes-1 reversed the effects of miR-524-5p on proliferation and invasion of glioma. Moreover, miR-524-5p levels in glioma samples were inversely correlated with Jagged-1 and Hes-1 and their overexpressions were associated with poor survival. Thus, we have identified that miR-524-5p behaves as a tumor suppressor by negatively targeting Jagged-1 and Hes-1 and provides an additional option to inhibit this oncogene in gliomas.
Carcinogenesis 08/2012; · 5.70 Impact Factor
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Lingchao Chen,
Junhe Zhang,
Yan Feng,
Ruiyan Li,
Xu Sun,
Wenzhong Du,
Xinyin Piao,
Hanbing Wang,
Dongbo Yang,
Ying Sun,
Xianfeng Li,
Tao Jiang,
Chunsheng Kang,
Yongli Li, Chuanlu Jiang
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ABSTRACT: MET, the receptor for hepatocyte growth factor receptor (HGF), has been reported to trigger multiple and sometimes opposing cellular responses in various types of tumor cells. It has been implicated in the regulation of tumor-cell survival, proliferation, angiogenesis, invasion and metastasis. However, the MET regulatory mechanism in glioma is not well known. MicroRNAs are a class of small noncoding RNAs that play important roles in a variety of biological processes including human cancers. In this study, we used computational and expressional analysis to identify that the 'seed sequence' of miR-410 matched the 3' UTR of the MET mRNA. Besides, the expression of miR-410 was inversely associated with MET in human glioma tissues. Using luciferase and western blot assay, we certified that miR-410 directly targeted MET in glioma cells. While restoring expression of miR-410 led to proliferation inhibition and reduced invasive capability in glioma cells. Furthermore, we showed that miR-410 played an important role in regulating MET-induced AKT signal transduction. While downregulation of MET by RNAi, we observed that MET knockdown resulted in effects similar to that with miR-410 transfection in glioma cells. Our findings suggest that miR-410, a direct regulator of MET, may function as a tumor suppressor in human gliomas.
The international journal of biochemistry & cell biology 06/2012; 44(11):1711-7. · 4.89 Impact Factor
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Lingchao Chen,
Lei Han,
Kailiang Zhang,
Zhendong Shi,
Junxia Zhang,
Anling Zhang,
Yongzhi Wang,
Yijun Song,
Yongli Li,
Tao Jiang,
Peiyu Pu, Chuanlu Jiang,
Chunsheng Kang
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ABSTRACT: Aberrant microRNA expression has been implicated in the development of human cancers. Here, we investigated the oncogenic significance and function of miR-23b in glioma. We identified that the expression of miR-23b was elevated in both glioma samples and glioma cells, indicated by real-time polymerase chain reaction analyses. Down-regulation of miR-23b triggered growth inhibition, induced apoptosis, and suppressed invasion of glioma in vitro. Luciferase assay and Western blot analysis revealed that VHL is a direct target of miR-23b. Restoring expression of VHL inhibited glioma proliferation and invasion. Mechanistic investigation revealed that miR-23b deletion decreased HIF-1α/VEGF expression and suppressed β-catenin/Tcf-4 transcription activity by targeting VHL. Furthermore, expression of VHL was inversely correlated with miR-23b in glioma samples and was predictive of patient survival in a retrospective analysis. Therefore, we demonstrated that downregulation of miR-23b suppressed tumor survival through targeting VHL, leading to the inhibition of β-catenin/Tcf-4 and HIF-1α/VEGF signaling pathways.
Neuro-Oncology 05/2012; 14(8):1026-36. · 5.72 Impact Factor
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Lingchao Chen,
Xiaofeng Wang,
Hanbing Wang,
Yongli Li,
Wei Yan,
Lei Han,
Kailiang Zhang,
Junxia Zhang,
Yongzhi Wang,
Yan Feng,
Peiyu Pu,
Tao Jiang,
Chunsheng Kang, Chuanlu Jiang
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ABSTRACT: MicroRNAs are strongly implicated in cancer but their specific roles and functions in the major cancers have yet to be fully elucidated. In this study, we defined the expression and function of miR-137, which we found to be downregulated in glioma samples and glioma cells by qRT-PCR. Ectopic expression of miR-137 in glioma cell lines inhibited proliferation and invasion. Using computational and expression analysis, Cox-2 was identified as a candidate target of miR-137. Reporter assay with 3'UTR of Cox-2 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-137, providing strong evidence that miR-137 was a direct regulator of Cox-2. Expression analysis further revealed that Cox-2 was elevated in glioma and associated with survival of patients. Furthermore, we observed that Cox-2 knockdown resulted in effects similar to those with miR-137 transfection in glioma cells. In conclusion, our study demonstrates that miR-137 deregulation is common in glioma, and restoration of its function inhibits cell proliferation and invasion, suggesting that miR-137 may act as a tumour suppressor.
European journal of cancer (Oxford, England: 1990) 03/2012; 48(16):3104-11. · 4.12 Impact Factor
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ABSTRACT: The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of glioblastoma (GBM) cases are refractory to TMZ. Previous studies have revealed that the PI3K/Akt pathway is activated in an ataxia telangiectasia and Rad3 related-dependent manner in response to TMZ. Thus, we hypothesized that PI3K inhibitors may act as antitumor agents against gliomas and potentiate the cytotoxicity of TMZ. The cytotoxicity of a PI3K inhibitor, LY294002, was examined both alone and in combination with TMZ in human glioma cell lines. Proliferation of tumor cells treated with LY294002 in combination with TMZ was significantly suppressed compared to treatment with either drug used alone. The combination treatment induced a higher apoptosis rate, while reducing the invasive capability of U87 cells. The apoptosis-associated proteins, cleaved-caspase-3 and Bax, were more significantly up-regulated by the combined treatment than by TMZ used alone. In addition, p-Akt and Bcl-2, which can promote TMZ resistance, were markedly decreased by LY294002. These findings suggest that LY294002 enhances the cytotoxicity of TMZ by down‑regulation of the PI3K/Akt pathway.
Molecular Medicine Reports 11/2011; 5(2):575-9. · 0.42 Impact Factor
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ABSTRACT: Because of the variety of factors affecting glioma prognosis, prediction of patient survival is particularly difficult. Protein-protein interaction (PPI) networks have been considered with regard to how their spatial characteristics relate to glioma. However, the dynamic nature of PPIs in vivo makes them temporally and spatially complex events. Integration of prognosis-specific co-expression information adds further dynamic features to these networks. Although some biomarkers for glioma prognosis have been identified, none is sufficient for accurate prediction of either prognosis or improved survival. We have established co-expressed protein-interaction networks that integrate protein-protein interactions with glioma gene-expression profiles related to different survival times. Biomarkers related to glioma prognosis were identified by comparative analysis of the dynamic features of the glioma prognosis network, particularly subnetworks. Four significantly differently expressed genes (SDEGs) are upregulated and ten SDEGs downregulated as lifetime is extended. In addition, 97 enhanced differently co-expressed protein interactions (DCPIs) and 99 weakened DCPIs were associated with glioma patient lifetime extension. We propose a method for estimating glioma prognosis on the basis of the construction of a dynamic modular network. We have used this method to identify dynamic genes and interactions related to glioma prognosis. Among these, enhanced MYC expression was related to lifetime extension, as were interactions between E2F1 and RB1 and between EGFR and p38. This method is a novel means of studying the molecular mechanisms determining prognosis in glioma.
Journal of Neuro-Oncology 11/2011; 107(2):281-8. · 3.21 Impact Factor
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ABSTRACT: A previous study showed that miR-221/222 can regulate cell apoptosis. p53 is a well known tumor suppressor which can influence the chemosensitivity of glioma cells. However, the effect of miR-221/222 in gliomas with different p53 status is unknown. Here, we demostrate that knockdown of miR-221/222 increases apoptosis in human gliomas of different p53 types (U251 cells, p53 mutant-type; LN308 cells, p53 null-type; and U87 cells, p53 wild-type). Furthermore, the effect of miR-221/22 caused no change of p53 expression in the glioma cells studied. In addition, when a specific siRNA against p53 was employed in U87 cells, no attenuation of apoptosis was found after knockdown of miR-221/222. Importantly, we found that As-miR-221/222-treated cells increased expression of Bax, cytochrome c, Apaf-1 and cleaved-caspase-3. Our results showed that low expression of miR-221/222 sensitized glioma cells to temozolomide (TMZ); in addition, ectopic expression of PUMA by pcDNA-PUMA had a similar effect. Taken together, our study indicates that downregulated miR-221/222 can sensitize glioma cells to TMZ by regulating apoptosis independently of p53 status.
Oncology Reports 11/2011; 27(3):854-60. · 1.84 Impact Factor
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ABSTRACT: The objective was to study the inhibitory effects of recombinant murine receptor activator of nuclear factor κB (RANK) protein on osteoclasts in vivo and in vitro.
The RANK protein was added to the cocultures of osteoclasts at concentrations of 10(-6), 10(-5), and 10(-4) g/L. The morphology and number of osteoclasts were examined. Female KM mice were ovariectomized and treated with RANK protein at 5 mg/kg body weight. Biochemical markers of bone metabolism, bone mineral density, and bone morphology were examined.
Three days after RANK treatment, the numbers of tartrate-resistant acid phosphatase-positive osteoclasts and resorption pits in bone slices decreased significantly in each treatment group, with the most significant decrease observed in the 10(-4) g/L group. Compared with the control group in vivo, the RANK-treated group exhibited higher bone mineral density and nearly complete inhibition of tartrate-resistant acid phosphatase-positive osteoclasts in bone slices.
Recombinant murine RANK protein effectively inhibits the activity of osteoclasts and the resulting bone resorption.
The Journal of craniofacial surgery 11/2011; 22(6):2084-9. · 0.81 Impact Factor
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Lingchao Chen,
Huibing Li,
Lei Han,
Kailiang Zhang,
Guangxiu Wang,
Yongzhi Wang,
Yanwei Liu,
Yongri Zheng,
Tao Jiang,
Peiyu Pu, Chuanlu Jiang,
Chunsheng Kang
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ABSTRACT: Our previous miRNAs profiling study showed that miR-27b was up-regulated in glioma cells compared with H4 low grade astrocytoma cells. However, the main function of miR-27b in glioma in not known yet. The aim of this study was to investigate the expression and function of miR-27b in the pathogenesis of glioma. Real-time PCR showed that miR-27b was up-regulated in glioma samples and glioma cells. Down-regulation of miR-27b triggered growth inhibition, induced apoptosis and inhibited invasion in glioma cells. Furthermore, TOPflash luciferase activity was decreased significantly, while FOPflash luciferase did not change significantly. In addition, Western blot assay showed that STAT3, c-myc and cyclin D1 were knocked down after treatment with miR-27b inhibitor. These findings suggest that aberrantly up-regulated miR-27b may be one of the critical factors that contribute to malignancy in human gliomas.
Oncology Reports 09/2011; 26(6):1617-21. · 1.84 Impact Factor
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ABSTRACT: Increasing evidence suggests that interplays between Wnt/β-catenin and PI3K/AKT signaling cascades are involved in tumor development and progression. However, the exact mechanism in glioma is not well known. Using aspirin, we found that the expression levels of AKT1 in glioma cells significantly correlated with the transcriptional activity of β-catenin. Similar observations were made when we subjected glioma cells to treatment with Tcf4 siRNA. Moreover, both aspirin and Tcf4 siRNA can suppress the proliferation and induce apoptosis of glioma. In addition, our analysis of the gene promoter of AKT1 revealed multiple putative Tcf-4 binding sites. In support of the concept that β-catenin/Tcf-4 is a transcriptional regulator for AKT1, results from our chromatin immunoprecipitation studies and luciferase assay showed that β-catenin/Tcf-4 binds to the potential binding sites in the gene promoter of AKT1. Furthermore, using immunohistochemistry, we found that Tcf-4 protein expression increased significantly in high-grade glioma in comparison to low-grade glioma and correlated with AKT1 expression. In conclusion, our results support the concept that β-catenin/Tcf-4 directly regulates AKT1 in glioma, and these two proteins may cooperate with each other in exerting their oncogenic effects in glioma.
International Journal of Oncology 06/2011; 39(4):883-90. · 2.40 Impact Factor
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ABSTRACT: We investigated cerebrospinal fluid (CSF) samples from 21 patients with idiopathic normal pressure hydrocephalus (INPH) and 14 controls without neurological disease. The concentrations of leucine-rich alpha-2-glycoprotein (LRG), transforming growth factor (TGF)-beta1, 2, 3 and TGF-beta type II receptor (TbetaR-II) in CSF were measured using ELISA. TGF-beta1, TbetaR-II and LRG CSF levels of patients with INPH were significantly higher than controls, whereas no significant differences in TGF-beta2 levels were found between INPH patients and controls. The present study suggests that TGF-betas expressions may be modulated differently in patients with INPH. These results also indicate that the CSF level assay of TGF-beta1, TbetaR-II and LRG is useful for the diagnosis of patients with INPH, and TGF-beta1, TbetaR-II and LRG may be involved in the pathogenesis of the disease.
Neuroscience Letters 03/2007; 413(2):141-4. · 2.11 Impact Factor
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ABSTRACT: We investigated cerebrospinal fluid (CSF) samples from 21 patients with idiopathic normal pressure hydrocephalus (INPH) and 14 controls without neurological disease. The concentrations of leucine-rich α-2-glycoprotein (LRG), transforming growth factor (TGF)-β1, 2, 3 and TGF-β type II receptor (TβR-II) in CSF were measured using ELISA. TGF-β1, TβR-II and LRG CSF levels of patients with INPH were significantly higher than controls, whereas no significant differences in TGF-β2 levels were found between INPH patients and controls. The present study suggests that TGF-βs expressions may be modulated differently in patients with INPH. These results also indicate that the CSF level assay of TGF-β1, TβR-II and LRG is useful for the diagnosis of patients with INPH, and TGF-β1, TβR-II and LRG may be involved in the pathogenesis of the disease.
Neuroscience Letters.
