RESUMO
Isocitrate dehydrogenase 1 (IDH1) mutation is an important prognostic marker in glioma. However, its downstream effect remains incompletely understood. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis in a number of human malignancies, including glioma. Here, we investigated whether and how lncRNA expression profiles would differ between gliomas with or without IDH1 mutation. By using our previously reported lncRNA mining approach, we performed lncRNA profiling in three public glioma microarray datasets. The differential lncRNA expression analysis was then conducted between mutant-type and wild-type IDH1 glioma samples. Comparison analysis identified 14 and 9 lncRNA probe sets that showed significantly altered expressions in astrocytic and oligodendroglial tumors, respectively (fold change ≥ 1.5, false discovery rate ≤ 0.1). Moreover, the differential expressions of these lncRNAs could be confirmed in the independent testing sets. Functional exploration of the lncRNAs by analyzing the lncRNA-protein interactions revealed that these IDH1 mutation-associated lncRNAs were involved in multiple tumor-associated cellular processes, including metabolism, cell growth and apoptosis. Our data suggest the potential roles of lncRNA in gliomagenesis, and may help to understand the pathogenesis of gliomas associated with IDH1 mutation.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , RNA Longo não Codificante/genética , Neoplasias Encefálicas/mortalidade , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Perfilação da Expressão Gênica , Glioma/metabolismo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Estatísticas não Paramétricas , Análise de SobrevidaRESUMO
Long non-coding RNAs (lncRNAs) represent the leading edge of cancer research, and have been implicated in cancer biogenesis and prognosis. We aimed to identify lncRNA signatures that have prognostic values in glioblastoma multiforme (GBM). Using a lncRNA-mining approach, we performed lncRNA expression profiling in 213 GBM tumors from The Cancer Genome Atlas (TCGA), randomly divided into a training (n=107) and a testing set (n=106). We analyzed the associations between lncRNA signatures and clinical outcome in the training set, and validated the findings in the testing set. We also validated the identified lncRNA signature in another two independent GBM data sets from Gene Expression Omnibus (GEO), which contained specimens from 68 and 101 patients, respectively. We identified a set of six lncRNAs that were significantly associated with the overall survival in the training set (P≤0.01). Based on this six-lncRNA signature, the training-set patients could be classified into high-risk and low-risk subgroups with significantly different survival (HR=2.13, 95% CI=1.38-3.29; P=0.001). The prognostic value of this six-lncRNA signature was confirmed in the testing set and the two independent data sets. Further analysis revealed that the prognostic value of this signature was independent of age and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. The identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GBM pathogenesis. This six-lncRNA signature may have clinical implications in the subclassification of GBM.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/genética , Glioblastoma/mortalidade , RNA Longo não Codificante/metabolismo , Fatores Etários , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/terapia , Guanina/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise em Microsséries , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de TempoRESUMO
Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation conferred malignant characteristics including proliferation, invasion, migration and angiogenesis in vitro, and increased tumor growth in vivo via the mitogen-activated protein kinase (MAPK) signaling pathway. Pathway analysis suggested genetic and pharmacologic inhibition of P4HB suppressed MAPK expression and its downstream targets were involved in angiogenesis and invasion. This is the first study that demonstrates the oncogenic roles of P4HB and its underlying mechanism in glioma. Since tumor invasion and Vascularisation are typical hallmarks in malignant glioma, our findings uncover a promising anti-glioma mechanism through P4HB-mediated retardation of MAPK signal transduction.
RESUMO
Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.
RESUMO
BACKGROUND: Cranionasal resection was first described in 1997 for the surgical resection of olfactory neuroblastoma. The endoscopic transnasal approach is used in cranionasal resection to replace the more invasive craniofacial resection. It has the advantages of avoiding the facial wound and its associated pain, swelling, and scar. The authors have routinely practiced cranionasal resection since 1996 for resection of all anterior skull base tumors in which the resultant skull base bony defect is limited to the nasal and sinus roof. The aim of this study was to review the results of cranionasal resection for olfactory neuroblastoma. METHODS: The results of cranionasal resection for olfactory neuroblastoma in six patients from 1996 to 2003 were reviewed. RESULTS: The Kadesh stages were 3A, 2B, and 1C. None of the patients had postoperative complications. Postoperative radiotherapy was given only to the patient with Kadesh stage C disease. There were no local recurrences. Two patients died of lung metastasis. CONCLUSIONS: Cranionasal resection is a safe and adequate procedure. Postoperative radiotherapy is not necessary after clear resection of Kadesh A and B tumors.