微RNA与神经胶质瘤的关系

近来研究表明,某些微RNA(microRNAs,miRNA)在不同组织分型的胶质瘤中呈特异性表达,通过上调或下调相应的miRNA可诱导胶质瘤细胞的凋亡或抑制其增殖。应用微阵列技术分析不同胶质瘤中miRNA表达谱将有助于进一步探讨胶质瘤发生发展的机制,实现胶质瘤的个性化诊断,探索miRNA为靶点的胶质瘤基因治疗的可行性。     

miRNA在胶质瘤化疗耐药中的研究进展

化疗现作为胶质瘤的常规治疗手段之一,对改善病人的预后起了重要的作用,而耐药是化疗失败的常见原因。胶质瘤化疗耐药的机制很复杂,包括DNA甲基化,基因突变等。microRNA(miRNA)是一类非编码的内源性小分子RNA,进化上保持高保守性,对基因表达进行转录后水平的调控。国内外学者对miRNA在肿瘤耐药中的作用做了积极的探索,发现miRNA在其中起十分重要的作用。本文对胶质瘤耐药相关的miRNA进行综述。     

Gliomas display a microRNA expression profile reminiscent of neural precursor cells

Gliomas express many genes that play a role in neural precursor cells (NPCs), but no direct comparison between glioma and stem cell (SC) gene expression profiles has been performed. To investigate the similarities and differences between gliomas and SCs, we compared the microRNA (miRNA) expression signatures of glial tumors, embryonic SCs (ESCs), NPCs, and normal adult brains from both human and mouse tissues. We demonstrated that both human gliomas (regardless of their grade) and methylcholanthrene-induced mouse glioma shared an miRNA expression profile that is reminiscent of NPCs. About half of the miRNAs expressed in the shared profile clustered in seven genomic regions susceptible to genetic/epigenetic alterations in various cancers. These clusters comprised the miR17 family, mir183-182, and the SC-specific clusters mir367-302 and mir371-373, which are upregulated in gliomas, ESCs, and NPCs. The bipartite cluster of 7 + 46 miRNAs on chromosome 14q32.31, which might represent the largest tumor suppressor miRNA cluster, was downregulated in the shared expression profile. This study provides the first evidence for association between these clusters and gliomas. Despite the broad similarity in the miRNA expression profiles, 15 miRNAs showed disparate expression between SC and gliomas. Ten miRNAs belong to the 2 SC-specific clusters and the remaining (mir135b, mir141, mir205, mir200C, and mir301a) have been previously shown to associate with malignancies. Our finding showed that all gliomas displayed NPC-like miRNA signatures, which may have implications for studies of glioma origins. Furthermore, careful study of the 15 miRNAs that differ in expression between SCs and gliomas, particularly those 5 that are not SC-specific, may enhance our understanding of gliomagenesis.     

MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis

MicroRNAs (miRNAs) are directly involved in the progression in various cancers. To date, no systematic researches have been performed on the expression pattern of miRNA during progression from low grade gliomas to anaplastic gliomas or secondary glioblastomas and those prognostic miRNAs in anaplastic gliomas and secondary glioblastomas. In the present study, high-throughput microarrays were used to measure miRNA expression levels in 116 samples in the different progression stages of glioma. We found that miRNA expression pattern totally altered when low grade gliomas progressed to anaplastic gliomas or secondary glioblastomas. However, anaplastic gliomas and secondary glioblastomas have similar expression pattern in miRNA level. Furthermore, we developed a five-miRNA signature (two protective miRNAs-miR-767-5p, miR-105; three risky miRNAs: miR-584, miR-296-5p and miR-196a) that could identify patients with a high risk of unfavorable outcome in anaplastic gliomas regardless of histology type. It should be highlighted that the five-miRNA signature can also identify patients who had a high risk of unfavorable outcome in secondary and TCGA Proneural glioblastomas, but not Neural, Classical and Mesenchymal glioblastomas. Taken together, our results demonstrate that miRNA expression patterns in the malignant progression of gliomas and a novel prognostic classifier, the five-miRNA signature, serve as a prognostic marker for patient risk stratification in anaplastic gliomas, Secondary and Proneural glioblastomas.     

MicroRNAs might be Promising Biomarkers of Human Gliomas

Recently, altered expression levels of several microRNAs have been observed in gliomas, the most frequentprimary brain tumor in adults. To review whether microRNAs might be promising biomarkers of human gliomas,we comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to 2010 with the languagelimitation of English. We found that further understanding of the functions of miRNAs in specific cellular eventsis needed; the continuous technological advances in accurate and cost-effective miRNAs detection provide theprospect of a very promising role for miRNAs as novel diagnostic biomarkers of gliomas.     

MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas

Gliomas are the most common type of malignant primary brain tumor. Despite advances in surgery, radiation therapy, and chemotherapy, the prognosis of patients with gliomas has not significantly improved. MicroRNAs (miRNAs), a class of non-coding RNAs, 21–25 nucleotides long, negatively regulate the expression of target genes by interacting with specific sites in mRNAs, and play a critical role in the development of gliomas. The EGFR/PTEN/AKT pathway is a promising target for anti-glioma therapy. Recent studies have showed that regulation of the EGFR/PTEN/AKT pathway by miRNAs plays a major role in glioma progression, indicating a novel way to investigate the tumorigenesis, diagnosis, and therapy of gliomas. Here, we focus on recent findings of miRNAs with respect to the EGFR/PTEN/AKT pathway in gliomas.     

MicroRNA biomarkers in glioblastoma

Recent research suggests that deregulation of microRNAs (miRNAs) is involved in initiation and progression of many cancers, including gliomas and that miRNAs hold great potential as future diagnostic and therapeutic tools in cancer. MiRNAs are a class of short non-coding RNA sequences (18–24 nucleotides), which base-pair to target messenger RNA (mRNA) and thereby cause translational repression or mRNA degradation based on the level of complementarity between strands. Profiling miRNAs in clinical glioblastoma samples has shown aberrant expression of numerous miRNAs when compared to normal brain tissues. Understanding these alterations is key to developing new biomarkers and intelligent treatment strategies. This review presents an overview of current knowledge about miRNA alterations in glioblastoma while focusing on the clinical future of miRNAs as biomarkers and discussing the strengths and weaknesses of various methods used in evaluating their expression.     

MicroRNAs involved in chemo- and radioresistance of high-grade gliomas

High-grade gliomas (HGGs) are malignant primary brain tumors of glial cell origin. Despite optimal course of treatment, including maximal surgical resection followed by adjuvant chemo- and/or radiotherapy, the prognosis still remains poor. The main reason is the commonly occurring chemo- and radioresistance of these tumors. In recent years, several signaling pathways, especially PI3K/AKT and ATM/CHK2/p53, have been linked to the resistance of gliomas. Moreover, additional studies have shown that these pathways are significantly regulated by microRNAs (miRNAs), short endogenous RNA molecules that modulate gene expression and control many biological processes including apoptosis, proliferation, cell cycle, invasivity, and angiogenesis. MiRNAs are not only highly deregulated in gliomas, their expression signatures have also been shown to predict prognosis and therapy response. Therefore, they present promising biomarkers and therapeutic targets that might overcome the resistance to treatment and improve prognosis of glioma patients. In this review, we summarize the current knowledge of the functional role of miRNAs in gliomas resistance to chemo- and radiotherapy.     

Comprehensive analysis of microRNA expression profile in malignant glioma tissues

Malignant gliomas represent the most devastating group of brain tumors in adults, among which glioblastoma multiforme (GBM) exhibits the highest malignancy rate. Despite combined modality treatment, GBM recurs and is invariably fatal. A further insight into the molecular background of gliomagenesis is required to improve patient outcomes. The primary aim of this study was to gain broad information on the miRNA expression pattern in malignant gliomas, mainly GBM. We investigated the global miRNA profile of malignant glioma tissues with miRNA microarrays, deep sequencing and meta‐analysis. We selected miRNAs that were most frequently deregulated in glioblastoma tissues, as well as in peritumoral areas, in comparison with normal human brain. We identified candidate miRNAs associated with the progression from glioma grade III to glioma grade IV. The meta‐analysis of miRNA profiling studies in GBM tissues summarizes the past and recent advances in the investigation of the miRNA signature in GBM versus noncancerous human brain and provides a comprehensive overview. We propose a list of 35 miRNAs whose expression is most frequently deregulated in GBM patients and of 30 miRNA candidates recognized as novel GBM biomarkers.     

miRNA在恶性肿瘤诊断与治疗中的进展

微小RNA(microRNA或miRNA)是指长度约21～25nt的某些特殊的小型非编码RNA组成的家族,miRNA在转录后水平通过促进靶mRNA的降解和/或抑制翻译过程而发挥负调控基因表达的过程,并与个体发育、干细胞分化和疾病发生密切相关,在包括胶质瘤在内的所有恶性肿瘤的发病机制、早期诊断以及寻找新的治疗策略的研究中意义重大。     

环状RNA在胶质瘤临床诊疗中的研究进展

环状RNA（circular RNAs，circRNAs）是一类共价闭合环状的单链RNA分子，具有高度的稳定性、丰度和保守性，并显示组织/发育阶段特异性表达。与其它非编码RNA类似，circRNAs的功能也具有多样性。近年来，circRNAs作为微小RNA（microRNAs，miRNAs）海绵和蛋白质海绵、翻译、转录和剪接等功能的调控机制逐渐被揭示，circRNAs可为癌症诊疗/预后提供新的生物标志物和靶点。越来越多的研究表明，circRNAs在神经元组织中高丰度存在，其失调与神经系统疾病（包括胶质瘤）的发生密切相关。本文就circRNAs在胶质瘤中诊疗的作用研究进展进行综述。     

MicroRNA and Brain Tumors

MicroRNAs(miRNAs)were first described in 1993 by Lee and col eagues,and the term microRNA was only introduced in 2001 in a set of three articles in Science[1].One of the biggest surprises in the past few years has been the emergence of miRNAs as a major new class of gene expression regulators.Recent studies suggest that miRNA alterations are involved in the initiation and progression of human cancer.The brain tumor, glioblastoma multiforme,is the most malignant and deadly form of gliomas. The prognosis is poor and the median survival with combined radiotherapy and chemotherapy is only 14.6 months.With the discovery of miRNA,the miRNA profiles may become useful biomarkers for brain tumor diagnostics, and miRNA therapy could be a powerful tool for brain tumor prevention and therapeutics.This review outlines the background of miRNA and its expression and therapeutic potential for brain tumors.     

胶质瘤中微RNA研究进展

微RNA(microRNA,miR)可在转录后水平负调控靶基因表达,miR异常表达与肿瘤生成密切相关.对胶质瘤中多个miR异常表达及其机制的研究将对进一步探讨胶质瘤的分子病理及其诊治开拓新途径.     

Methylation of the miR-126 gene associated with glioma progression

Gliomas are the most common and the most malignant brain tumors, accouting for 45–55 % of all intracranial tumors. The incidence of glioma worldwide is about 6–12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21–23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP–DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of miR-126 was found in 40 % of glioma patients in our study (20/50 cases), resulting in significantly decreased miR-126 expression (0.1715 ± 0.1376; P < 0.05). Our results indicate that we verified successfully the miRNA-126 down-regulation phenomenon in patients with glioma which showed in the results of glioma tissue miRNAs chip and the miRNA-126 down-regulation through methylation in patients with glioma. So we could say that epigenetic modification is a crucial mechanism for controlling the expression of miR-126 in glioma.     

MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas

High-grade gliomas are some of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in gliomas, paraffin-embedded glioma tissue samples from 193 patients with grade I, II, III, and IV tumors were analyzed by in situ hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels in each of these compartments. The miR-21 levels correlated significantly with grade [p = 0.027, r _s = 0.161, 95 % confidence interval (CI), 0.015–0.301] with the highest levels measured in glioblastomas. Only tumor cell miR-21 was associated with poor prognosis when adjusting for known clinical parameters (age, grade, and sex) in a multivariate analysis [p = 0.049, hazard ratio (HR) = 1.545, 95 % CI, 1.002–2.381]. In conclusion, we have shown that miR-21 is located in both tumor cells and tumor blood vessels and that its level in the tumor cell compartment holds unfavorable prognostic value in gliomas.     

MicroRNA and brain tumors

MicroRNAs (miRNAs) were first described in 1993 by Lee and colleagues/ and the term microRNA was only introduced in 2001 in a set of three articles in Science^[1]. One of the biggest surprises in the past few years has been the emergence of miRNAs as a major new class of gene expression regulators. Recent studies suggest that miRNA alterations are involved in the initiation and progression of human cancer. The brain tumor, glioblastoma multiforme, is the most malignant and deadly form of gliomas. The prognosis is poor and the median survival with combined radiotherapy and chemotherapy is only 14.6 months. With the discovery of miRNA, the miRNA profiles may become useful biomarkers for brain tumor diagnostics, and miRNA therapy could be a powerful tool for brain tumor prevention and therapeutics. This review outlines the background of miRNA and its expression and therapeutic potential for brain tumors.     

Differential expression of miR200a-3p and miR21 in grade II–III and grade IV gliomas: Evidence that miR200a-3p is regulated by O6-methylguanine methyltransferase and promotes temozolomide responsiveness

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is among the deadliest of human cancers. Dysregulation of microRNAs (miRNAs) expression is an important step in tumor progression as miRNAs can act as tumor suppressors or oncogenes and may affect cell sensitivity to chemotherapy. Whereas the oncogenic miR21 has been shown to be overexpressed in gliomas, the expression and function of the tumor-supressor miR200a in GBMs remains unknown. In this study, we show that miR21 is upregulated in grade IV (GBMs) vs. grade II–III (LGs) gliomas, confirming that miR21 expression level is correlated with tumor grade, and that it may be considered as a marker of tumor progression. Conversely, miR200a is demonstrated for the first time to be downregulated in GBMs compared with LGs, and overexpression of miR200a in GBM cells is shown to promote TMZ-sensitivity. Interestingly, miR200a but not miR21 expression level is significantly higher in TMZ-responsive vs. -unresponsive tumoral glial cells in primary culture. Furthermore, miR200a appears negatively correlated with the expression of the DNA repair enzyme O⁶-methylguanine methyltransferase (MGMT), and the inhibition of MGMT activity results in an increase of miR200a expression in GBM cells. Taken together, these data strongly suggest that miR200a is likely to act as a crucial antitumoral factor regarding glioma progression. Interplay between miR200a and MGMT should be considered as potential mechanism involved in therapeutic response.