Mini Review
MicroRNA involvement in glioblastoma pathogenesis

https://doi.org/10.1016/j.bbrc.2009.06.034Get rights and content

Abstract

MicroRNAs are endogenously expressed regulatory noncoding RNAs. Altered expression levels of several microRNAs have been observed in glioblastomas. Functions and direct mRNA targets for these microRNAs have been relatively well studied over the last years. According to these data, it is now evident, that impairment of microRNA regulatory network is one of the key mechanisms in glioblastoma pathogenesis. MicroRNA deregulation is involved in processes such as cell proliferation, apoptosis, cell cycle regulation, invasion, glioma stem cell behavior, and angiogenesis. In this review, we summarize the current knowledge of miRNA functions in glioblastoma with an emphasis on its significance in glioblastoma oncogenic signaling and its potential to serve as a disease biomarker and a novel therapeutic target in oncology.

Introduction

Glioblastoma is the most frequent and the most malignant brain tumor, with an incidence 3.55 new cases per 100,000 Caucasians per year [1]. Despite progress in surgical techniques, radiotherapy and chemotherapy, the prognosis remains poor, with a median survival less than one year [1], [2]. Glioblastoma is characterized by rapid diffusely infiltrative growth and high level of cellular heterogeneity associated with therapeutic resistance. Glioblastomas are also characterized by multiple genetic alterations. Epidermal growth factor receptor (EGFR) amplification and PTEN mutations are typical for primary glioblastomas developing rapidly de novo, whereas TP53 mutations are frequent in the pathway leading to secondary glioblastomas developing usually from lower grade astrocytomas. Loss of heterozygosity (LOH) 10q is the most frequent abberation in both primary and secondary glioblastomas [3], [4]. Recent knowledge of glioblastoma molecular pathology, however, is not sufficient to enable significant progress in individualized and targeted therapy of glioblastoma patients.

One of the novel approaches for molecular characterization of tumors is based on the expression profiling of microRNAs (miRNAs). miRNAs are endogenously expressed short noncoding RNAs, 18–25 nucleotides in length, that repress protein translation through binding to target mRNAs [5]. Until recently, more than 700 miRNAs were discovered in human cell [6]. Bioinformatics and cloning studies estimated that miRNAs regulate up to one-third of human genes [7]. By regulating translation of oncogenes and tumor suppressors, they participate also in processes involved in molecular pathology of cancer [8]. Moreover, miRNAs are frequently located in cancer-associated genomic regions or in fragile sites [9], [10].

Physiological roles of only a small fraction of identified miRNAs have been elucidated to date. miRNAs play an important role in cell cycle control, cell proliferation, differentiation, and apoptosis [5]. Impaired miRNA expression levels, consequently, were identified in most solid cancers and hematological malignancies [5]. In this paper, we review and summarize the studies analyzing miRNA expression levels and their role in the pathogenesis of glioblastomas.

Section snippets

miR-21

In the first study exploring expression levels of miRNAs in glioblastomas, Chan et al. identified miR-21 upregulation [11]. The authors also demonstrated that knockdown of miR-21 in cultured glioblastoma cell lines triggered the caspase activation and associated apoptotic cell death, suggesting an anti-apoptotic function of miR-21. Many other following studies confirmed overexpression of this miRNA in glioblastomas [12], [13], [14], [15]. miR-21 was overexpressed even in less malignant gliomas

Conclusions and future directions

The discovery of miRNAs has enabled deeper insight into regulation of gene expression and complexity of this process. Recent data demonstrated that deregulation of miRNA expression is an integral process of cancer pathogenesis. It is evident that miRNAs play a crucial role also in glioblastoma pathogenetic pathways. However, it is not known whether the deregulation of miRNAs is a reason or consequence of cancer transformation. A few smaller studies analyzed the expression levels of miRNAs in

Acknowledgment

This work was supported by Grant IGA NR 9875-4 of the Czech Ministry of Health and Project No. MZ0MOU2005 of the Czech Ministry of Health.

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