WHAT IS MIRNAS ROLE IN THE FUTURE NEUROSURGERY?

During the past decade, the role of miRNAs in a variety of pathological processes including neuronal development, apoptosis, inflammation, and angiogenesis has been discovered. A few studies assessed the role of miRNAs in Alzheimer disease and amyotrophic lateral sclerosis. However, a significant attention has been focused on the role of miRNAs in brain tumor development and progression.

Although still not well characterized, recent evidences indicate that miRNAs can function as tumor suppressors and oncogenes, and may have a central role in tumorigenesis. For example, it is well established that both epidermal growth factor receptor (EGFR) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways play a major role in the pathogenesis of human gliomas. In glioblastoma multiforme (GBM), EGFR overexpression and/or expression of its constitutively activated variant, EGFRvIII, result in the downstream activation of the PI3K/Akt pathway. The Akt activation is correlated with the increased tumorigenicity and invasiveness in gliomas. It has been shown that miR-7 potently and directly regulates EGFR, and the Akt pathway is directly inhibited by miR-7. The Notch pathway, which also plays an important role in glioma cell survival, has been shown to be inhibited by miR-326.[ 4 5 ]

Moreover, aberrant expression of miRNAs has also been shown to be involved in tumorigenesis. EGFR amplification and phosphatase tensin homolog on chromosome ten (PTEN) loss are two common genetic alterations seen in gliomas. PTEN, a tumor suppressor gene, is lost in up to 70% of glioblastomas. Downregulation of miR-21 with a specific antisense oligonucleotide inhibits EGFR pathway and suppresses the growth of human GBM cells, independent of PTEN status.[ 11 ] Exploring the underlying mechanisms of miRNA action in glioma biology will provide novel therapeutic targets, and will be useful for the clinical management of this lethal and devastating neurological disorder. The miRNAs have a role not only in glioma biology, but also in medulloblastoma tumorigenesis. A recent study showed the association between cyclin dependent kinase 6 (CDK6) and miR-124 in medulloblastoma cell lines. It has been shown that miR-124 is significantly decreased in medulloblastoma cells. The re-expression of miR-124 in medulloblastoma cells decreased expression of CDK6 protein, which is known to be an important regulator of cell cycle progression.[ 8 ] It is important to note that overexpression of CDK6 has been shown to correlate significantly with poor prognosis in medulloblastoma. Moreover, there is an increasing interest in an association between miRNA expression in brain tumors and chemo- and radiosensitivity, prognosis, and invasiveness. Not surprisingly, these results may provide the grounds for new therapeutic strategies in central nervous system (CNS) tumors in the near future. However, the puzzle is waiting to be solved.

As summary, the miRNAs contribute to various cellular processes, but the detailed mechanisms remain poorly understood. A detailed knowledge of the biogenesis, functions, and targets of miRNAs would be important for a better understanding of their potential in the treatment or prevention of CNS disorders.

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