MicroRNAs or exosomes are small noncoding RNAs of 20-25 nucleotides in length.

More and more evidence shows that microRNAs (miRNAs) play an important role in the diagnosis and prognosis of human diseases.

MicroRNAs (miRs) act as oncogenes or tumor-suppressor genes and regulate the proliferation, apoptosis, invasion, differentiation, angiogenesis, and behavior of glioma stem cells, which are important in glioma recurrence and development.

microRNAs (miRNAs) regulate gene expression and significantly influence the essential cellular processes associated with CNS repair after trauma and neuropathological conditions including stroke and neurodegenerative disorders. A number of specific miRNAs are implicated in regulating the development and propagation of CNS injury, as well as its subsequent regeneration 1).

Alteration in microRNAs (miRNAs) expression is a frequent finding in human cancers. In particular, widespread miRNAs downregulation is a hallmark of malignant transformation.

Circulating miRNAs are emerging as an interesting research area, because of their potential role as a novel biomarkers and therapeutic targets.

They mediate transcriptional silencing of various metabolic enzymes that are involved in various life processes,

Remarkably, 98% of the RNA within a cell is not translated into proteins.

miRNAs bind to 3′untranslated regions (UTRs) of mRNAs and then affect the translation and/or stability of that mRNA, leading to a reduction in protein levels.

Tumors analyzed by miRNA profiling have exhibited significantly distinct miRNA signatures compared to normal cells from the same tissue 2) 3).

The abnormal levels of miRNAs in tumors have important pathogenetic consequences.

Some miRNAs are over-expressed in tumors and act as oncogenes, promoting tumor aggravation by down-regulating tumor suppressors.

Aberrant miRNA expression has been observed in human glioblastoma (Glioblastoma).

Circulating microRNAs (miRNAs) hold great promise as novel clinically blood-based biomarkers for cancer diagnosis and prognosis.

A growing number of studies suggest that dysregulation of miRNAs is a frequent event contributing to the pathogenesis of gliomas.

The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently decreased in a variety of malignancies.

Among noncoding RNAs, microRNAs (miRNAs) have been most extensively studied, and their biology has repeatedly been proven critical for central nervous system pathological conditions.

Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers.

Depending on the genes targeted, miRNAs can act as either oncogenes or tumor suppressors.

Deregulation of microRNAs (miRNAs) expression has been associated with cancer formation through alterations in gene targets.

MicroRNA (miRNA) contributes to the pathogenesis of various types of tumor, including glioblastoma (Glioblastoma). So far, miRNA has been shown to function in regulating protein-coding gene expression. This allows miRNAs to have direct function in regulation of various cellular events, including cell proliferation, apoptosis, and differentiation. Great progress has been made in identifying novel tumor-related miRNAs and their potential target genes 4).

miRNA may play a critical role during progression from Low-grade gliomas to anaplastic gliomas or secondary glioblastomas and not contribute to the malignant progression from anaplastic gliomas to secondary glioblastomas 5).

Wnt/beta-catenin signaling pathway is frequently dysregulated in human tumors and plays a critical role in tumorigenesis; however, the roles of microRNAs in mediating Wnt/β-catenin pathway are not well understood.

As the involvement of miRNAs in the carcinogenesis is well known, Ivo D'Urso et al carried out a pilot study to identify, as potential biomarkers, differentially expressed microRNAs in blood samples of patients affected by glioma. We studied the miRNAs' expression, by means of microarray and Real-Time PCR, in 30 blood samples from glioma patients and in 82 blood samples of patients suffering from: (a) various neurological disorders (n=30), (b) primary B-lymphoma of the Central Nervous System (PCNSL, n=36) and © secondary brain metastases (n=16). By quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR), we identified significantly increased levels of two candidate biomarkers, miR-15b and miR 21, in blood of patients affected by gliomas. ROC analysis of miR-15b biomarker levels allowed to differentiate patients with tumour from patients without glioma. Furthermore, combined expression analyses of miR15b and miR-21 distinguished between patients with and without glioma (90% sensitivity and 100% specificity). In addition, a decrement in the expression levels of miR-16 characterized glioblastomas compared to low grade and anaplastic gliomas. In conclusion, this pilot study suggest that it's possible to identify the disease state by meaning miR-15b and miR-21 markers in blood, while miR-16 can be used to distinguish glioblastoma from other grade gliomas. They can potentially be used as biomarkers for non-invasive diagnosis of gliomas; further studies are mandatory to confirm our preliminary findings 6).

miR 9

miR 16

miR 19a

miR 21

miR 22

miR 24

miR 25-5p

miR 26a

miR 26b

miR 29a

miR 34

miR 105

miR 126

miR 128

miR 130b

miR 132

miR 144

miR 145

miR 148

miR 151

miR 152

miR 155

miR 181c

miR 181d

miR 182

miR 199

miR 200

miR 203

miR 205

miR 206

miR 215

miR 218

miR 221

miR 302a

miR 328

miR 351

miR 361-5p

miR 375

miR 378

miR 431

miR 433

miR 448

miR 489

miR 494

miR 497

miR 588

miR 613

miR 720

miR 942

miR 944

miR 1118

miR 1297 …..

Jiang et al., found a positive correlation between the levels of miR-127-3p and the cell migration and invasion abilities in several human Glioblastoma cell lines. Theyshowed that miR-127-3p promoted cell migration and invasion of Glioblastoma cells using in vitro cell lines and in vivo mouse models. They identified SEPT7, a known tumor-suppressor gene that has been reported to suppress Glioblastoma cell migration and invasion, as a direct target of miR-127-3p. SEPT7 was able to partially abrogate the effect of miR-127-3p on cell migration and invasion. In addition, microarray analysis revealed that miR-127-3p regulated a number of migration and invasion-related genes. Finally, they verified that miR-127-3p affected the remodeling of the actin cytoskeleton mediated by SEPT7 in Glioblastoma cells 7).

MiR-132, miR-15a and miR-16 have been implicated in the pathogenesis of many types of cancer, including pituitary tumors. However, the molecular mechanism of these miRNAs in pituitary tumor growth and metastases is still unclear. Here, we showed that miR-132 and miR-15a/16 were less expressed in pituitary tumor cell lines, as well as in invasive pituitary tumor tissues, compared to non-invasive tumor tissues. We described that overexpression of miR-132 and miR-15a/16 resulted in the suppression of pituitary tumor cell proliferation, migration and invasion, respectively, and also inhibits the expression of proteins involved in Epithelial to Mesenchymal Transition (EMT). Then, we show that these miRNAs synergistically target Sox5 in pituitary tumor. Moreover, we found that Sox5 overexpression partially rescued miR-132, miR-15a and miR-16-mediated inhibition of cell migration, invasion and cell growth. Finally, we confirmed that Sox5 was upregulated in invasive pituitary tumor tissues, compared to non-invasion tissues. In conclusion, our data indicate that miR-132 and miR-15a/16 act as tumor suppressor genes in pituitary tumor by directly targetting Sox5, and imply that these miRNAs have potential as therapeutic targets for invasive pituitary tumor 8).

Results support that dysregulated microRNAs may have a pathogenic role in intracranial aneurysms. Disruption of the protein translation process may have a pathogenic role in the development of intracranial aneurysms 9).

The molecular mechanisms behind intracranial aneurysm formation and rupture remain poorly understood.

The miRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled.

A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and miRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix miRNA microarrays were used to analyze miRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets.

Overall, 7 unruptured intracranial aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple miRNAs were significantly differentially expressed, with miR-21 (fold change 16.97) being the most upregulated, and miR-143-5p (fold change -11.14) being the most downregulated. From these, miR-21, miR-143, and miR-145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms.

This analysis identified differentially expressed genes and miRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for miRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed 10).

A total of 50 microRNAs were found to be differentially expressed in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) compared with healthy controls. Among them, 2 were increased and 48 were decreased. The 6 significant differentially expressed candidate microRNAs (miR-3613-5p, miR-4668-5p, miR-8071, miR-197-5p, miR-4322, and miR-6781-5p ) in exosome were validated. The bioinformatics analysis showed that the potential target genes of these microRNAs were involved in biological processes, molecular functions, and cellular components. Similarly, these microRNAs also affected axon guidance, pathways in cancer, regulation of the actin cytoskeleton, focal adhesion, the calcium signaling pathway, the MAPK signaling pathway, and the PI3K-Akt signaling pathway. Among 6 candidate microRNAs, miR-8071 had the best diagnostic value for mTLE-HS with 83.33% sensitivity and 96.67% specificity, and was associated with seizure severity. This study indicated that exosomal microRNAs, may be regulators for the seizure development in mTLE-HS, and can be used as potential therapeutic targets and biomarker for diagnosis in mTLE-HS 11).

Roitbak T. MicroRNAs and Regeneration in Animal Models of CNS Disorders. Neurochem Res. 2019 Mar 15. doi: 10.1007/s11064-019-02777-6. [Epub ahead of print] PubMed PMID: 30877519.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–8707.
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–866.
Wang H, Xu T, Jiang Y, Yan Y, Qin R, Chen J. MicroRNAs in human glioblastoma: from bench to beside. Front Biosci (Landmark Ed). 2015 Jan 1;20:105-118. PubMed PMID: 25553442.
Yan W, Li R, Liu Y, Yang P, Wang Z, Zhang C, Bao Z, Zhang W, You Y, Jiang T. MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis. Oncotarget. 2014 Dec 30;5(24):12908-15. PubMed PMID: 25415048; PubMed Central PMCID: PMC4350338.
Ivo D'Urso P, Fernando D'Urso O, Damiano Gianfreda C, Mezzolla V, Storelli C, Marsigliante S. miR-15b and miR-21 as Circulating Biomarkers for Diagnosis of Glioma. Curr Genomics. 2015 Oct;16(5):304-311. PubMed PMID: 27047250.
Jiang H, Hua D, Zhang J, Lan Q, Huang Q, Yoon JG, Han X, Li L, Foltz G, Zheng S, Lin B. MicroRNA-127-3p promotes glioblastoma cell migration and invasion by targeting the tumor-suppressor gene SEPT7. Oncol Rep. 2014 Mar 5. doi: 10.3892/or.2014.3055. [Epub ahead of print] PubMed PMID: 24604520.
Renjie W, Haiqian L. MiR-132, miR-15a and miR-16 synergistically inhibit pituitary tumor cell proliferation, invasion and migration by targeting Sox5. Cancer Lett. 2015 Jan 28;356(2 Pt B):568-78. doi: 10.1016/j.canlet.2014.10.003. Epub 2014 Oct 8. PubMed PMID: 25305447.
Liu D, Han L, Wu X, Yang X, Zhang Q, Jiang F. Genome-wide microRNA changes in human intracranial aneurysms. BMC Neurol. 2014 Oct 10;14:188. doi: 10.1186/s12883-014-0188-x. PubMed PMID: 25300531; PubMed Central PMCID: PMC4210474.
Bekelis K, Kerley-Hamilton JS, Teegarden A, Tomlinson CR, Kuintzle R, Simmons N, Singer RJ, Roberts DW, Kellis M, Hendrix DA. MicroRNA and gene expression changes in unruptured human cerebral aneurysms. J Neurosurg. 2016 Dec;125(6):1390-1399. PubMed PMID: 26918470; PubMed Central PMCID: PMC5001931.
Yan S, Zhang H, Xie W, Meng F, Zhang K, Jiang Y, Zhang X, Zhang J. Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget. 2016 Dec 1. doi: 10.18632/oncotarget.13744. [Epub ahead of print] PubMed PMID: 27926529.
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