Biological implications and clinical potential of invasion and migration related miRNAs in glioma.

Gliomas are the most common primary malignant brain tumors and are highly aggressive. Invasion and migration are the main causes of poor prognosis and treatment resistance in gliomas. As migration and invasion occur, patient survival and prognosis decline dramatically. MicroRNAs (miRNAs) are small, non-coding 21-23 nucleotides involved in regulating the malignant phenotype of gliomas, including migration and invasion. Numerous studies have demonstrated the mechanism and function of some miRNAs in glioma migration and invasion. However, the biological and clinical significance (including diagnosis, prognosis, and targeted therapy) of glioma migration and invasion-related miRNAs have not been systematically discussed. This paper reviews the progress of miRNAs-mediated migration and invasion studies in glioma and discusses the clinical value of migration and invasion-related miRNAs as potential biomarkers or targeted therapies for glioma. In addition, these findings are expected to translate into future directions and challenges for clinical applications. Although many biomarkers and their biological roles in glioma invasion and migration have been identified, none have been specific so far, and further exploration of clinical treatment is still in progress; therefore, we aimed to further identify specific markers that may guide clinical treatment and improve the quality of patient survival.

Neuroprotective Role of Exogenous Brain-Derived Neurotrophic Factor in Hypoxia-Hypoglycemia-Induced Hippocampal Neuron Injury via Regulating Trkb/MiR134 Signaling.

Hypoxic-ischemic brain injury is an important cause of neonatal mortality and morbidity. Brain-derived neurotrophic factor (BDNF) has been reported to play a neuroprotective role in hypoxic-ischemic brain injury; however, the specific effects and mechanism of BDNF on hypoxic-hypoglycemic hippocampal neuron injury remains unknown. The current study investigated the action of BDNF in regulating cerebral hypoxic-ischemic injury by simulating hippocampal neuron ischemia and hypoxia. We found that BDNF, p-Trkb, and miR-134 expression levels decreased, and that exogenous BDNF increased survival and reduced apoptosis in hypoxic-hypoglycemic hippocampal neurons. The results also show that BDNF inhibits MiR-134 expression by activating the TrkB pathway. Transfection with TrkB siRNA and pre-miR-134 abrogated the neuroprotective role of BDNF in hypoxic-hypoglycemic hippocampal neurons. Our results suggest that exogenous BDNF alleviates hypoxic-ischemic brain injury through the Trkb/MiR-134 pathway. These findings may help to identify a potential therapeutic agent for the treatment of hypoxic-ischemic brain injury.

AMPK Plays a Dual Role in Regulation of CREB/BDNF Pathway in Mouse Primary Hippocampal Cells.

The hippocampus is vulnerable to damage under conditions of ischemia and hypoxia, causing multiple mental illnesses. cAMP response element-binding protein (CREB) plays a pivotal role in preventing the apoptosis of neurons and many other cells. Here, we found that AMP-activated protein kinase (AMPK) and CREB are oppositely regulated in mouse primary hippocampal neurons impaired by hypoxia-hypoglycemia. AMPK overexpression reduced the CREB level by upregulating SIRT1 and was negatively posttranscriptionally regulated by miR-134, suggesting a negative regulatory role of AMPK in the expression of CREB. Interestingly, the downstream genes of CREB, brain-derived neurotrophic factor (BDNF), and Bcl-2 remained unchanged when CREB was downregulated by AMPK expression. In addition, in AMPK(-/-) primary hippocampal neurons, comparisons between the effect of upregulation and silencing of miR-134 on the expression of CREB, BDNF, and Bcl-2 were made. The results reveal that AMPK is crucial for the activation of CREB via phosphorylation. Therefore, AMPK plays a dual role in the regulation of CREB in mouse primary hippocampal cells: a negative effect on total CREB expression by elevating SIRT1/miR-134 and a positive effect on activity via phosphorylation.

miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling.

microRNA-134 (miR-134) has been reported to be a brain-specific miRNA and is differently expressed in brain tissues subjected to ischemic injury. However, the underlying mechanism of miR-134 in regulating cerebral ischemic injury remains poorly understood. The current study was designed to delineate the molecular basis of miR-134 in regulating cerebral ischemic injury. Using the oxygen-glucose deprivation (OGD) model of hippocampal neuron ischemia in vitro, we found that the overexpression of miR-134 mediated by recombinant adeno-associated virus (AAV) vector infection significantly promoted neuron death induced by OGD/reoxygenation, whereas the inhibition of miR-134 provided protective effects against OGD/reoxygenation-induced cell death. Moreover, cyclic AMP (cAMP) response element-binding protein (CREB) as a putative target of miR-134 was downregulated and upregulated by miR-134 overexpression or inhibition, respectively. The direct interaction between miR-134 and the 3'-untranslated region (UTR) of CREB mRNA was further confirmed by dual-luciferase reporter assay. Overexpression of miR-134 also inhibited the expression of the downstream gene of CREB, including brain-derived neurotrophic factor (BDNF) and the anti-apoptotic gene Bcl-2, whereas the inhibition of miR-134 upregulated the expression of BDNF and Bcl-2 in neurons after OGD/reoxygenation. Notably, the knockdown of CREB by CREB siRNA apparently abrogated the protective effect of anti-miR-134 on OGD/reoxygenation-induced cell death. Taken together, our study suggests that downregulation of miR-134 alleviates ischemic injury through enhancing CREB expression and downstream genes, providing a promising and potential therapeutic target for cerebral ischemic injury.