Correction: MiR-181b-5p Downregulates NOVA1 to Suppress Proliferation, Migration and Invasion and Promote Apoptosis in Astrocytoma.

[This corrects the article DOI: 10.1371/journal.pone.0109124.].

Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas.

BACKGROUND: miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. METHODS: CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. RESULTS: miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. CONCLUSIONS: In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy.

Stereotactic Catheter Drainage Versus Conventional Craniotomy for Severe Spontaneous Intracerebral Hemorrhage in the Basal Ganglia.

Intracerebral hemorrhage (ICH) is one of the most devastating forms of cerebrovascular pathology. However, its treatment remains a matter of debate among neurosurgeons and neurologists. The study was to explore the efficacy of minimally invasive surgery (stereotactic catheter drainage, SCD) for patients with severe intracerebral hemorrhage (Glasgow Coma Scale, GCS) score ≤ 8 and hematoma volume ≥ 30 cm3) and to determine predisposing factors for good clinical outcome. A total of 75 patients with severe ICH were included in this retrospective study. Patients were assigned to the SCD group (n=38) or the conventional craniotomy group (n=37). Patients were followed up for 12 months postoperatively, and their clinical parameters were compared. During the operation, the SCD group exhibited a lower bleeding volume (p<0.001) and shorter operating time (p<0.001) than the conventional craniotomy group. For postoperative efficacy, the rates of pneumonia and tracheotomy were lower (p=0.002 and p=0.027, respectively), and the duration of hospital and neurosurgery intensive care unit (NSICU) in days were significantly shorter in the SCD group (p=0.046 and p=0.047, respectively). Furthermore, patients in the SCD group showed improved modified Rankin Scale (mRS) scores at discharge (p<0.018) and at 12-month follow up (p<0.001). Predisposing factors for good clinical outcomes were hematoma volume (<50 cm3, 95% confidence interval (CI): 1.043-1.956, p<0.046), initial GCS score (>6, 95% CI: 3.248-187.466, p<0.001), hypertension (none, 95% CI: 1.440-2.922, p<0.001), and treatment modality (SCD, 95% CI: 1.422-3.226, p<0.001). Taken together, SCD surgery is safe and effective in patients with severe ICH and has fewer complications and better clinical outcomes than conventional craniotomy.

Behavioral and neurophysiological abnormalities during cued continuous performance tasks in patients with mild traumatic brain injury.

Objective: This study's aim was to investigate the features and neural mechanisms of sustained attention in patients with mild traumatic brain injury (mTBI) by comparing and analyzing neuropsychological, behavioral, event-related potentials, and event-related desynchronization and synchronization between mTBI patients and healthy controls. Methods: Twenty mTBI patients with mTBI and 20 healthy controls underwent the Mini-Mental State Examination (MMSE) and a cued continuous performance task (AX-CPT). Neuropsychological, behavioral, and electroencephalogram (EEG) data were collected and analyzed. Results: There were significant differences between the mTBI group and the control group in their MMSE total scores, attention, and calculation, but there were no significant differences in orientation, memory, recall, and verbal scores. There were significant differences between the mTBI group and the control group in hitting the number, reaction time, and the number of errors of omission, but there were no significant differences in the number of false errors. The amplitude of Go-N2 and Nogo-N2 was significantly smaller for the mTBI group than that for the control group. The amplitude of Go-P3 was significantly smaller for the mTBI group than that for the control group, but not for the amplitude of Nogo-P3. The Go-αERS were significantly less for the mTBI group than for the control group during the 0-200 ms after the stimulus onset. The Go-αERD and Nogo-αERD were significantly less for the mTBI group than for the control group during the 600-1,000 ms after the stimulus onset. The Go-ßERS were significantly less for the mTBI group than for the control group during the 200-400 ms after the stimulus onset. There were no significant differences in the Nogo-αERS and Nogo-ßERD/ERS between the mTBI group and the control group. Conclusion: Patients with mTBI exhibited impairments in sustained attention and conflict monitoring, while response inhibition may have been spared.

Detection of specific Chlamydia pneumoniae and cytomegalovirus antigens in human carotid atherosclerotic plaque in a Chinese population.

To explore the relationship between certain pathogens, such as chlamydia pneumonia (Cpn) and cytomegalovirus (CMV), and carotid atherosclerosis (AS) in a Chinese population.Twenty-five carotid atherosclerotic stenosis patients from the Beijing Tiantan Hospital (affiliated with Capital Medical University) participated in the study. After undergoing digital subtraction angiography (DSA) and/or computed tomography angiography (CTA), the degree of carotid artery stenosis was over 70% in all cases, and the patients underwent carotid endarterectomy. Plaque specimens were obtained during surgery. The streptavidin-peroxidase (SP) method was used to test the Cpn and CMV antigens in the specimens, and the relationship between the Cpn and CMV pathogen infections and AS was analyzed based on the test results. In the group of 25 carotid atherosclerotic specimens, the detection rate of the Cpn-specific antigens was 84.0% (21/25). In the control group, the detection rate was 13.3% (2/15) in the ascending aortic intima. Thus, the between-group difference was significant (P<0.01). The CMV-specific antigen detection rate was 72.0% (18/25) using the same experimental group specimens, and the detection rate was zero in the control group. Thus, there were significant between-group differences (P<0.01). Due to the high detection rate of Cpn- and CMV-specific antigens in carotid atherosclerotic plaque in a Chinese population, it can be inferred that pathogens such as Cpn and CMV are one factor associated with carotid atherosclerosis.

Long non-coding RNA in glioma: signaling pathways.

Glioma is regarded as the most prevalent malignant carcinoma of the central nervous system. Thus, the development of new therapeutic strategies targeting glioma is of significant clinical importance. Long non-coding RNAs (lncRNAs) are functional RNA molecules without a protein-coding function and are reportedly involved in the initiation and progression of glioma. Dysregulation of lncRNAs in glioma is due to activation of several signaling pathways, such as the BRD4-HOTAIR-ß-catenin/PDCD4, p53-Hif-H19/IGF2 and CRNDE/mTOR pathways. Furthermore, microRNAs (miRNAs) such as miR-675 also interact with lncRNAs in glioma. Thus, exploring the mechanisms by which lncRNA control processes will be instrumental for devising new effective therapies against glioma.

Review: Traumatic brain injury and hyperglycemia, a potentially modifiable risk factor.

Hyperglycemia after severe traumatic brain injury (TBI) occurs frequently and is associated with poor clinical outcome and increased mortality. In this review, we highlight the mechanisms that lead to hyperglycemia and discuss how they may contribute to poor outcomes in patients with severe TBI. Moreover, we systematically review the proper management of hyperglycemia after TBI, covering topics such as nutritional support, glucose control, moderated hypothermia, naloxone, and mannitol treatment. However, to date, an optimal and safe glycemic target range has not been determined, and may not be safe to implement among TBI patients. Therefore, there is a mandate to explore a reasonable glycemic target range that can facilitate recovery after severe TBI.

miR-137 acts as a tumor suppressor in astrocytoma by targeting RASGRF1.

Astrocytoma is one of the most common primary central nervous system tumors and has both high mortality and a poor 5-year survival rate. MicroRNAs (miRNAs) play important roles in carcinogenesis by acting on multiple signaling pathways. Although we have demonstrated that miR-137 is downregulated in astrocytoma tissues, the role of miR-137 in astrocytoma still remains unknown. In the present study, we aimed to investigate the function of miR-137 and its possible target genes in astrocytoma. miR-137 was significantly downregulated in astrocytoma tissues, and its expression level was inversely correlated with the clinical stage. Restoring miR-137 was able to dramatically inhibit cell proliferation, migration, and invasion and enhance apoptosis in vitro, whereas silencing its expression inhibited these processes. By overexpressing or inhibiting miR-137 in cancer cells, we experimentally confirmed that miR-137 directly recognized the 3'-UTR (3'-untranslated region) of the RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1) transcript and regulated RASGRF1 expression. Furthermore, an inverse correlation was observed between miR-137 levels and RASGRF1 protein levels, but not mRNA levels, in astrocytoma samples. The silencing of RASGRF1 resulted in similar effects to miR-137 restoration in cancer cells. Finally, overexpression of RASGRF1 rescued the inhibitory effects of miR-137. Taken together, our results indicate that miR-137 acts as a tumor suppressor in astrocytoma by targeting RASGRF1. These findings suggest that miR-137 may serve as a novel therapeutic target in astrocytoma treatment.

The Use of Three Long Non-Coding RNAs as Potential Prognostic Indicators of Astrocytoma.

Long noncoding RNAs (lncRNAs) are pervasively transcribed and play a key role in tumorigenesis. The aim of the study was to determine the lncRNA expression profile in astrocytomas and to assess its potential clinical value. We performed a three-step analysis to establish the lncRNA profile for astrocytoma: a) the lncRNA expression was examined on 3 astrocytomas as well as 3 NATs (normal adjacent tissues) using the lncRNA microarray; b) the top-hits were validated in 40 astrocytomas (WHO grade II-IV) by quantitative real time-PCR (qRT-PCR); c) the hits with significant differences were re-evaluated using qRT-PCR in 90 astrocytomas. Finally, 7 lncRNAs were found to have a significantly different expression profile in astrocytoma samples compared to the NAT samples. Unsupervised clustering analysis further revealed the potential of the 7-lncRNA profile to differentiate between tumors and NAT samples. The upregulation of ENST00000545440 and NR_002809 was associated with advanced clinical stages of astrocytoma. Using Kaplan-Meier survival analysis, we showed that the low expression of BC002811 or XLOC_010967, or the high expression of NR_002809 was significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors. Our results indicate that the lncRNA profile may be a potential prognostic biomarker for the prediction of post-surgical outcomes.

Identification of 9 serum microRNAs as potential noninvasive biomarkers of human astrocytoma.

BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for human cancer. In the current study, we investigated the potential use of serum miRNAs as biomarkers for diagnosis and prognosis in a cohort of Chinese astrocytoma patients. METHODS: An initial screening of the circulating miRNA expression profile was performed on pooled serum samples from 10 preoperative patients and 10 healthy controls using a TaqMan low-density array. The selected serum miRNAs were then validated in 90 preoperative patients and 110 healthy controls who were randomly divided into a training set and a validation set. An additional double-blind test was performed in 50 astrocytomas and 50 controls to assess the serum miRNA-based biomarker accuracy in predicting astrocytoma. The differentially expressed miRNAs were evaluated in paired preoperative and postoperative serum samples from 73 astrocytoma patients. The correlation of the miRNA levels with survival in astrocytoma samples was estimated. RESULTS: Nine serum miRNAs were significantly increased in the astrocytoma patients. The biomarker composed of these 9 miRNAs had high sensitivity, specificity, and accuracy. These 9 miRNAs were markedly decreased in the serum after operation. The upregulation of miR-20a-5p, miR-106a-5p, and miR-181b-5p was associated with advanced clinical stages of astrocytoma. Kaplan-Meier survival analysis showed that the high expression of miR-19a-3p, miR-106a-5p, and miR-181b-5p was significantly associated with poor patient survival. Finally, the combined 3-miRNAs panel was an important prognostic predictor, independent of other clinicopathological factors. CONCLUSIONS: The results indicated the potential of serum miRNAs as novel diagnostic and prognostic biomarkers for human astrocytoma.

MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma.

MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3'-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma.

MicroRNAs in neuroblastoma: small-sized players with a large impact.

Neuroblastoma, a malignant embryonal tumor of the sympathetic nervous system, is the most common solid extracranial malignancy of childhood and accounts for 15 % of all childhood cancer deaths. The biological behavior of neuroblastoma is extensively heterogeneous, ranging from spontaneous regression to rapid progression despite multimodal aggressive therapy. Although the molecular basis of neuroblastoma has received considerable attention over the past decade, elucidating the mechanisms for the aggressive progression of neuroblastoma is needed for improving the efficacy of treatment. miRNAs (microRNAs) are small non-coding RNA molecules generally 19-22 nucleotides in length. miRNAs regulate 60 % of human gene expression at the post-transcriptional level by targeting regions of sequence complementarity on the 3'-untranslated regions (3'-UTRs) of specific mRNAs. miRNAs can either cause degradation of mRNAs or can inhibit their translation and therefore play major roles in normal growth and development. miRNA dysregulation has oncogenic or tumor-suppressive functions in virtually all forms of cancer, including neuroblastoma. The present review highlights the current insights on dysregulated miRNAs in neuroblastoma and on their roles in the diagnosis, prognosis, and treatment of this malignancy. As a rapidly evolving field of basic and biomedical sciences, miRNA research holds a great potential to impact on the management of neuroblastoma.

miR-106a-5p inhibits the proliferation and migration of astrocytoma cells and promotes apoptosis by targeting FASTK.

Astrocytomas are common malignant intracranial tumors that comprise the majority of adult primary central nervous system tumors. MicroRNAs (miRNAs) are small, non-coding RNAs (20-24 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In our previous studies, we found that the downregulation of miR-106a-5p in astrocytomas is associated with poor prognosis. However, its specific gene target(s) and underlying functional mechanism(s) in astrocytomas remain unclear. In this study, we used mRNA microarray experiments to measure global mRNA expression in the presence of increased or decreased miR-106a-5p levels. We then performed bioinformatics analysis based on multiple target prediction algorithms to obtain candidate target genes that were further validated by computational predictions, western blot analysis, quantitative real-time PCR, and the luciferase reporter assay. Fas-activated serine/threonine kinase (FASTK) was identified as a direct target of miR-106a-5p. In human astrocytomas, miR-106a-5p is downregulated and negatively associated with clinical staging, whereas FASTK is upregulated and positively associated with advanced clinical stages, at both the protein and mRNA levels. Furthermore, Kaplan-Meier analysis revealed that the reduced expression of miR-106a-5p or the increased expression of FASTK is significantly associated with poor survival outcome. These results further supported the finding that FASTK is a direct target gene of miR-106a-5p. Next, we explored the function of miR-106a-5p and FASTK during astrocytoma progression. Through gain-of-function and loss-of-function studies, we demonstrated that miR-106a-5p can significantly inhibit cell proliferation and migration and can promote cell apoptosis in vitro. The knockdown of FASTK induced similar effects on astrocytoma cells as those induced by the overexpression of miR-106a-5p. These observations suggest that miR-106a-5p functions as a tumor suppressor during the development of astrocytomas by targeting FASTK.

A microRNA expression signature predicts meningioma recurrence.

The aberrant expression of microRNAs (miRNAs) is associated with a variety of diseases, including cancer. In our study, we examined the miRNA expression profile of meningiomas, which is a common type of benign intracranial tumor derived from the protective meninges membranes that surround the brain and spinal cord. To define a typical human meningioma miRNA profile, the expression of 200 miRNAs in a training sample set were screened using quantitative reverse transcription polymerase chain reaction analysis, and then significantly altered miRNAs were validated in a secondary independent sample set. Kaplan-Meier and univariate/multivariate Cox proportional hazard regression analyses were performed to assess whether miRNA expression could predict the recurrence of meningioma after tumor resection. After a two-phase selection and validation process, 14 miRNAs were found to exhibit significantly different expression profiles in meningioma samples compared to normal adjacent tissue (NAT) samples. Unsupervised clustering analysis indicated that the 14-miRNA profile differed between tumor and NAT samples. Downregulation of miR-29c-3p and miR-219-5p were found to be associated with advanced clinical stages of meningioma. Kaplan-Meier analysis showed that high expression of miR-190a and low expression of miR-29c-3p and miR-219-5p correlated significantly with higher recurrence rates in meningioma patients. Cox proportional hazard regression analysis revealed that miR-190a expression level is an important prognostic predictor that is independent of other clinicopathological factors. Our results suggest that the use of miRNA profiling has significant potential as an effective diagnostic and prognostic marker in defining the expression signature of meningiomas and in predicting postsurgical outcomes.

From small to big: microRNAs as new players in medulloblastomas.

Medulloblastomas (MB) are the most common malignant neoplasms of the central nervous system in children. Although the molecular basis of medulloblastoma has received considerable attention over the past decade, the underlying cellular and molecular mechanisms of medulloblastoma initiation, maintenance, and progression remain unclear. MicroRNAs (miRNAs) are short non-coding RNAs that function as key regulators of diverse biological processes by exerting negative gene regulation at the post-transcriptional level. Emerging evidence indicates that miRNAs play an important role in the development of human cancers; miRNA deregulation results in altered activities of downstream tumor suppressors, oncogenes, and other signaling molecules. In this review, we comprehensively discuss the versatile roles of miRNAs in medulloblastoma and their potential applications in the diagnosis, prognosis, and treatment of this malignancy. As a rapidly evolving field of basic and biomedical sciences, miRNA research will certainly have a revolutionary impact on the management of medulloblastoma.

The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma.

BACKGROUND: The aberrant expression of microRNAs (miRNAs) is associated with a variety of diseases including cancers. In the present study, the miRNA expression profile was examined in astrocytoma, a malignant and prevalent intracranial tumour in adults. METHODS: We screened the expression profile of 200 miRNAs in a training sample set consisting of 84 astrocytoma samples and 20 normal adjacent tissue (NAT) samples using the method of stem-loop quantitative RT-PCR. The significantly altered miRNAs were validated in another independent sample set consisting of 40 astrocytoma samples and 40 NAT samples. The correlation of the miRNA levels with survival in astrocytoma samples was estimated by performing Kaplan-Meier survival analysis and univariate/multivariate Cox proportional hazard regression analysis. RESULTS: After a two-phase selection and validation process, seven miRNAs were found to have a significantly different expression profile in astrocytoma samples upon comparison to the NAT samples. Unsupervised clustering analysis further revealed the great potential of the 7-miRNA profile to differentiate between tumours and normal brain tissues. The down-regulation of hsa-miR-137 in astrocytomas was shown to be associated with advanced clinical stages of this disease. Using Kaplan-Meier survival analysis we showed that low expression of hsa-miR-181b or hsa-miR-106a, or high expression of hsa-miR-21 was significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors. CONCLUSIONS: Our results suggest a great potential for the use of miRNA profiling as a powerful diagnostic and prognostic marker in defining the signature of astrocytomas and in predicting the post-surgical outcome.