Yuze Cao

Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network

Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a poor prognosis. Cross-talk between competitive endogenous RNAs (ceRNAs) plays a critical role in tumor development and physiology. In this study, we present a multi-step computational approach to construct a functional GBM long non-coding RNA (lncRNA)-mediated ceRNA network (LMCN) by integrating genome-wide lncRNA and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. LncRNAs in the LMCN exhibited specific topological features consistent with a regulatory association with coding mRNAs across GBM pathology. We determined that the lncRNA MCM3AP-AS was involved in RNA processing and cell cycle-related functions, and was correlated with patient survival. MCM3AP-AS and MIR17HG acted synergistically to regulate mRNAs in a network module of the competitive LMCN. By integrating the expression profile of this module into a risk model, we stratified GBM patients in both the The Cancer Genome Atlas and an independent GBM dataset into distinct risk groups. Finally, survival analyses demonstrated that the lncRNAs and network module are potential prognostic biomarkers for GBM. Thus, ceRNAs could accelerate biomarker discovery and therapeutic development in GBM.

Detecting Key Genes Regulated by miRNAs in Dysfunctional Crosstalk Pathway of Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular autoimmune disorder resulting from autoantibodies attacking components of the neuromuscular junction. Recent studies have implicated the aberrant expression of microRNAs (miRNAs) in the pathogenesis of MG; however, the underlying mechanisms remain largely unknown. This study aimed to identify key genes regulated by miRNAs in MG. Six dysregulated pathways were identified through differentially expressed miRNAs and mRNAs in MG, and significant crosstalk was detected between five of these. Notably, crosstalk between the “synaptic long-term potentiation” pathway and four others was mediated by five genes involved in the MAPK signaling pathway. Furthermore, 14 key genes regulated by miRNAs were detected, of which six—MAPK1, RAF1, PGF, PDGFRA, EP300, and PPP1CC—mediated interactions between the dysregulated pathways. MAPK1 and RAF1 were responsible for most of this crosstalk (80%), likely reflecting their central roles in MG pathogenesis. In addition, most key genes were enriched in immune-related local areas that were strongly disordered in MG. These results provide new insight into the pathogenesis of MG and offer new potential targets for therapeutic intervention.

NSDNA: a manually curated database of experimentally supported ncRNAs associated with nervous system diseases

The Nervous System Disease NcRNAome Atlas (NSDNA) (http://www.bio-bigdata.net/nsdna/) is a manually curated database that provides comprehensive experimentally supported associations about nervous system diseases (NSDs) and noncoding RNAs (ncRNAs). NSDs represent a common group of disorders, some of which are characterized by high morbidity and disabilities. The pathogenesis of NSDs at the molecular level remains poorly understood. ncRNAs are a large family of functionally important RNA molecules. Increasing evidence shows that diverse ncRNAs play a critical role in various NSDs. Mining and summarizing NSD–ncRNA association data can help researchers discover useful information. Hence, we developed an NSDNA database that documents 24 713 associations between 142 NSDs and 8593 ncRNAs in 11 species, curated from more than 1300 articles. This database provides a user-friendly interface for browsing and searching and allows for data downloading flexibility. In addition, NSDNA offers a submission page for researchers to submit novel NSD–ncRNA associations. It represents an extremely useful and valuable resource for researchers who seek to understand the functions and molecular mechanisms of ncRNA involved in NSDs.

Tenuigenin inhibits LPS-induced inflammatory responses in microglia via activating the Nrf2-mediated HO-1 signaling pathway

&NA; Tenuigenin (TGN), a major active component of polygala tenuifolia root, has been reported to have anti‐inflammatory effect. In this study, we investigated the anti‐neuroinflammatory effects of TGN on LPS‐induced inflammation both in vitro and in vivo. The levels of tumor necrosis factor ‐&agr; (TNF‐&agr;), Interleukin‐1&bgr; (IL‐1&bgr;), Interleukin‐6 (IL‐6), and prostaglandin E2 (PGE2) were measured by ELISA. The expression of Nuclear factor E2–related factor 2 (Nrf2) and heme oxygenase 1 (HO‐1) were detected by western blot analysis. The results showed that TGN strongly inhibited LPS‐induced TNF‐&agr;, IL‐1&bgr;, IL‐6, and PGE2 production. The expression of Nrf2 and HO‐1 were up‐regulated by TGN in a dose‐dependent manner. Furthermore, the anti‐inflammatory effects of TGN were significantly inhibited by transfection with Nrf2 siRNA or protoporphyrin (SnPP), an HO‐1 activity inhibitor. In vivo, TGN attenuated LPS‐induced memory deficit in the Morris water maze and passive avoidance tasks. Also, TGN inhibited LPS‐induced TNF‐&agr; and IL‐1&bgr; expression in brain tissues. In conclusion, the results of this study indicated that TGN inhibited LPS‐induced inflammatory responses in microglia via activating the Nrf2‐mediated HO‐1 signaling pathway.

Genome-Wide DNA Methylation Patterns Analysis of Noncoding RNAs in Temporal Lobe Epilepsy Patients

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy and frequently evolving drug resistance. Although there is growing consensus that noncoding ribonucleic acids (ncRNAs) are modulators of TLE, the knowledge about the deoxyribonucleic acid (DNA) methylation patterns of ncRNAs in TLE remains limited. In the current study, we constructed DNA methylation profiles from 30 TLE patients and 30 healthy controls for ncRNAs, primarily focusing on long ncRNAs (lncRNAs) and microRNAs (miRNAs), by reannotating data of DNA methylation BeadChip. Statistics analyses have revealed a global hypermethylation pattern in miRNA and lncRNA gene in TLE patients. Bioinformatic analyses have found aberrantly methylated miRNAs and lncRNAs are related to ion channel activity, drug metabolism, mitogen-activated protein kinase (MAPK) signaling pathway, and neurotrophin signaling pathway. Aberrantly methylated ncRNA and pathway target might be involved in TLE development and progression. The methylated and demethylated ncRNAs identified in this study provide novel insights for developing TLE biomarkers and potential therapeutic targets.

Autophagy-related gene expression is an independent prognostic indicator of glioma

In this study, we identified 74 differentially expressed autophagy-related genes in glioma patients. Analysis using a Cox proportional hazard regression model showed that MAPK8IP1 and SH3GLB1, two autophagy-related genes, were associated with the prognostic signature for glioma. Glioma patients from the CGGA batches 1 and 2, GSE4412 and TCGA datasets could be divided into high- and low-risk groups with different survival times based on levels of MAPK8IP1 and SH3GLB1 expression. The autophagy-related signature was an independent predictor of survival outcomes in glioma patients. MAPK8IP1 overexpression and SH3GLB1 knockdown inhibited glioma cell proliferation, migration and invasion, and improved Temozolomide sensitivity. These findings suggest autophagy-related genes like MAPK8IP1 and SH3GLB1 could be potential therapeutic targets in glioma.In this study, we identified 74 differentially expressed autophagy-related genes in glioma patients. Analysis using a Cox proportional hazard regression model showed that MAPK8IP1 and SH3GLB1, two autophagy-related genes, were associated with the prognostic signature for glioma. Glioma patients from the CGGA batches 1 and 2, GSE4412 and TCGA datasets could be divided into high- and low-risk groups with different survival times based on levels of MAPK8IP1 and SH3GLB1 expression. The autophagy-related signature was an independent predictor of survival outcomes in glioma patients. MAPK8IP1 overexpression and SH3GLB1 knockdown inhibited glioma cell proliferation, migration and invasion, and improved Temozolomide sensitivity. These findings suggest autophagy-related genes like MAPK8IP1 and SH3GLB1 could be potential therapeutic targets in glioma.

Identifying a Polymorphic ‘Switch’ That Influences miRNAs' Regulation of a Myasthenia Gravis Risk Pathway

The significant roles of genetic variants in myasthenia gravis (MG) pathogenesis have been demonstrated in many studies, and recently it has been revealed that aberrant level/regulation of microRNAs (miRNAs) might contribute to the initiation and progression of MG. However, the dysfunction of miRNA associated with single nucleotide polymorphisms (miRSNPs) has not been well investigated in MG. In this study, we created a contemporary catalog of 89 MG risk genes via manual literature-mining. Based on this risk gene catalog, we obtained 18 MG risk pathways. Furthermore, we identified 93 miRNAs that target MG risk pathways and revealed the miRSNPs ‘switches’ in miRNA regulation in the MG risk pathways by integrating the database information of miRSNPs. We also constructed a miRNA-mediated SNP switching pathway network (MSSPN) to intuitively analyze miRNA regulation of MG risk pathways and the relationship of the polymorphism ‘switch’ with these changes in regulation. Moreover, we carried out in-depth dissection on the correlation between hsa05200 (pathway in cancer) and MG development, and elaborated the significance of 4 high-risk genes. By network analysis and literature mining, we proposed a potential mechanism of miRSNPs→gene→pathway effects on MG pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family)→IGF1R→hsa05200 (pathway in cancer). Therefore, our studies have revealed a functional role for genetic modulators in MG pathogenesis at a systemic level, which could be informative for further miRNA and miRSNPs studies in MG.

MicroRNA-9a-5p Alleviates Ischemia Injury After Focal Cerebral Ischemia of the Rat by Targeting ATG5-Mediated Autophagy

Background/Aims: Previous studies have suggested that autophagy is activated in distinct cerebrovascular diseases, including stroke. However, the underlying regulatory mechanism of autophagy under stroke remained elusive. Accumulating evidence indicates that dysfunctions of microRNAs (miRNAs) are involved in the pathological process of stroke. Therefore, this study was taken to identify the effect of microRNA-9a-5p (miR-9a-5p) on autophagy in rats following stroke. Methods: The rat model of focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) surgery; The neurological outcomes were defined by neurological evaluation and infarct volume; The western blotting and immunofluorescence assays were used to detected the protein levels of microtubule-associated protein 1 light chain 3 (LC3) and autophagy related 5 (ATG5); The mRNA level of miR-9a-5p, LC3 and ATG5 were quantified by real-time RT-PCR; The luciferase activities of ATG5 and miR-9a-5p was detected by luciferase assay. Results: We showed here that the level of miR-9a-5p was decreased in the ischemic region of rats after MCAO. Overexpression of miR-9a-5p by miR-9a-5p agomir reduced infarct volume and alleviated neurological deficit. Moreover, we found that autophagy was activated by miR-9a-5p inhibition and inactivated by miR-9a-5p overexpression both in the MCAO rat and in SY-5Y cell lines, and unchanged by miR-masks as indicated by LC3 expression. Furthermore, the protein level of ATG5 was decreased by miR-9a-5p overexpression, but increased by miR-9a-5p inhibition and unchanged by miR-masks transfection. In addition, the luciferase assay data showed that miR-9a-5p suppressed the luciferase activity of 3’UTR of ATG5, whereas the repressive effect was relieved by mutation of binding sites. Conclusion: Our study demonstrated that miR-9a-5p may play a critical role in regulating the process of autophagy through targeting ATG5 expression, and overexpression of miR-9a-5p may be a potential approach in alleviating ischemia injury induced by MCAO.

Corrigendum to “Detecting Key Genes Regulated by miRNAs in Dysfunctional Crosstalk Pathway of Myasthenia Gravis”

[This corrects the article DOI: 10.1155/2015/724715.].

The long noncoding RNA MALAT-1 functions as a competing endogenous RNA to regulate MSL2 expression by sponging miR-338-3p in myasthenia gravis: KONG et al.

Myasthenia gravis (MG) is a cell‐dependent autoimmune disease commonly associated with thymic pathology. Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT‐1) has been associated with gene regulation and alternative splicing. It has shown relationship with proliferation, apoptosis, migration, and invasion. In this study, we found that MALAT‐1 expression was downregulated in MG. The level of the miR‐338‐3p was increased in peripheral blood mononuclear cells from MG patients compared with those from control subjects. MALAT‐1 competed for binding to miR‐338‐3p with male‐specific lethal 2 (MSL2) in luciferase reporter assays. We confirmed the MALAT‐1‐miR‐338‐3p‐MSL2 interaction network in MG in vitro. Thus, MALAT‐1 directly induced MSL2 expression in MG by acting as a competing endogenous RNA for miR‐338‐3p, suggesting that it may serve as a therapeutic target for MG treatment.