The essential role of long non-coding RNA GAS5 in glioma: interaction with microRNAs, chemosensitivity and potential as a biomarker.
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ABSTRACT:
SUBMITTER: Tan X
PROVIDER: S-EPMC7738835 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
The essential role of long non-coding RNA GAS5 in glioma: interaction with microRNAs, chemosensitivity and potential as a biomarker.
Tan Xuewen X Jiang Haifeng H Fang Yilong Y Han Dafei D Guo Yawei Y Wang Xinming X Gong Xun X Hong Wenming W Tu Jiajie J Wei Wei W
Journal of Cancer 20210101 1
Glioma is a malignant brain tumor with a generally poor prognosis. Dysregulation of a long non-coding RNA, GAS5, has been detected in numerous cancers, including glioma. Previous studies have suggested that GAS5 plays a significant functional role in glioma, affecting proliferation, metastasis, invasion, and apoptosis. In this review, we describe the roles and mechanisms of GAS5 in glioma. GAS5 may be a biomarker for diagnosis and prognosis, and even a potential target for glioma treatment, and ...[more]
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Project description:Cancer has become one of the most important diseases that affect human health and life. The effects of cancer in the digestive system are particularly prominent. Recently, long non-coding RNA (lncRNA) has attracted the attention of more and more researchers and has become an emerging field of gene research. The lncRNA growth arrest-specific 5 (GAS5) is a novel lncRNA that has attracted the attention of researchers in recent years and plays an important role in the development of tumors, especially in digestive system tumors. GAS5 was first identified in a mouse cDNA library. It was generally considered that it has the role of tumor suppressor genes, but there are still studies that have a certain ability to promote cancer. Furthermore, the 5-bp indel polymorphism (rs145204276) in the GAS5 promoter region also has a carcinogenic effect. The discovery of GAS5 and in-depth study of single nucleotide polymorphism (SNP) mechanism can provide a new way for the prevention and treatment of digestive system tumors.
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Project description:We have previously identified the long non-coding RNA LINC01021 as a direct p53 target (Hünten et al. Mol Cell Proteomics. 2015; 14:2609-2629). Here, we show that LINC01021 is up-regulated in colorectal cancer (CRC) cell lines upon various p53-activating treatments. The LINC01021 promoter and the p53 binding site lie within a MER61C LTR, which originated from insertion of endogenous retrovirus 1 (ERV1) sequences. Deletion of this MER61C element by a CRISPR/Cas9 approach, as well as siRNA-mediated knockdown of LINC01021 RNA significantly enhanced the sensitivity of the CRC cell line HCT116 towards the chemotherapeutic drugs doxorubicin and 5-FU, suggesting that LINC01021 is an integral part of the p53-mediated response to DNA damage. Inactivation of LINC01021 and also its ectopic expression did not affect p53 protein expression and transcriptional activity, implying that LINC01021 does not feedback to p53. Furthermore, in CRC patient samples LINC01021 expression positively correlated with a wild-type p53-associated gene expression signature. LINC01021 expression was increased in primary colorectal tumors and displayed a bimodal distribution that was particularly pronounced in the mesenchymal CMS4 consensus molecular subtype of CRCs. CMS4 tumors with low LINC01021 expression were associated with poor patient survival. Our results suggest that the genomic redistribution of ERV1-derived p53 response elements and generation of novel p53-inducible lncRNA-encoding genes was selected for during primate evolution as integral part of the cellular response to various forms of genotoxic stress.
| S-EPMC5732690 | biostudies-literature
Project description:ObjectiveThe long non-coding RNA (lncRNA) growth arrest‑specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results.MethodsPubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models.ResultsThe pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations.ConclusionThese findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.
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Project description:BackgroundCirculating long noncoding RNA (lncRNA) plays a vital role in clinical disease diagnosis and prognosis. Here, we evaluate the role of a lncRNA, named growth arrest specific 5 (GAS5), in atrial fibrillation (AF).MethodsExpression of GAS5 was measured by qRT-PCR. Diagnostic and prognostic values of GAS5 were assessed by the receiver operating characteristics curve (ROC), Kaplan-Meier (KM) and Cox regression analyses.ResultsA total of 173 participants were enrolled in this study. Circulating GAS5 expression was significantly down-regulated in AF patients. This change occurred prior to enlargement of the left atrial volume and was strongly associated with AF progression, which demonstrates the potential use of GAS5 as an early biomarker. The area under the ROC curve (AUC) was 0.858 (95% CI 0.789-0.926, P < .001). Seventy of the 85 AF patients received radiofrequency catheter ablation (RFCA), and 22 (31.4%) had relapsed by the 1-year follow-up. The KM analysis (log-rank test, P = .031) and multivariable Cox analysis (HR = 0.127, 95% CI 0.026-0.616; P = .01) revealed that GAS5 has a role in predicting recurrence after RFCA.ConclusionCirculating lncRNA GAS5 is a potential biomarker for AF diagnosis and prognosis. Down-regulation of GAS5 occurs prior to left atrial enlargement and can be used for the prognosis of AF progression and recurrence.
| S-EPMC7843296 | biostudies-literature
Project description:BackgroundEpithelial ovarian cancer (EOC) is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance of chemotherapeutic drugs like cisplatin (DDP) occurring in very early stage is one of the important factors of the poor prognosis of epithelial ovarian cancer. Here we aim to study the dysregulation of a particular long noncoding RNA, lncRNA GAS5, and its role in EOC progression.MethodsThe low expression of lncRNA GAS5 in EOC tissues and OC cell lines was determined by microarray analyses and Real-Time qPCR. Flow cytometer assays were used to detect cell cycle and apoptosis of OC cells. CCK8 assay were performed to investigate the DDP sensitivity of OC cells. Western blot was carried out to detect cell growth markers, apoptotic markers, PARP1, E2F4, MAPK pathway protein expression and other protein expression in OC cell lines. The binding of GAS5 and E2F4 were proved by RNA pull-down and RIP assay. The effect of E2F4 on PARP1 were determined by CHIP-qPCR assay and luciferase reporter assay. The effect of lncRNA GAS5 on OC cells was assessed in vitro and in vivo.ResultsBy microarray (3 EOC tissues νs. 3 normal ovary tissues) and RT- qPCR (53 EOC tissues νs. 10 normal ovary tissues) we identified lncRNA GAS5 to be dramatically low expressed in EOC samples and correlated with prognosis. Compared with sensitive cell lines, GAS5 was also low expressed in DDP resistant OC cell lines, and over-expression of GAS5 significantly enhanced the sensitivity of OC cells to DDP in vivo and in vitro. Meanwhile the over-expression of GAS5 also caused OC cells G0/G1 arrest and apoptosis increase. Mechanistically, GAS5 might regulate PARP1 expression by recruiting the transcription factor E2F4 to its promoter, and then affect the MAPK pathway activity. Due to the 5'TOP structure, GAS5 could be regulated by transcription inhibitor rapamycin in OC cells.ConclusionHere we explored the specific mechanisms of EOC cisplatin resistance and tumor progress due to lncRNA-GAS5, presented the GAS5-E2F4-PARP1-MAPK axis and its role in OC drug-sensitivity and progression for the first time, and the results may provide experimental basis for clinical application.
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Project description:Long non-coding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides long. Though do not encode proteins, they play functional roles in gene expression regulation. LncRNAs are notably abundant in the brain, however, their neural functions are largely unknown. Here we demonstrate that repeated short- and long-term cocaine administrations all decreased the expression of lncRNA Gas5 in the nucleus accumbens (NAc) of adult male mice. To illustrate the functional role of Gas5, we performed viral mediated overexpression of Gas5 in the NAc and found decreased cocaine-induced conditioned place preference. Furthermore, Gas5 overexpression also led to decreased drug intake, lower motivation, repressed compulsivity to acquire cocaine, and faster extinction of drug during cocaine self-administration. Transcriptome profiling identified numerous Gas5 mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5 regulated gene expression changes significantly overlap with chronic cocaine induced transcriptome alterations, which suggests that Gas5 may serve as a main transcription regulator of cocaine response. Our study therefore displays a novel lncRNA based molecular mechanism of cocaine action.
2020-06-26 | GSE146005 | GEO
Project description:Glioma is one of the most common types of malignant primary central nervous system tumor, and prognosis for this disease is poor. As autophagic drugs have been reported to induce glioma cell death, we investigated the potential prognostic role of autophagy-associated long non-coding RNA (lncRNA) in glioma patients. In this study, we obtained 879 lncRNAs and 216 autophagy genes from the Chinese Glioma Genome Atlas microarray, and found that 402 lncRNAs are correlated with the autophagy genes. Subsequently, 10 autophagy-associated lncRNAs with prognostic value (PCBP1-AS1, TP53TG1, DHRS4-AS1, ZNF674-AS1, GABPB1-AS1, DDX11-AS1, SBF2-AS1, MIR4453HG, MAPKAPK5-AS1 and COX10-AS1) were identified in glioma patients using multivariate Cox regression analyses. A prognostic signature was then established based on these prognostic lncRNAs, dividing patients into low-risk and high-risk groups. The overall survival time was shorter in the high-risk group than that in the low-risk group [hazard ratio (HR) = 5.307, 95% CI: 4.195-8.305; P < 0.0001]. Gene set enrichment analysis revealed that the gene sets were significantly enriched in cancer-related pathways, including interleukin (IL) 6/Janus kinase/signal transducer and activator of transcription (STAT) 3 signaling, tumor necrosis factor ? signaling via nuclear factor ?B, IL2/STAT5 signaling, the p53 pathway and the KRAS signaling pathway. The Cancer Genome Atlas dataset was used to validate that high-risk patients have worse survival outcomes than low-risk patients (HR = 1.544, 95% CI: 1.110-2.231; P = 0.031). In summary, our signature of 10 autophagy-related lncRNAs has prognostic potential for glioma, and these autophagy-related lncRNAs may play a key role in glioma biology.
| S-EPMC6443865 | biostudies-literature
Project description:BackgroundIncreasing evidence has shown that long non-coding RNAs (lncRNAs) are important prognostic biomarkers and epigenetic regulators with critical roles in cancer initiation and progression. However, the expression and clinical prognostic value of antisense lncRNAs in diffuse glioma patients remain unknown.MethodsHere, we profiled differentially expressed antisense lncRNAs in glioma using RNA sequencing data from Chinese Glioma Genome Atlas database. Cox regression was performed to evaluate the prognostic value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were used for functional analysis of antisense LncRNAs.ResultsExpression profiling identified 169 aberrantly expressed antisense lncRNAs between lower grade glioma (LGG) (grade II and III) and glioblastoma multiforme (GBM), 113 antisense lncRNAs between LGG IDH-wt and IDH-mut samples, and 70 antisense lncRNAs between GBM IDH-wt and IDH-mut samples, respectively. Among them, three antisense lncRNAs (WDFY3-AS2, MCM3AP-AS1 and LBX2-AS1) were significantly associated with prognosis and malignant progression of patients. WDFY3-AS2, the top one of downregulated antisense lncRNAs in GBM with fold change of 0.441 (P?<?0.001), showed specific decreased expression in classical, mesenchymal, LGG IDH-wt, GBM IDH-wt or MGMT promoter unmethylated stratified patients. Chi square test found that WDFY3-AS2 was significantly associated with the clinical and molecular features of glioma. Univariate and multivariate Cox regression analysis indicated that WDFY3-AS2 was independently correlated with overall survival (OS) of patients. Kaplan-Meier analysis found that patients with high WDFY3-AS2 expression had longer OS than the low expression ones in the stratified cohorts. Additionally, GO and GSEA showed that gene sets correlated with WDFY3-AS2 expression were involved in regulation of synaptic transmission, glutamate receptor and TNF signaling pathway.ConclusionOur findings provided convincing evidence that WDFY3-AS2 is a novel valuable prognostic biomarker for diffuse glioma.
| S-EPMC6064140 | biostudies-literature
Project description:Background: Isocitrate dehydrogenase (IDH) mutant is one of the most robust and important genetic aberrations in glioma. However, the underlying regulation mechanism of long non-coding RNA (lncRNA) in IDH mutant glioma has not been systematically portrayed. Methods:In this work, 775 IDH mutant glioma samples with transcriptome data, including 167 samples from the Chinese Glioma Genome Atlas (CGGA) RNAseq dataset, 390 samples from The Cancer Genome Atlas (TCGA) dataset, 79 samples from GSE16011 dataset, and 139 samples from CGGA microarray dataset, were enrolled. R language and GraphPad Prism software were applied for the statistical analysis and graphical work. Results: By comparing the differentially lncRNA genes between IDH mutant and IDH wild-type glioma samples, a four-lncRNA (JAG1, PVT1, H19, and HAR1A) signature was identified in IDH mutant glioma patients. The signature model was established based on the expression level and the regression coefficient of the four lncRNA genes. IDH mutant glioma samples could be successfully stratified into low-risk and high-risk groups in CGGA RNAseq, TCGA, GSE16011, and CGGA microarray databases. Meanwhile, multivariate Cox analysis showed that the four-lncRNA signature was an independent prognostic biomarker after adjusting for other clinicopathologic factors. Moreover, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the immune response and cellular metabolism were significantly associated with the four-lncRNA risk signature. Conclusion: Taken together, the four-lncRNA risk signature was identified as a novel prognostic marker for IDH mutant glioma patients and may potentially lead to improvements in the lives of glioma patients.
| S-EPMC7714930 | biostudies-literature