Dataset Information

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

ABSTRACT: Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-associated ?-galactosidase-positive cells, decrease of cell proliferation, accumulation of cells in the G2/M phase and reduction of autophagic activity. The cells with knockdown AK156230 expression also exhibited increased levels of p21, p53 and phosphorylated p53, and a decreased activity of CDK1. Moreover, rapamycin-induced autophagy offered cytoprotective effect and rescued cellular senescence in AK156230 knockdown cells. Gene expression profile showed that the dysregulation of autophagy and cell cycle genes contributed to the induction of cellular senescence after AK1561230 silencing. Taken together, these results suggest that downregulation of AK156230 is involved in the induction of cellular senescence through its roles in autophagy and cell cycle progression. Our study identifies AK156230 as a critical lncRNA that has a role in regulating cellular senescence in MEFs.

SUBMITTER: Chen YN

PROVIDER: S-EPMC5288140 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

Chen Yu-Ning YN Cai Meng-Yun MY Xu Shun S Meng Mei M Ren Xingcong X Yang Jay W JW Dong Yu-Qi YQ Liu Xinguang X Yang Jin-Ming JM Xiong Xing-Dong XD

Oncotarget 20160801 33

Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-as ...[more]

PMID: 27343551

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Project description:BackgroundCellular senescence, a novel hallmark of cancer, is associated with patient outcomes and tumor immunotherapy. However, at present, there is no systematic study on the use of cellular senescence-related long non-coding RNAs (CSR-lncRNAs) to predict survival in patients with osteosarcoma. In this study, we aimed to identify a CSR-lncRNAs signature and to evaluate its potential use as a survival prognostic marker and predictive tool for immune response of osteosarcoma.MethodsWe downloaded a cohort of patients with osteosarcoma from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We performed differential expression and co-expression analyses to identify CSR-lncRNAs. We performed univariate and multivariate Cox regression analyses along with the random forest algorithm to identify lncRNAs significantly correlated with senescence. Subsequently, we assessed the predictive models using survival curves, receiver operating characteristic curves, nomograms, C-index, and decision curve analysis. Based on this model, patients with osteosarcoma were divided into two groups according to their risk scores. Then, using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we compared their clinical characteristics to uncover functional differences. We further conducted immune infiltration analyses using estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE), cell-type identification by estimating relative subsets of rna transcripts (CIBERSORT), and single-sample gene set enrichment analysis for the two groups. We also evaluated the expression of the target genes of immune checkpoint inhibitors (ICIs).ResultsWe identified six lncRNAs that were significantly correlated with senescence and accordingly established a novel cellular senescence-related lncRNA prognostic signature incorporating these lncRNAs. The nomogram indicated that the risk model was an independent prognostic factor that could predict the survival of patients with osteosarcoma. This model demonstrated high accuracy upon validation. Further analysis revealed that patients with osteosarcoma in the low-risk group exhibited better clinical outcomes and enhanced immune infiltration.ConclusionsThe six-CSR-lncRNA prognostic signature effectively predicted survival outcomes and patients in the low-risk group might have improved immune infiltration.

Project description:Zmpste24 is a metalloproteinase responsible for the posttranslational processing and cleavage of prelamin A into mature laminA. Zmpste24(-/-) mice display a range of progeroid phenotypes overlapping with mice expressing progerin, an altered version of lamin A associated with Hutchinson-Gilford progeria syndrome (HGPS). Increasing evidence has demonstrated that miRNAs contribute to the regulation of normal aging process, but their roles in progeroid disorders remain poorly understood. Here we report the miRNA transcriptomes of mouse embryonic fibroblasts (MEFs) established from wild type (WT) and Zmpste24(-/-) progeroid mice using a massively parallel sequencing technology. With data from 19.5 × 10(6) reads from WT MEFs and 16.5 × 10(6) reads from Zmpste24(-/-) MEFs, we discovered a total of 306 known miRNAs expressed in MEFs with a wide dynamic range of read counts ranging from 10 to over 1 million. A total of 8 miRNAs were found to be significantly down-regulated, with only 2 miRNAs upregulated, in Zmpste24(-/-) MEFs as compared to WT MEFs. Functional studies revealed that miR-365, a significantly down-regulated miRNA in Zmpste24(-/-) MEFs, modulates cellular growth phenotypes in MEFs. Overexpression of miR-365 in Zmpste24(-/-) MEFs increased cellular proliferation and decreased the percentage of SA-?-gal-positive cells, while inhibition of miR-365 function led to an increase of SA-?-gal-positive cells in WT MEFs. Furthermore, we identified Rasd1, a member of the Ras superfamily of small GTPases, as a functional target of miR-365. While expression of miR-365 suppressed Rasd1 3' UTR luciferase-reporter activity, this effect was lost with mutations in the putative 3' UTR target-site. Consistently, expression levels of miR-365 were found to inversely correlate with endogenous Rasd1 levels. These findings suggest that miR-365 is down-regulated in Zmpste24(-/-) MEFs and acts as a novel negative regulator of Rasd1. Our comprehensive miRNA data provide a resource to study gene regulatory networks in MEFs.

Dataset Information

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

Publications

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

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