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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells.

ABSTRACT: BACKGROUND:Extracellular vesicles (EVs) are endogenous membrane vesicles with a diameter of 30-200?nm. It has been reported that hypoxic cancer cells can release numerous EVs to mediate multiple regional and systemic effects in the tumor microenvironment. METHODS:In this study, we used ultracentrifugation to extract EVs secreted by TE-13, an esophageal squamous carcinoma (ESCC) cell line during normoxia and hypoxia and performed high-throughput sequencing to detect exosomal miRNAs. Gene ontology (GO) and KEGG pathway analyses were used to reveal pathways potentially regulated by the miRNAs. RESULTS:A total of 10 810 miRNAs were detected; 50 were significantly upregulated and 34 were significantly downregulated under hypoxic environment. GO analysis identified enrichment of protein binding, regulation of transcription (DNA-templated), and membrane as molecular function, biological process, and cellular component, respectively. KEGG pathway analysis revealed cancer-associated pathways, phospholipase D signaling pathway, autophagy, focal adhesion and AGE-RAGE signaling as the key pathways. Further verification experiment from qRT-PCR indicated that miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5 were significantly upregulated in EVs from hypoxia TE-13 cells while miR-340-5p was significantly upregulated in two other ESCC cells, ECA109 and TE-1. CONCLUSION:This study, for the first time reveals changes in the expression of exosomal miRNAs in hypoxic ESCC cells and these findings will act as a resource to study the hypoxic tumor microenvironment and ESCC EVs.

SUBMITTER: Chen F

PROVIDER: S-EPMC7049507 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells.

Chen Fangyu F Chu Li L Li Jie J Shi Yu Y Xu Bing B Gu Junjie J Yao Xijuan X Tian Meng M Yang Xi X Sun Xinchen X

Thoracic cancer 20200110 3

<h4>Background</h4>Extracellular vesicles (EVs) are endogenous membrane vesicles with a diameter of 30-200 nm. It has been reported that hypoxic cancer cells can release numerous EVs to mediate multiple regional and systemic effects in the tumor microenvironment.<h4>Methods</h4>In this study, we used ultracentrifugation to extract EVs secreted by TE-13, an esophageal squamous carcinoma (ESCC) cell line during normoxia and hypoxia and performed high-throughput sequencing to detect exosomal miRNAs ...[more]

PMID: 31922357

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal carcinoma. Protein coding genes and non-coding RNAs can be powerful prognostic factors in multiple cancers, including ESCC. However, there is currently no model that integrates multiple types of RNA expression signatures to predict clinical outcomes.MethodsThe sequencing data (RNA-sequencing and miRNA-sequencing) and clinical data of ESCC patients were obtained from The Cancer Genome Atlas (TCGA) database, and Differential gene expression analysis, Cox regression analysis and Spearman correlation analysis were used to construct prognosis-related lncRNA-mRNA co-expression network and scoring system with multiple types of RNA. The potential molecular mechanisms of prognostic mRNAs were explored by functional enrichment analysis.ResultsA total of 62 prognostic lncRNAs, eight prognostic miRNAs and 66 prognostic mRNAs were identified in ESCC (P-value < 0.05) and a prognosis-related lncRNA-mRNA co-expression network was created. Five prognosis-related hub RNAs (CDCA2, MTBP, CENPE, PBK, AL033384.1) were identified. Biological process analysis revealed that mRNAs in prognosis-related co-expression RNA network were mainly enriched in cell cycle, mitotic cell cycle and nuclear division. Additionally, we constructed a prognostic scoring system for ESCC using ten signature RNAs (MLIP, TNFSF10, SIK2, LINC01068, LINC00601, TTTY14, AC084262.1, LINC01415, miR-5699-3p, miR-552-5p). Using this system, patients in the low-risk group had better long-term survival than those in the high-risk group (log-rank, P-value < 0.0001). The area under the ROC curve (AUCs) revealed that the accuracy of the prediction model was higher than the accuracy of single type of RNA prediction model.ConclusionIn brief, we constructed a prognostic scoring system based on multiple types of RNA for ESCC that showed high predicting prognosis performance, and deeply understood the regulatory mechanism of prognosis-related lncRNA-mRNA co-expression network.

Project description:BackgroundSystemic sclerosis (SSc) is a disease that features severe fibrosis of the skin and lacks effective therapy. Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) are potential stem cell-based tools for the treatment of SSc.MethodsBMSCs were isolated from the bone marrow of mice and identified with surface markers according to multilineage differentiation. EVs were isolated from the BMSC culture medium by ultracentrifugation and identified with a Nanosight NS300 particle size analyzer, transmission electron microscopy (TEM), and western blot. The microRNAs (miRNAs) of BMSC-derived EVs (BMSC-EVs) were studied via miRNA sequencing (miRNA-seq) and bioinformatic analysis. An SSc mouse model was established via subcutaneous bleomycin (BLM) injection, and the mice were treated with BMSCs or BMSC-derived EVs. Skin tissues were dissociated and analyzed with H&E staining, RNA sequencing (RNA-seq), western blot, and immunohistochemical staining.ResultsEvident pathological changes, like fibrosis and inflammation, were induced in the skin of BLM-treated mice. BMSCs and BMSC-EVs effectively intervened such pathological manifestations and disease processes in a very similar way. The effects of the BMSC-EVs were found to be caused by the miRNAs they carried, which were proven to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple EV-related biological processes. Furthermore, TGF-β1-positive cells and α-SMA-positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice but evidently reduced in the scleroderma skin of the EV-treated SSc group. In addition, the numbers of mast cells and infiltrating macrophages and lymphocytes were evidently increased in the skin of BLM-treated mice but significantly reduced by EV treatment. In line with these observations, there were significantly higher mRNA levels of the inflammatory cytokines Il6, Il10, and Tnf-α in SSc mice than in control mice, but the levels decreased following EV treatment. Through bioinformatics analysis, the TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes seen in mouse SSc, and these pathways could be therapeutic targets for treating the disease.ConclusionsBMSC-derived EVs could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy. The effects of EVs are generated by the miRNAs they carry, which alleviate SSc pathogenic changes by regulating the WNT and TGFβ signaling pathways.

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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells.

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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells.

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