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MiRNA?mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin?induced acute kidney injury identifies roles for miR?210/Serpine1 and miR?378/Fos in regulating inflammation.

ABSTRACT: The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin?induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear models for microarray data method and mRNA targets of DEMs were predicted using the miRWalk2.0 database. The crucial DEGs were screened by constructing a protein?protein interaction (PPI) network and module analysis. Functions of target genes were analyzed using the database for annotation, visualization and integrated discovery. Small molecule drugs were predicted using the connectivity map database. As a result, 5 DEMs were identified to be shared and oppositely expressed in comparisons between AKI model and control groups, and between MSC treatment and AKI model groups. The 103 DEGs were overlapped with the target genes of 5 common DEMs, and the resulting list was used for constructing the miRNA?mRNA regulatory network, including rno?miR?210/Serpine1 and rno?miR?378/Fos. Serpine1 (degree=17) and Fos (degree=42) were predicted to be hub genes according to the topological characteristic of degree in the PPI network. Function analysis indicated Serpine1 and Fos may be inflammation?related. Furthermore, gliclazide was suggested to be a potential drug for the treatment of AKI because the enrichment score was the closest to ?1 (?0.9). In conclusion, it can be speculated that gliclazide may have a similar mechanism to MSC as a potential therapeutic agent for cisplatin?induced AKI, by regulating miR?210/Serpine1 and miR?378?/Fos?mediated inflammation and cell apoptosis.

SUBMITTER: Zhang C

PROVIDER: S-EPMC6625446 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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miRNA‑mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin‑induced acute kidney injury identifies roles for miR‑210/Serpine1 and miR‑378/Fos in regulating inflammation.

Zhang Chunmei C Ma Piyong P Zhao Zhongyan Z Jiang Nan N Lian Dede D Huo Pengfei P Yang Hailing H

Molecular medicine reports 20190613 2

The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin‑induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear mod ...[more]

PMID: 31257474

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Project description:BackgroundBreast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA (miRNA) expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated.MethodsThe miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex assay, flow cytometry and transwell inserts were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively.ResultsThe most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential regulated downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a known mediator on invasion and metastasis, and the tumor suppressor gene RUNX3.ConclusionsIn summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have a specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers.

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Dataset Information

MiRNA?mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin?induced acute kidney injury identifies roles for miR?210/Serpine1 and miR?378/Fos in regulating inflammation.

Publications

miRNA‑mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin‑induced acute kidney injury identifies roles for miR‑210/Serpine1 and miR‑378/Fos in regulating inflammation.

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