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A systematic analysis of miRNA-mRNA paired variations reveals widespread miRNA misregulation in breast cancer.

ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by binding to target mRNAs and induce translation repression or RNA degradation. There have been many studies indicating that both miRNAs and mRNAs display aberrant expression in breast cancer. Previously, most researches into the molecular mechanism of breast cancer examined miRNA expression patterns and mRNA expression patterns separately. In this study, we systematically analysed miRNA-mRNA paired variations (MMPVs), which are miRNA-mRNA pairs whose pattern of regulation can vary in association with biopathological features, such as the oestrogen receptor (ER), TP53 and human epidermal growth factor receptor 2 (HER2) genes, survival time, and breast cancer subtypes. We demonstrated that the existence of MMPVs is general and widespread but that there is a general unbalance in the distribution of MMPVs among the different biopathological features. Furthermore, based on studying MMPVs that are related to multiple biopathological features, we propose a potential crosstalk mechanism between ER and HER2.

SUBMITTER: Zhong L

PROVIDER: S-EPMC4052615 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A systematic analysis of miRNA-mRNA paired variations reveals widespread miRNA misregulation in breast cancer.

Zhong Lei L Zhu Kuixi K Jin Nana N Wu Deng D Zhang Jianguo J Guo Baoliang B Yan Zhaoqi Z Zhang Qingyuan Q

BioMed research international 20140518

MicroRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by binding to target mRNAs and induce translation repression or RNA degradation. There have been many studies indicating that both miRNAs and mRNAs display aberrant expression in breast cancer. Previously, most researches into the molecular mechanism of breast cancer examined miRNA expression patterns and mRNA expression patterns separately. In this study, we systematically analysed miRNA-mRNA paired variati ...[more]

PMID: 24949432

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Project description:In this study we performed a systematic evaluation of functional miRNA-mRNA interactions associated with the aggressiveness of breast cancer cells using a combination of integrated miRNA and mRNA expression profiling, bioinformatics prediction, and functional assays. Analysis of the miRNA expression identified 11 miRNAs that were differentially expressed, including 7 down-regulated (miR-200c, miR-205, miR-203, miR-141, miR-34a, miR-183, and miR-375) and 4 up-regulated miRNAs (miR-146a, miR-138, miR-125b1 and miR-100), in aggressive cell lines when compared to normal and less aggressive cell lines. Transient overexpression of miR-200c, miR-205, and miR-375 in MDA-MB-231 cells led to the inhibition of cell migration and invasion. The integrated analysis of miRNA and mRNA expression identified 35 known and novel target genes of miR-200c, miR-205, and mir-375, including CFL2, LAMC1, TIMP2, ZEB1, CDH11, PRKCA, PTPRJ, PTPRM, LDHB, and SEC23A. Surprisingly, the majority of these genes (27 genes) were target genes of miR-200c, suggesting that it plays a more important role in regulating the aggressiveness of breast cancer cells. We characterized one of the target genes of miR-200c, CFL2, and demonstrated that CFL2 is overexpressed in aggressive breast cancer cell lines and can be significantly down-regulated by exogenous miR-200c. Tissue microarray analysis further revealed that CFL2 expression in primary breast cancer tissue correlated with tumor grade. To our knowledge, this study is the first systematic screening of functional miRNA target genes in aggressive breast cancer cells. The results obtained from this study may improve our understanding of the role of these candidate miRNAs and their target genes in relation to breast cancer aggressiveness and ultimately lead to the identification of novel biomarkers associated with prognosis. Affymetrix miRNA 1.0 arrays were performed according to the manufacturer's directions on small RNA extracted from 12 breast cancer cell lines including 4 aggressive cell lines, 6 less aggressive cell lines and 2 imortalized breast epithelium cell lines

Project description:BackgroundExosomes play important roles in angiogenesis, drug resistance, and metastasis of colorectal cancer (CRC), but the underlying mechanism has seldom been reported. Herein, our study aimed to reveal an exosomal miRNA-mRNA network involved in CRC by performing bioinformatical analysis.MethodsThe mRNA and miRNA data of colon adenocarcinoma and rectal adenocarcinoma were downloaded from The Cancer Genome Atlas (TCGA) database, and exosomal miRNAs data were downloaded from the GEO dataset GSE39833. The differential expression analysis was performed using "limma" and "edgeR". Target mRNAs of miRNAs were predicted using FunRich 3.1.3, miRNAtap and multiMiR. The candidate mRNAs and exosomal miRNAs were obtained by intersecting two groups of differentially expressed miRNAs and intersection of the differential expressed mRNAs and the target mRNAs, respectively. Key mRNAs and exosomal miRNAs were identified by the least absolute shrinkage and selection operator regression analysis, and used to construct the exosomal miRNA-mRNA network. The network verified was by receiver operating characteristic curve, GEPIA and LinkedOmics. Functional enrichment analysis was also performed for studied miRNAs and mRNAs.ResultsA total of 6568 differentially expressed mRNAs and 531 differentially expressed miRNAs from TCGA data, and 166 differentially expressed exosomal miRNAs in GSE39833 dataset were identified. Next, 16 key mRNAs and five key exosomal miRNAs were identified from the 5284 candidate mRNAs and 61 candidate exosomal miRNAs, respectively. The exosomal miRNA-mRNA network with high connectivity contained 13 hub mRNAs (CBFB, CDH3, ETV4, FOXQ1, FUT1, GCNT2, GRIN2D, KIAA1549, KRT80, LZTS1, SLC39A10, SPTBN2, and ZSWIM4) and five hub exosomal miRNAs (hsa-miR-126, hsa-miR-139, hsa-miR-141, hsa-miR-29c, and hsa-miR-423). The functional annotation revealed that these hub mRNAs were mainly involved in the regulation of B cell receptor signaling pathway and glycosphingolipid biosynthesis related pathways. All hub mRNAs and hub exosomal miRNAs exhibited high diagnosis value for CRC. Furthermore, the association of the hub mRNAs with overall survival, stages, and MSI phenotype of CRC revealed their important roles in CRC progression.ConclusionThis study constructed an exosomal miRNA-mRNA network which may play crucial roles in the carcinogenesis and progression of CRC, thus providing potential diagnostic biomarkers and therapeutic targets for CRC.

Project description:In this study we performed a systematic evaluation of functional miRNA-mRNA interactions associated with the aggressiveness of breast cancer cells using a combination of integrated miRNA and mRNA expression profiling, bioinformatics prediction, and functional assays. Analysis of the miRNA expression identified 11 miRNAs that were differentially expressed, including 7 down-regulated (miR-200c, miR-205, miR-203, miR-141, miR-34a, miR-183, and miR-375) and 4 up-regulated miRNAs (miR-146a, miR-138, miR-125b1 and miR-100), in aggressive cell lines when compared to normal and less aggressive cell lines. Transient overexpression of miR-200c, miR-205, and miR-375 in MDA-MB-231 cells led to the inhibition of cell migration and invasion. The integrated analysis of miRNA and mRNA expression identified 35 known and novel target genes of miR-200c, miR-205, and mir-375, including CFL2, LAMC1, TIMP2, ZEB1, CDH11, PRKCA, PTPRJ, PTPRM, LDHB, and SEC23A. Surprisingly, the majority of these genes (27 genes) were target genes of miR-200c, suggesting that it plays a more important role in regulating the aggressiveness of breast cancer cells. We characterized one of the target genes of miR-200c, CFL2, and demonstrated that CFL2 is overexpressed in aggressive breast cancer cell lines and can be significantly down-regulated by exogenous miR-200c. Tissue microarray analysis further revealed that CFL2 expression in primary breast cancer tissue correlated with tumor grade. To our knowledge, this study is the first systematic screening of functional miRNA target genes in aggressive breast cancer cells. The results obtained from this study may improve our understanding of the role of these candidate miRNAs and their target genes in relation to breast cancer aggressiveness and ultimately lead to the identification of novel biomarkers associated with prognosis. Affymetrix U133 plus arrays were performed according to the manufacturer's directions on RNA extracted from 12 breast cancer cell lines including 4 aggressive cell lines, 6 less aggressive cell lines and 2 imortalized breast epithelium cell lines

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A systematic analysis of miRNA-mRNA paired variations reveals widespread miRNA misregulation in breast cancer.

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A systematic analysis of miRNA-mRNA paired variations reveals widespread miRNA misregulation in breast cancer.

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