Sequencing-based analyses characterize a tumor suppressive role of mir-1271 repressed by DNA hypermethylation in gastric cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE87785 | GEO | 2018/06/12
REPOSITORIES: GEO
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Project description:Here, we investigated the transcriptome-wide impact of schizophrenia-associated miR-1271-5p in response to bidirectional modulation. Alteration of miR-1271-5p induced considerable changes to mRNA abundance and translation which spanned a diverse range of cellular functions, including directly targeted genes strongly associated with cytoskeletal dynamics and cellular junctions. Mechanistic analyses additionally revealed that upregulation of miR-1271-5p predominantly repressed mRNAs through destabilisation, wherein 3´UTR and CDS binding sites exhibited similar efficacy. Knockdown, however, produced no discernible trend in target gene expression and strikingly resulted in increased expression of the highly conserved miR-96-5p which shares an identical seed region with miR-1271-5p, suggesting the presence of feedback mechanisms which sense disruptions to miRNA levels. These findings indicate that while bidirectional regulation of miR-1271-5p results in substantial remodelling of the neuronal transcriptome, these effects are not inverse in nature. In addition, we provide further support for the idea that destabilisation of mRNA is the predominant mechanism by which miRNAs regulate complementary mRNAs.
2020-04-18 | GSE148827 | GEO
Project description:Sequencing-based analyses characterize a tumor suppressive role of mir-1271 repressed by DNA hypermethylation in gastric cancer
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Project description:The set of expressed microRNAs in a given cell type, or “miRNome”, can be explored under many different aspects. Many studies report modulations of the miRNome in a wide variety of cancers. Papillary thyroid cancer is the most prevalent type of endocrine cancer. The presence of nodal metastases increases the risk of recurrence and mortality. In our study, we performed microRNA deep sequencing (miRSeq) of 3 PTC, their matching normal tissues and nodal metastases and designed a new bioinformatic framework to analyze variations of the different aspects of the miRNome: expression profile, isomiRs and non-templated additions distributions, mutation or A-to-I RNA-editing. Furthermore, we validated our results using qRT-PCR on independent samples from 14 patients and using the collection of miRSeq data from The Cancer Genome Atlas (up to 495 miRseq of PTC). We gave a particular attention to cell content and contamination. We showed that microRNA expression profiles of thyrocytes are altered during tumorigenesis. These alterations involve known up regulations of microRNAs such as miR-146b-5p or miR-22-3p but also down regulations such as miR-7-5p, miR-7-2-5p, miR-1179 or miR-204-5p. Furthermore, some expression modulations were increased following the nodal metastatic process such as miR-7-2-3p or miR-138-1-3p. However, we did not find variations in the other aspects of the miRNome analyzed. We used our bioinformatic frameworks on the largest PTC miRSeq data collection available, to our knowledge. It allowed us, in one study on the different aspects of the miRNome, to find modulated microRNAs that could act as biomarkers of PTC.
2015-12-01 | GSE57780 | GEO
Project description:To clarify the role of micro (mi) RNAs in gastric carcinogenesis, we studied the expression and function of miRNAs in gastric carcinoma (GC) cells. Initially, we performed microarray analysis using total RNA from three human GC cell lines and non-cancerous gastric tissue. Among the down-regulated miRNAs in GC cells,miR-212 expression was decreased in all eight GC cell lines examined and a significant decrease of miR-212 expression in human primary GC tissues was also observed in 6 of 11 cases. Transfection of the precursor miR-212 molecule induced decreased growth of a GC cell line. Using three different databases, methyl-CpG-binding protein MeCP2 was postulated to be a target of miR-212. As seen on reporter assaying, miR-212 repressed the construct with the MECP2 3'-UTR. Ectopic expression of miR-212 repressed expression of the MeCP2 protein,but not the MECP2 mRNA level. These data suggest that down-regulation of miR-212 may be related to gastric carcinogenesis through its target genes, such as MECP2.
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Project description:Breast Cancer is the cancer with most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients versus 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based upon the expression levels of 5 microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the over-expression and down-regulation of proteins differently expressed in the serum of breast cancer patients versus that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a-5p, mir-497-5p, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of mir-125b-5p, miR-29c-3p, mir-16-5p, miR-1260, and miR-451a was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of mir-16-5p with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and use of the predictor here described might be of potential importance for breast cancer prediction.
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Project description:The expression of miR-214 is up-regulated in the liver of chronic viral hepatitis. Functional relevance of miR-214 was analyzed in human stellate cell line, Lx-2. Pro fibrotic genes were repressed, while translation related genes were up-regulated by LNA-antimiR-214
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Project description:Glucocorticoids (GCs) are commonly used to treat patients suffering from lymphoid malignancies i.e. leukemia and multiple myeloma. Although GCs are known to be strong inducers of apoptosis in lymphoid cells, the molecular determinants of GC therapy resistance are poorly understood. Although GC treatment triggers important changes in gene expression, few studies have addressed the regulatory role of small regulatory microRNAs (miRNAs) in GC therapy response. Only recently, aberrant microRNA expression has been linked to the development of haematological malignancies and microRNAs have become master regulators of drug resistance. We identified GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate multiple genes involved in cell cycle control, cell organization and cell death in MM1S, which remain unaffected in MM1R cells. Correspondingly, GCs selectively trigger cell death in MM1S but not in MM1R. Out of 32 microRNAs responsive to GC in MM1S cells but not in MM1R cells, mir-150 was identified as the most persistent GC responsive microRNA. Furthermore, Ingenuity Pathways Analysis (IPA) revealed that ectopic transfection of a synthetic mir-150 mimics GC therapy response in MM1S cells, associated with selective changes in mRNA levels of typical GR transactivated and transrepressed target genes. Although mir-150 largely mirrors GC responsive changes in gene expression of the transcription factor Myb, GR chaperone FKBP5, cell cycle modulator proteins (IL23A, SKP2, CDKN1A), chemokine signaling proteins (CXCR4, CX3CR1, CCL3) and mTOR/UPR stress related proteins (DDIT4, TXNIP), we also observed mir-150 selective effects on transcription factors (NR3C2 (MR), Myb, Fos, Jun, C/EBP-beta, IRF4, NFE2L1, ATF3, ATF4,), chaperone molecules HSPA8, HSP90AB1), the sodium channel SCNN1G and UPR stress proteins (TRIB3, DDIT3). Remarkably, mir-150 overexpression was not able to overcome GC therapy resistance, since we could not detect GC like effects of mir-150 in GR (NR3C1) deficient MM1R cells. Altogether GC-inducible mir-150 adds a novel complex layer of regulation for fine tuning GC specific therapeutic responses in multiple myeloma.
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Project description:microRNAs (miRNAs) regulate virtually all biological processes, but little is known of their role in germinal center (GC) B cells. While the GC reaction is crucial to ensure a competent immune response, GC B cells are also the origin of most human lymphomas. Here we report that miR-217 is specifically upregulated in GC B cells. Gain- and loss-of-function mouse models reveal that miR-217 functions as a positive modulator of the GC response through the regulation of a DNA repair gene network. Moreover, we show that miR-217 overexpression promotes mature B cell lymphomagenesis. Therefore miR-217 provides a novel molecular link between the normal GC response and B cell transformation
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Project description:Analysis of miRNA expression in human breast cancer samples with Agilent's miRNA arrays. These samples are part of a study where we have investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. We observed that indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Abstract of paper: Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. Indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these microRNAs silence anti-proliferative genes, which themselves are E2F1 targets. Thus, microRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative microRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Together these findings position microRNAs as novel key players in the mammalian cellular proliferation network. Keywords: Breast Cancer, miRNA, p53. 18 Primary human breast cancer samples analyzed for their miRNA expression. From two to four replicates were performed for each sample. Quality check (QC) were performed with Feature Extraction 9.1.3.44 and arrays not passing QC were excluded
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