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: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.
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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: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:The contribution of microRNA-mediated posttranscriptional regulation on the final proteome in differentiating cells remains elusive. Here, we evaluated the impact of microRNAs (miRNAs) on the proteome of human umbilical cord blood-derived unrestricted somatic stem cells (USSC) during retinoic acid (RA) differentiation by a systemic approach using next generation sequencing analysing mRNA and miRNA expression and quantitative mass spectrometry-based proteome analyses. Interestingly, regulation of mRNAs and their dedicated proteins highly correlated during RA-incubation. Additionally, RA-induced USSC demonstrated a clear separation from native USSC thereby shifting from a proliferating to a metabolic phenotype. Bioinformatic integration of up- and downregulated miRNAs and proteins initially implied a strong impact of the miRNome on the XXL-USSC proteome. However, quantitative proteome analysis of the miRNA contribution on the final proteome after ectopic overexpression of downregulated miR-27a-5p and miR-221-5p or inhibition of upregulated miR-34a-5p, respectively, followed by RA-induction revealed only minor proportions of differentially abundant proteins. In addition, only small overlaps of these regulated proteins with inversely abundant proteins in non-transfected RA-treated USSC were observed. Hence, mRNA transcription rather than miRNA-mediated regulation is the driving force for protein regulation upon RA-incubation, strongly suggesting that miRNAs are fine-tuning regulators rather than active primary switches during RA-induction of USSC.
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