Plasma miR-9-3p and miR-136-3p levels as novel diagnostic biomarkers for mild traumatic brain injury
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ABSTRACT:
PROVIDER: PRJNA667347 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12772353.fastq.gz | Fastqsanger.gz | |||
| SRR12772354.fastq.gz | Fastqsanger.gz | |||
| SRR12772355.fastq.gz | Fastqsanger.gz | |||
| SRR12772356.fastq.gz | Fastqsanger.gz | |||
| SRR12772357.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: High throughput small RNA-Seq analysis from circulating biofluids is crucial in driving the discovery of non-invasive miRNA biomarkers for TBI. In this study, we focused our analysis on acute post-TBI alterations in plasma miRNA profiles in adult, male Sprague-Dawley rats. We compared the plasma miRNA profiles from naive, sham-operated controls and rats with mild and severe TBI. The aim was to identify a miRNA signature that would distinguish the rats with mTBI from the naive and sham-operated controls. Next, we compared the rats with mild and severe TBIs to investigate if a dose-dependent increase would occur in the plasma miRNA levels with corresponding increase in injury severities. Finally, we analysed if the sham surgery itself results in alterations in circulating miRNA profiles, by comparing the naive and sham-operated controls. Methods: TBI was induced with the lateral fluid percussion injury (FPI) model. Tail-vein plasma was collected at 2 days post-TBI from 31 adult male, Sprague-Dawley rats (5 naive, 8 sham-operated controls, 10 mTBI and 8 sTBI) under inhalation of isoflurane anesthesia. Small RNA-Seq was performed from plasma samples of a subset of 20 rats (5 cases each from naive, sham-operated controls, mTBI and sTBI groups). For each case, RNA was isolated from 200 µL plasma using the miRNeasy serum/plasma kit. The extracted RNA was subjected to qPCR-based quality control (QC). Small RNA library preparation was performed with the QIASeq miRNA library kit for Illumina NGS systems. Single-end sequencing of 75 bp reads was performed at a depth of 12M, with one sample/lane in the Illumina NextSeq 550. One naive plasma sample failed at the library preparation step. Hence, small RNA-Seq was succesful for 19/20 cases. The raw fastq files obtained from small RNA-Seq were first manually inspected with FastQC (v0.11.3) to check the overall quality of the sequencing data. For primary quantification of read counts, the fastq files were then uploaded to the Qiagen Geneglobe Data analysis center (DAC), a freely available web resource to analyze data from Qiagen’s QIASeq NGS library kits (https://geneglobe.qiagen.com/in/analyze/). Mapping was performed in the DAC portal with bowtie, using the rat reference genome RGSC Rnor_6.0. Annotation of miRNAs was performed with miRBase v21. Following primary quantification, differential expression analysis for miRNAs was performed with DESeq2 (v1.22.2) in R environment (v3.5.3). Logistic regression (LR) with feature selection utilizing nested leave-one-out cross-validation was also performed to identify miRNAs (“features”) contributing most to groupwise differences (differences between naïve, sham, mTBI, sTBI, sTBI + mTBI and naïve + sham). Results: A total of 748 miRNAs were detected across all samples, out of which 723 (97%) were expressed in all the four groups (naive, sham-operated, mTBI and sTBI). Based on the differential expression and logistic regression analyses, we identified five miRNA candidates that contributed most to the seperation between the mTBI and naive groups: rno-miR-9a-3p, rno-miR-153-3p, rno-miR-15a-3p, rno-miR-136-3p and rno-miR-434-3p. We validated the small RNA-Seq data for these miRNA candidates with miRCURY reverse transcriptase quantitative PCR (RT-qPCR). We could succesfully validate elevated levels of miR-9a-3p, miR-136-3p and miR-434-3p in the mTBI group in comparison to naive. When analysed from the whole cohort, the elevated levels of these miRNAs were consistently observed in the mTBI group compared to the naive, both with RT-qPCR and droplet digital PCR (ddPCR). Further, all the three miRNAs revealed elevated plasma levels in the sTBI group in comparison to the mTBI. Conclusions: Elevated plasma miRNA signature of miR-9a-3p, miR-136-3p and miR-434-3p distinguishes rats with mTBI from the naive, in the lateral FPI model of TBI. Further, all these miRNAs exhibit a dose-dependent increase in plasma levels with increase in injury severities.
2021-03-03 | GSE159011 | GEO
Project description:Plasma miR-9-3p and miR-136-3p levels as novel diagnostic biomarkers for mild traumatic brain injury
| PRJNA667347 | ENA
Project description:This is a prospective-retrospective study to determine if the expression of the miRNA’s miR-31-3p and miR-31-5p are prognostic of patient outcomes or predictive of the benefit from anti-EGFR therapy in stage III Colon Cancer. The present study will utilize FFPE tumor samples collected from patients enrolled in the PETACC-8 study conducted by the Fédération Francophone de Cancérologie Digestive (FFCD). This phase 3 clinical trial prospectively randomized fully resected stage III colon cancer patients to receive adjuvant treatment with either FOLFOX-4 plus cetuximab or FLOFOX-4 alone.
| 2260465 | ecrin-mdr-crc
Project description:Oxaliplatin (oxPt) resistance in colorectal cancers (CRC) is a major unsolved problem. Consequently, predictive markers and a better understanding of resistance mechanisms are urgently needed. To investigate if the recently identified predictive miR-625-3p is functionally involved in oxPt resistance, stable and inducible models of miR-625-3p dysregulation were analyzed. Ectopic expression of miR-625-3p in CRC cells led to increased resistance towards oxPt. The mitogen-activated protein kinase (MAPK) kinase 6 (MAP2K6/MKK6) – an activator of p38 MAPK - was identified as a functional target of miR-625-3p, and, in agreement, was down-regulated in patients not responding to oxPt therapy. The miR-625-3p resistance phenotype could be reversed by anti-miR-625-3p treatment and by ectopic expression of a miR-625-3p insensitive MAP2K6 variant. Transcriptome, proteome and phosphoproteome profiles revealed inactivation of MAP2K6-p38 signaling as a possible driving force behind oxPt resistance. We conclude that miR-625-3p induces oxPt resistance by abrogating MAP2K6-p38 regulated apoptosis and cell cycle control networks.
2017-03-29 | MSV000080762 | MassIVE
Project description:Noninvasive, affordable circulating biomarkers for difficult-to-diagnose mild traumatic brain injury (mTBI) are an unmet medical need. Although blood microRNA (miRNA) levels are reportedly altered after traumatic brain injury (TBI), their diagnostic potential for mTBI remains inconclusive. We hypothesized that acutely altered plasma miRNAs could serve as diagnostic biomarkers both in the lateral fluid percussion injury (FPI) model and clinical mTBI. We performed plasma small RNA-sequencing from adult male Sprague-Dawley rats (n = 31) at 2 days post-TBI, followed by polymerase chain reaction (PCR)-based validation of selected candidates. miR-9a-3p, miR-136-3p, and miR-434-3p were identified as the most promising candidates at 2 days after lateral FPI. Digital droplet PCR (ddPCR) revealed 4.2-, 2.8-, and 4.6-fold elevations in miR-9a-3p, miR-136-3p, and miR-434-3p levels (p < 0.01 for all), respectively, distinguishing rats with mTBI from naïve rats with 100% sensitivity and specificity. DdPCR further identified a subpopulation of mTBI patients with plasma miR-9-3p (n = 7/15) and miR-136-3p (n = 5/15) levels higher than one standard deviation above the control mean at <2 days postinjury. In sTBI patients, plasma miR-9-3p levels were 6.5- and 9.2-fold in comparison to the mTBI and control groups, respectively. Thus, plasma miR-9-3p and miR-136-3p were identified as promising biomarker candidates for mTBI requiring further evaluation in a larger patient population.
| S-EPMC7913923 | biostudies-literature
Project description:Oxaliplatin (oxPt) resistance in colorectal cancers (CRC) is a major unsolved problem. Consequently, predictive markers and a better understanding of resistance mechanisms are urgently needed. To investigate if the recently identified predictive miR-625-3p is functionally involved in oxPt resistance, stable and inducible models of miR-625-3p dysregulation were analyzed. Ectopic expression of miR-625-3p in CRC cells led to increased resistance towards oxPt. The mitogen-activated protein kinase (MAPK) kinase 6 (MAP2K6/MKK6) – an activator of p38 MAPK - was identified as a functional target of miR-625-3p, and, in agreement, was down-regulated in patients not responding to oxPt therapy. The miR-625-3p resistance phenotype could be reversed by anti-miR-625-3p treatment and by ectopic expression of a miR-625-3p insensitive MAP2K6 variant. Transcriptome, proteome and phosphoproteome profiles revealed inactivation of MAP2K6-p38 signaling as a possible driving force behind oxPt resistance. We conclude that miR-625-3p induces oxPt resistance by abrogating MAP2K6-p38 regulated apoptosis and cell cycle control networks. Experimental design for mass spectrometry SILAC experiments can be found at https://figshare.com/s/8e79f008e0e58ec6efc2 or https://doi.org/10.6084/m9.figshare.4888139
2016-08-12 | PXD002172 | Pride
Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.
2024-01-26 | PXD042904 | Pride
Project description:Long non-coding RNAs (lncRNAs) play pivotal roles in diseases such as osteoarthritis (OA). However, knowledge of the biological roles of lncRNAs is limited in OA. We aimed to explore the biological function and molecular mechanism of HOTTIP in chondrogenesis and cartilage degradation. We used the human mesenchymal stem cell (MSC) model of chondrogenesis, in parallel with, tissue biopsies from normal and OA cartilage to detect HOTTIP, CCL3, and miR-455-3p expression in vitro. Biological interactions between HOTTIP and miR-455-3p were determined by RNA silencing and overexpression in vitro. We evaluated the effect of HOTTIP on chondrogenesis and degeneration, and its regulation of miR-455-3p via competing endogenous RNA (ceRNA). Our in vitro ceRNA findings were further confirmed within animal models in vivo. Mechanisms of ceRNAs were determined by bioinformatic analysis, a luciferase reporter system, RNA pull-down, and RNA immunoprecipitation (RIP) assays. We found reduced miR-455-3p expression and significantly upregulated lncRNA HOTTIP and CCL3 expression in OA cartilage tissues and chondrocytes. The expression of HOTTIP and CCL3 was increased in chondrocytes treated with interleukin-1β (IL-1β) in vitro. Knockdown of HOTTIP promoted cartilage-specific gene expression and suppressed CCL3. Conversely, HOTTIP overexpression reduced cartilage-specific genes and increased CCL3. Notably, HOTTIP negatively regulated miR-455-3p and increased CCL3 levels in human primary chondrocytes. Mechanistic investigations indicated that HOTTIP functioned as ceRNA for miR-455-3p enhanced CCL3 expression. Taken together, the ceRNA regulatory network of HOTTIP/miR-455-3p/CCL3 plays a critical role in OA pathogenesis and suggests HOTTIP is a potential target in OA therapy.
2019-08-12 | PXD014988 | Pride
Project description:This study aimed to elucidate the role of microRNA miR-92a-3p in the pathogenesis of adenomyosis. We focused on understanding how miR-92a-3p in exosomes derived from ectopic lesions influences the behavior of endometrial cells, DRG neurons, and Human Umbilical Vein Endothelial Cells (HUVECs), and its potential as a non-invasive diagnostic biomarker. Our findings revealed that MiR-92a-3p is significantly upregulated in exosomes derived from ectopic lesions of adenomyosis. This upregulation was associated with enhanced migration and invasion capabilities in eutopic endometrial cells, DRG neurons, and HUVECs. Furthermore, the study demonstrated a significant correlation between the levels of MiR-92a-3p in urinary exosomes and the clinical symptoms of adenomyosis, suggesting its potential as a non-invasive biomarker for the disease. This study elucidates an exosomal signaling process via miR-92a-3p that drives pathological infiltration and angiogenesis to promote adenomyosis progression. Upregulated miR-92a-3p in biofluid exosomes shows promising non-invasive biomarker potential for diagnosis and monitoring of this disease. Our findings unveil novel targets and tools for improved clinical management.
2024-04-01 | GSE262302 | GEO
Project description:RNA-seq on Kelly neuroblastoma cells transfected with the following miRNA: non-targeting scrambled control, miR-99b-5p, miR-380-3p, miR-485-3p, miR-100-3p, miR-1915-3p, miR-1283
| PRJNA733448 | ENA