Pancreatic juice-derived microRNA-4516 and microRNA-4674 as novel biomarkers for pancreatic ductal adenocarcinoma
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE226519 | GEO | 2024/03/01
REPOSITORIES: GEO
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Project description:Background: Tumor stage predicts pancreatic cancer (PDAC) prognosis, but prolonged and short survivals have been described in patients with early-stage tumors. Circulating microRNA (miRNA) are an emerging class of suitable biomarkers for PDAC prognosis. Our aim was to identify whether serum miRNA signatures predict survival of early-stage PDAC. Methods: Se-rum RNA from archival 15 stage I-III PDAC patients and 4 controls was used for miRNAs ex-pression profile (Agilent microarrays). PDAC patients with comparable age, gender, diabetes, jaundice and surgery were classified according to survival: less than 14 months (7/15 pts, group A) and more than 22 months (8/15 pts, group B). Bioinformatic data analysis was performed by two-class Significance Analysis of Microarray (SAM) algorithm. Binary logistic regression analyses considering PDAC diagnosis and outcome as dependent variables, and ROC analyses were also performed. Results: 2549 human miRNAs were screened out. At SAM, 76 differen-tially expressed miRNAs were found among controls and PDAC (FDR = 0.4%), the large major-ity (50/76, 66%) of them being downregulated in PDAC with respect to controls. Six miRNAs were independently correlated with early PDAC, and among these, hsa-miR-6821-5p was asso-ciated with the best ROC curve area in distinguishing controls from early PDAC. Among the 71 miRNAs differentially expressed between groups A and B, the most significant were hsa-miR-3135b expressed in group A only, hsa-miR-6126 and hsa-miR-486-5p expressed in group B only. Eight miRNAs were correlated with the presence of lymph-node metastases; among these, hsa-miR-4669 is of potential interest. hsa-miR-4516, increased in PDAC and found as an independent predictor of survival, has among its putative targets a series of gens involved in key pathways of cancer progression and dissemination, such as Wnt and p53 signaling pathways. Conclusions: A series of serum miRNAs was identified as potentially useful for the early diag-nosis of PDAC, and for establishing a prognosis
2021-07-20 | GSE168996 | GEO
Project description:MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are
differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression
profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples,
including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245
known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with
paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with
normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two
hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR)
o0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with
potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially
expressed between pCRC and the corresponding metastases (FDR o0.1), consisting of five known miRs (miR-320b, miR-320d,
miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These
results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition,
miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis
or response to treatment in patients with advanced CRC
| EGAS00001001127 | EGA
Project description:MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.
| EGAD00001001644 | EGA
Project description:Adenomatous polyps adjacent to colorectal cancer (CRC) were found to exhibit two distinct microRNAs (miRs) patterns from normal mucosa to low- and separately, to high-grade dysplasia; presence in screen-detected adenoma of non-cancer patients is unknown. Global miR expression was performed on biopsies obtained from 109 healthy patients undergoing screening/surveillance colonoscopy. Included were normal mucosa (NM); hyperplastic polyp (HP); tubular adenoma (TA), tubulovillous adenoma, with or without, high-grade dysplasia (TVHG) and serrated-polyps; sessile serrated adenoma (SSA) and traditional serrated adenoma (TSA). Logistic regression was used to model miRs predictive of histology and CRC risk. We identified 99 miRs that differed across five histologic groups (FDR=0.05) and that accurately separated on histology (Concordance Index (CI)=0.96). In HPNM, miRs-145, -143, -107a, -23b, and -24 were upregulated whereas miRs-663, -1268, -320b, -1275, and -671 where overexpressed in TVHGs (FDR P<0 .05). The expression of miR-145 and -30a showed high accuracy to separate low from high-risk polyps independent of serrated status (CI= 97.1%; AUC 93.4%). For TSAs, miR-125b and -199a were uniquely downregulated relative to HPNMs and miR-335 discriminated between non-serrated and serrated histology. Histologically advanced polyps from non-cancer patients share miR alterations with those reported for CRC and high-grade adenoma adjacent to tumor including downregulation of immune regulatory miRs-125 and -199a in TSAs; polyp that frequently present with in situ carcinoma. These data extend evidence that miR patterns of high-risk adenoma are detectable in subset of screen-detected adenoma for which measurement may be useful in in adenoma risk stratification.
2015-09-29 | GSE73487 | GEO
Project description:Objective: microRNAs (miRs) are small non-coding molecules that regulate post-transcriptional target gene expression and are involved in mechano-regulation of cellular activities in all physiological systems. It is unknown whether such epigenetic mechanisms are regulated in response to increasing magnitudes of load. This study investigated mechano-regulation of miRs in articular cartilage subjected to ‘physiological’ and ‘non-physiological’ compressive loads in vitro as a model system and validated findings in an in vivo model of abnormal joint loading. Design: Bovine full-depth articular cartilage explants were loaded to 2.5MPa (physiological) or 7MPa (non-physiological) (1Hz, 15 minutes) and mechanically-regulated miRs identified using Next Generation Sequencing and verified using quantitative PCR. Downstream targets were verified using miR-specific mimics or inhibitors in conjunction with 3’-UTR luciferase activity assays. Results: A subset of miRs were mechanically-regulated in ex vivo cartilage explants and in vivo joint cartilage. miR-221, miR-222, miR-21-5p, and miR-27a-5p were increased and miR-483 levels decreased with increasing load magnitude. Tissue Inhibitor of Metalloproteinase 3 (TIMP3) and Cytoplasmic Polyadenylation Element Binding Protein 3 (CPEB3) were identified as putative downstream targets. Conclusion: Our data confirms miR-221 and -222 mechano-regulation and demonstrates novel mechano-regulation of miR-21-5p and miR-27a-5p in ex vivo and in vivo cartilage loading models. TIMP3 and CPEB3 are putative miR targets in chondrocytes. Identification of specific miRs that are regulated by increasing load magnitude, and their potential to impact on tissue homeostasis, has direct relevance to other mechano-sensitive physiological systems and provides a mechanism by which load-induced tissue behaviour is regulated, both in health and pathology.
2020-10-20 | GSE158571 | GEO
Project description:Lifestyle disorders like obesity, type 2 diabetes (T2D), and cardiovascular diseases can be prevented and treated by regular physical activity. During exercise, skeletal muscles release signaling factors that communicate with other organs and mediate beneficial effects of exercise. These factors include myokines, metabolites, and extracellular vesicles (EVs). In the present study, we have examined how electrical pulse stimulation (EPS) of myotubes, a model of exercise, affects the cargo of released EVs. Chronic low frequency EPS was applied for 24 h to human myotubes isolated and differentiated from biopsy samples from 6 morbidly obese females with T2D, and EVs, both exosomes and microvesicles (MV), were isolated from cell media 24 h thereafter. Size and concentration of EV subtypes were characterized by nanoparticle tracking analysis, surface markers were examined by flow cytometry and Western blotting, and morphology was confirmed by transmission electron microscopy. Protein content was assessed by high-resolution proteomic analysis (LC-MS/MS), non-coding RNA was quantified by Affymetrix microarray, and selected microRNAs (miRs) validated by real time RT-qPCR. The size and concentration of exosomes and MV were unaffected by EPS. Of the 400 miRs identified in the EVs, EPS significantly changed the level of 15 exosome miRs, of which miR-1233-5p showed the highest fold change. The miR pattern of MV was unaffected by EPS. Totally, about 1000 proteins were identified in exosomes and 2000 in MV. EPS changed the content of 73 proteins in exosomes, 97 in MVs, and of these 4 were changed in both exosomes and MV (GANAB, HSPA9, CNDP2, and ATP5B). By matching the EPS-changed miRs and proteins in exosomes, 31 targets were identified, and among these several promising signaling factors. Of particular interest were CNDP2, an enzyme that generates the appetite regulatory metabolite Lac-Phe, and miR-4433b-3p, which targets CNDP2. Several of the regulated miRs, such as miR-92b-5p, miR-320b, and miR-1233-5p might also mediate interesting signaling functions.
2023-03-17 | PXD040935 | Pride
Project description:Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of progressive and genetic neuromuscular disorders that involve weakness and wasting of predominantly pelvic and shoulder girdle muscles. More than 30 subtypes have been identified, with variable phenotype. In the early stages of the disease, these LGMD share common clinical and histopathological characteristics among different subtypes and with other neuromuscular disorders, complicating the disease-subtype identification and thus, lengthening the final diagnosis of the disease. In the present study, we try to identify by a non-invasive method a molecular signature including biochemical and epigenetic parameters with a potential value for LGMD patient prognosis and stratification. Circulating miRNome was obtained by smallRNA-seq in plasma samples from LGMD patients (n=6) and matched controls (n=6). Over-representation analysis (ORA) using GO terms and KEGG database was used to study the functional enrichment of target genes. Biochemical parameters related to calcium metabolism, hormonal status, and muscle metabolism were also analyzed in these patients. Thirteen differentially expressed miRs (FDR < 0.05) were able to separate each clinical group by hierarchical clustering. Indeed, most of differentially expressed miRs were up-regulated. Functional enrichment analysis of the target genes for the dysregulated miRs revealed that targets of up-regulated miRs modulated cell cycle and cancer related pathways, while targets of down-regulated miRs were involved in muscle tissue development, regeneration and senescence. Four of the circulating miRs (miR-19b-3p, miR-192-5p, miR-122-5p and miR 323-3p) were further validated by qPCR in LGMD and in the more frequent muscular dystrophies: Duchenne (DMD)(n=5) and facioscapulohumeral muscular dystrophy (FSHD)(n=4). Receiver operating characteristic curve analysis revealed high AUC values for selected miRs (1.0 for miR-19b-3p, miR-192-5p and miR-122-5p; 0.75 for miR-323-3p) suggesting that these miRs could be good biomarker candidates for LGMD. The covariates gender, age at disease onset, and ambulation did not correlate with the expression levels of these miRs. However, differential expression of miR-122-5p (≥10-60 fold, p< 0.0001), miR-192-5p (≥10-60 fold, p< 0.0001) and miR-323-3p (≤ 2-10 fold, p<0.05) levels compared to matched controls could discriminate LGMD from DMD or FSHD dystrophies. In addition, a strong correlation between some of these circulating miRs and biochemical variables such as CK, vitamin D3, ALP and PTH was found only in LGMD patients.
2022-07-18 | GSE208206 | GEO
Project description:Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen allergic patients with and without allergen specific immunotherapy (AIT). Induced sputum samples of healthy controls (HC), AIT treated and untreated grass pollen allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE2 levels were measured using ELISA. Two Hundred and fifty nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL13 levels, inflammatory cell load, sputum eosinophils and symptom burden.While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR3935 and its predicted target gene, the prostaglandin E3 receptor, which might mediate AIT effects through suppression of the PGE2-PTGER3 axis.
2022-05-31 | GSE184382 | GEO
Project description:While microRNAs (miRs) have been extensively studied in the context of malignancy and tumor progression, their functions in regulating T cell activation are less clear. We found reduced levels of miR-15a/16 at 3-18 h post-T cell receptor (TCR) stimulation, suggesting a role in shaping T cell activation. An inducible miR15a/16 transgenic mouse model was developed to determine how elevating miR-15a/16 levels during early stages of activation would affect T cell proliferation and to identify TCR signaling pathways regulated by this miR pair. Doxycyclin (DOX) induced expression of miR-15a/16 from 0-18 h post-TCR stimulation decreased ex vivo proliferation as well as in vivo antigen-specific proliferation. Bioinformatic and proteomic approaches were combined to identify MEK1 as a target of miR-15a/16. MEK1 targeting by miR-15a/16 was confirmed using miR mimics that decreased MEK1 containing the 3’-UTR target nucleotide sequence (UGCUGCUA) but did not decrease MEK1 containing a mutated control sequence (AAAAAAAA). Phosphorylation of downstream signaling molecules ERK1/2 and Elk1 were decreased with DOX-induced miR-15a/16 expression. In addition to MEK1, ERK1 was subsequently found to be targeted by miR-15a/16, with DOX induced miR-15a/16 reducing total ERK1 levels in T cells. These findings show that TCR stimulation reduces miR-15a/16 levels at early stages of T cell activation to facilitate increased MEK1 and ERK1, and this promotes sustained MEK1-ERK1/2-Elk1 signaling required for optimal proliferation.
2022-04-04 | PXD030935 | Pride
Project description:In this study, we performed laser capture microdissection (LCM) of PDAC samples to define their cancer- and stroma-specific molecular subtypes and identify a prognostic gene expression signature for short-term and long-term survival. LCM and RNA-seq analysis of cancer and adjacent stroma of 19 treatment-naïve PDAC tumors were performed. Gene expression signatures were tested for their robustness in a large independent validation set. An RNA in situ hybridization (RNA-ISH) assay with pooled probes for genes associated with disease-free survival (DFS) was developed to probe 111 PDAC tumor samples. Gene expression profiling identified four subtypes of cancer cells (C1-C4) and three subtypes of cancer-adjacent stroma (S1-S3). These stroma-specific subtypes were associated with DFS (p=5.55E-07), with S1 associated with better prognoses when paired with C1 and C2. Thirteen genes were found to be predominantly expressed in cancer cells and corresponded with DFS in a validation using existing RNA-seq datasets. A second validation on an independent cohort of patients using RNA-ISH probes to six of these prognostic genes demonstrated significant association with overall survival (median 17 versus 25 months; p<0.02). Our results identified specific signatures from the epithelial and the stroma components of PDAC, which add clarity to the nature of PDAC molecular subtypes and may help predict survival.
2021-06-30 | GSE164665 | GEO