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International Journal of Molecular... Nov 2023Glioblastoma (GBM) is a primary brain tumor arising from glial cells. The tumor is highly aggressive, the reason for which it has become the deadliest brain tumor type... (Review)
Review
Glioblastoma (GBM) is a primary brain tumor arising from glial cells. The tumor is highly aggressive, the reason for which it has become the deadliest brain tumor type with the poorest prognosis. Like other cancers, it compromises molecular alteration on genetic and epigenetic levels. Epigenetics refers to changes in gene expression or cellular phenotype without the occurrence of any genetic mutations or DNA sequence alterations in the driver tumor-related genes. These epigenetic changes are reversible, making them convenient targets in cancer therapy. Therefore, we aim to review critical epigenetic dysregulation processes in glioblastoma. We will highlight the significant affected tumor-related pathways and their outcomes, such as regulation of cell cycle progression, cell growth, apoptosis, angiogenesis, cell invasiveness, immune evasion, or acquirement of drug resistance. Examples of molecular changes induced by epigenetic modifications, such as DNA epigenetic alterations, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) regulation, are highlighted. As understanding the role of epigenetic regulators and underlying molecular mechanisms in the overall pro-tumorigenic landscape of glioblastoma is essential, this literature study will provide valuable insights for establishing the prognostic or diagnostic value of various non-coding transcripts, including miRNAs.
Topics: Humans; Glioblastoma; DNA Methylation; Gene Expression Regulation, Neoplastic; MicroRNAs; Epigenesis, Genetic
PubMed: 38003512
DOI: 10.3390/ijms242216320 -
Current Cardiology Reports Jul 2023Heart failure is a severe clinical syndrome with complex and unclarified mechanisms, and it poses a serious threat to human health. MicroRNA, a non-coding RNA, can... (Review)
Review
PURPOSE OF REVIEW
Heart failure is a severe clinical syndrome with complex and unclarified mechanisms, and it poses a serious threat to human health. MicroRNA, a non-coding RNA, can directly bind to target genes and regulate their expression. The important role of microRNAs in the development of HF has become a hot topic of research in recent years. This paper summarizes and prospects the mechanisms of microRNAs in regulating cardiac remodeling during heart failure to provide reference ideas for further research and clinical treatment.
RECENT FINDINGS
With extensive research, more target genes for microRNAs have been clarified. By modulating various molecules, microRNAs affect the contractile function of the myocardium and alter the process of myocardial hypertrophy, myocyte loss, and fibrosis, thereby interfering with the process of cardiac remodeling and exerting an important effect in the process of heart failure. Based on the above mechanism, microRNAs have promising applications in the diagnosis and treatment of heart failure. MicroRNAs form a complex post-transcriptional control mechanism of gene expression, and the increase or decrease of their content during heart failure largely alters the course of cardiac remodeling. By continuously identifying their target genes, it is expected to achieve more precise diagnosis and treatment of this important topic of heart failure.
Topics: Humans; MicroRNAs; Ventricular Remodeling; Heart Failure; Myocardium; Gene Expression Regulation
PubMed: 37233923
DOI: 10.1007/s11886-023-01895-6 -
Experimental Eye Research Nov 2023Keratoconus (KC) is a corneal thinning disorder and a leading cause of corneal transplantation worldwide. Exosomes are small, secreted extracellular vesicles...
Keratoconus (KC) is a corneal thinning disorder and a leading cause of corneal transplantation worldwide. Exosomes are small, secreted extracellular vesicles (30-150 nm) that mediate cellular communication via their protein, lipid, and nucleic acid content. We aimed to characterize the exosomes secreted by primary corneal fibroblasts from subjects with or without KC. Using human keratoconus stromal fibroblast cells (HKC, n = 4) and healthy stromal fibroblasts (HCF, n = 4), we collected and isolated exosomes using serial ultracentrifugation. Using nanoparticle tracking analysis (NTA) with ZetaView®, we compared the size and concentration of isolated exosomes. Different exosomal markers were identified and quantified using a transmission electron microscope (TEM) (CD81) and Western blot (CD9 and CD63). Exosomal miRNA profiles were determined by qRT-PCR using Exiqon Human panel I miRNA assays of 368 pre-selected miRNAs. Proteomic profiles were determined using a label-free spectral counting method with mass spectrometry. Differential expression analysis for miRNAs and proteins was done using student's t-test with a significance cutoff of p-value ≤0.05. We successfully characterized exosomes isolated from HCFs using several complementary techniques. We found no significant differences in the size, quantity, or morphology between exosomes secreted by HCFs with or without KC. Expression of CD81 was confirmed by immuno-EM, and expression of CD63 and CD9 with western blots in all exosome samples. We detected the expression of 72-144 miRNAs (threshold cycle Ct < 36) in all exosome samples. In HKC-derived exosome samples, miR-328-3p, miR-532-5p, miR-345-5p, and miR-424-5p showed unique expression, while let-7c-5p and miR-665 have increased expression. Protein profiling identified 157 proteins in at least half of the exosome samples, with 38 known exosomal proteins. We identified 12 up- and 2 down-regulated proteins in HKC-derived exosomes. The proteins are involved in membrane-bounded vesicles, cytoskeletal, calcium binding, and nucleotide binding. These proteins are predicted to be regulated by NRF2, miR-205, and TGF-β1, which are involved in KC pathogenesis. We successfully characterized the HKC-derived exosomes and profiled their miRNA and protein contents, suggesting their potential role in KC development. Further studies are necessary to determine if and how these exosomes with differential protein/miRNA profiles contribute to the pathogenesis of KC.
Topics: Humans; Keratoconus; Exosomes; Proteomics; MicroRNAs; Stromal Cells
PubMed: 37714423
DOI: 10.1016/j.exer.2023.109642 -
Obesity (Silver Spring, Md.) Dec 2023MicroRNA 484 (miR-484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether...
OBJECTIVE
MicroRNA 484 (miR-484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether miR-484 is involved in lipid metabolism or exerts a role in nonalcoholic fatty liver disease remains unclear.
METHODS
miR-484 levels were examined in the livers of male mice fed a high-fat diet and in hepatocytes treated with free fatty acids. Sorbin and SH3 structural domain-containing protein 2 (Sorbs2) were identified as a novel target of miR-484 by sequencing mRNA in the livers of miR-484 knockout mice. Sorbs2 liver-specific knockdown mice were constructed by tail vein injection of adeno-associated virus vector to miR-484 knockout mice. In addition, genetic manipulation of SORBS2 was performed in human hepatocyte lines, mouse primary hepatocytes, and the liver.
RESULTS
Serum and hepatic miR-484 levels are upregulated in nonalcoholic fatty liver disease mice. miR-484 knockdown ameliorated hepatocyte steatosis, whereas miR-484 overexpression increased hepatocyte lipid load. miR-484 knockdown-mediated alleviation of hepatic steatosis, liver injury, inflammation, and apoptosis was compromised after high-fat diet-induced knockdown of Sorbs2 in mouse liver and free fatty acid-induced primary mouse hepatocytes.
CONCLUSIONS
These results identify Sorbs2-mediated mitochondrial β-oxidation and apoptosis that promote miR-484 knockdown-mediated remission of hepatic steatosis.
Topics: Male; Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Down-Regulation; MicroRNAs; Liver; Hepatocytes; Lipid Metabolism; Diet, High-Fat; Mice, Knockout; Mice, Inbred C57BL; RNA-Binding Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37752619
DOI: 10.1002/oby.23884 -
Molecular Medicine Reports May 2024Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently...
Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently observed in recurrent miscarriage. Several microRNAs (miRs), including miR‑155‑5p, are aberrantly upregulated in recurrent miscarriage; however, the underlying molecular mechanisms remain unclear. The centrosome orchestrates microtubule networks and coordinates cell cycle progression. In addition, it is a base for primary cilia, which are antenna‑like organelles that coordinate signaling during development and growth. Thus, deficiencies in centrosomal functions can lead to several disease, such as breast cancer and microcephaly. In the present study, the signaling cascades were analyzed by western blotting, and the centrosome and primary cilia were observed and analyzed by immunofluorescence staining. The results showed that overexpression of miR‑155‑5p induced centrosome amplification and blocked primary cilia formation in trophoblast cells. Notably, centrosome amplification inhibited trophoblast cell growth by upregulating apoptotic cleaved‑caspase 3 and cleaved‑poly (ADP‑ribose) polymerase in miR‑155‑5p‑overexpressing trophoblast cells. In addition, overexpression of miR‑155‑5p inhibited primary cilia formation, thereby inhibiting epithelial‑mesenchymal transition and trophoblast cell invasion. All phenotypes could be rescued when cells were co‑transfected with the miR‑155‑5p inhibitor, thus supporting the role of miR‑155‑5p in centrosomal functions. It was also found that miR‑155‑5p activated autophagy, whereas disruption of autophagy via the depletion of autophagy‑related 16‑like 1 alleviated miR‑155‑5p‑induced apoptosis and restored trophoblast cell invasion. In conclusion, the present study indicated a novel role of miR‑55‑5p in mediating centrosomal function in recurrent miscarriage.
Topics: Pregnancy; Female; Humans; MicroRNAs; Trophoblasts; Cell Proliferation; Centrosome; Cell Movement; Abortion, Habitual
PubMed: 38551159
DOI: 10.3892/mmr.2024.13209 -
BMC Cancer Jul 2023Studies have shown that microRNA-191 (miR-191) is involved in the development and progression of a variety of tumors. However, the function and mechanism of miR-191 in...
BACKGROUND
Studies have shown that microRNA-191 (miR-191) is involved in the development and progression of a variety of tumors. However, the function and mechanism of miR-191 in oral squamous cell carcinoma (OSCC) have not been clarified.
METHODS
The expression level of miR-191 in tumor tissues of patients with primary OSCC and OSCC cell lines were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. OSCC cells were treated with miR-191 enhancers and inhibitors to investigate the effects of elevated or decreased miR-191 expression on OSCC cells proliferation, migration, cell cycle, and tumorigenesis. The target gene of miR-191 in OSCC cells were analyzed by dual-Luciferase assay, and the downstream signaling pathway of the target genes was detected using western blot assay.
RESULTS
The expression of miR-191 was significantly upregulated in OSCC tissues and cell lines. Upregulation of miR-191 promoted proliferation, migration, invasion, and cell cycle progression of OSCC cells, as well as tumor growth in nude mice. Meanwhile, reduced expression of miR-191 inhibited these processes. Phospholipase C delta1 (PLCD1) expression was significantly downregulated, and negatively correlated with the expression of miR-191 in OSCC tissues. Dual-Luciferase assays showed that miR-191-5p could bind to PLCD1 mRNA and regulate PLCD1 protein expression. Western blot assay showed that the miR-191 regulated the expression of β-catenin and its downstream gene through targeting PLCD1.
CONCLUSION
MicroRNA-191 regulates oral squamous cell carcinoma cells growth by targeting PLCD1 via the Wnt/β-catenin signaling pathway. Thus, miR-191 may serve as a potential target for the treatment of OSCC.
Topics: Animals; Mice; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Mice, Nude; MicroRNAs; Mouth Neoplasms; Phospholipase C delta; Squamous Cell Carcinoma of Head and Neck; Wnt Signaling Pathway; Humans
PubMed: 37460940
DOI: 10.1186/s12885-023-11113-9 -
Clinical and Experimental Medicine Nov 2023Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for... (Meta-Analysis)
Meta-Analysis
Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for optimizing OA treatment is to find early effective diagnostic biomarkers. The contribution of microRNAs (miRNAs) in OA progression is now being increasingly recognized. This review provides a comprehensive summary on studies reporting the expression profiling of miRNAs in OA and associated signaling pathways. We performed a systematic search of the Embase, Web of Science, PubMed, and Cochrane library databases. This systematic review is reported according to the PRISMA checklist. Studies which identified miRNAs with aberrant expression compared to controls during OA progression were included, and a meta-analysis was performed. Results from the random effects model were provided as log10 odds ratios (logORs) and 95% confidence intervals. Sensitivity analysis was conducted to confirm the accuracy of the results. Subgroup analysis was conducted based on tissue source. The target genes of miRNAs identified in this study were extracted from the MiRWalk database, and these target genes were enriched in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. A total of 191 studies reporting 162 miRNAs were included in our meta-analysis. Among them, 36 miRNAs distributed across 96 studies were expressed in the same direction in at least two studies (13 up-regulated and 23 down-regulated). Subgroup analysis of tissue source revealed that the highest number of studies was conducted using articular cartilage, where the most up-regulated miRNAs were miR-146a-5p (logOR 7.355; P < 0.001) and miR-34a-5p (logOR 6.955; P < 0.001), and the most down-regulated miRNAs were miR-127-5p (logOR 6.586; P < 0.001) and miR-140-5p (logOR 6.373; P < 0.001). Enrichment analysis of 752 downstream target genes of all identified miRNAs was performed, and the regulatory relationships among them were displayed. Mesenchymal stem cells and transforming growth factor-β were found to be the most important downstream effectors regulated by miRNA in OA. This study highlighted the importance of miRNA signaling in OA progression and identified a number of prominent miRNAs including miR-146a-5p, miR-34a-5p, miR-127-5p, and miR-140-5p which might be considered as potential biomarkers for OA.
Topics: Humans; MicroRNAs; Osteoarthritis; Biomarkers
PubMed: 37027064
DOI: 10.1007/s10238-023-01063-8 -
Clinical Cancer Research : An Official... Aug 2023Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor...
PURPOSE
Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi.
EXPERIMENTAL DESIGN
To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models.
RESULTS
We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy.
CONCLUSIONS
Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Cell Line, Tumor; Proteins; MicroRNAs
PubMed: 37223910
DOI: 10.1158/1078-0432.CCR-22-3929 -
Journal of Dental Research Dec 2023Several array-based microRNA (miRNA) expression studies independently showed increased expression of miRNAs hsa-miR-130a-3p, -142-3p, -144-3p, -144-5p, -223-3p, -17-5p,...
Several array-based microRNA (miRNA) expression studies independently showed increased expression of miRNAs hsa-miR-130a-3p, -142-3p, -144-3p, -144-5p, -223-3p, -17-5p, and -30e-5p in gingiva affected by periodontal inflammation. We aimed to determine direct target genes and signaling pathways regulated by these miRNAs to identify processes relevant to gingival inflammatory responses and tissue homeostasis. We transfected miRNA mimics (mirVana) for each of the 7 miRNAs separately into human primary gingival fibroblasts cultured from 3 different donors. Following RNA sequencing, differential gene expression and second-generation gene set enrichment analyses were performed. miRNA inhibition and upregulation was validated at the transcript and protein levels using quantitative reverse transcriptase polymerase chain reaction, Western blotting, and reporter gene assays. All 7 miRNAs significantly increased expression of the gene proto-oncogene, receptor tyrosine kinase (). Expression of known periodontitis risk genes , , and was significantly repressed by hsa-miR-130a-3p, -144-3p, and -144-5p, respectively. The genes , , , and showed the most significant and strongest downregulation after hsa-miR-142-3p, -17-5p, -223-3p, and -30e-5p transfection, respectively. The most significantly regulated gene set of each miRNA related to cell cycle (hsa-miRNA-144-3p and -5p [ = 4 × 10 and = 4 × 10], -miR-17-5p [ = 9.5 × 10], -miR-30e-5p [ = 8.2 × 10], -miR-130a-3p [ = 5 × 10]), integrin cell surface interaction (-miR-223-3p [ = 2.4 × 10]), and interferon signaling (-miR-142-3p [ = 5 × 10]). At the end of acute inflammation, gingival miRNAs bring together complex regulatory networks that lead to increased expression of the gene . This underscores the importance of mesenchymal cell migration and invasion during gingival tissue remodeling and proliferation in restoring periodontal tissue homeostasis after active inflammation. , a receptor of the mitogenic hepatocyte growth factor fibroblast secreted, is a core gene of this process.
Topics: Humans; Gingiva; MicroRNAs; Signal Transduction; Up-Regulation; Inflammation; Gene Expression Profiling
PubMed: 37822091
DOI: 10.1177/00220345231197984 -
Leukemia Oct 2023Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a...
Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intratumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus demethylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single-cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus demethylation at diagnosis associate with suboptimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78).
Topics: Adult; Humans; Child; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Burkitt Lymphoma; MicroRNAs
PubMed: 37640845
DOI: 10.1038/s41375-023-02009-5