Dysregulation Of miRNA Expression Research Articles

Circulating miRNAs as Potential Biomarkers Distinguishing Relapsing-Remitting from Secondary Progressive Multiple Sclerosis. A Review.

Multiple sclerosis (MS) is a debilitating neurodegenerative, highly heterogeneous disease with a variable course. The most common MS subtype is relapsing–remitting (RR), having interchanging periods of worsening and relative stabilization. After a decade, in most RR patients, it alters into the secondary progressive (SP) phase, the most debilitating one with no clear remissions, leading to progressive disability deterioration. Among the greatest challenges for clinicians is understanding disease progression molecular mechanisms, since RR is mainly characterized by inflammatory processes, while in SP, the neurodegeneration prevails. This is especially important because distinguishing RR from the SP subtype early will enable faster implementation of appropriate treatment. Currently, the MS course is not well-correlated with the biomarkers routinely used in clinical practice. Despite many studies, there are still no reliable indicators correlating with the disease stage and its activity degree. Circulating microRNAs (miRNAs) may be considered valuable molecules for the MS diagnosis and, presumably, helpful in predicting disease subtype. MiRNA expression dysregulation is commonly observed in the MS course. Moreover, knowledge of diverse miRNA panel expression between RRMS and SPMS may allow for deterring disability progression through successful treatment. Therefore, in this review, we address the current state of research on differences in miRNA panel expression between the phases.

The MiR-320 Family Is Strongly Downregulated in Patients with COVID-19 Induced Severe Respiratory Failure.

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.

Adding a "Notch" to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach.

Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models.

The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA’s role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn’s disease (CD)—the two main forms of IBD—and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD.

MicroRNAs in Huntington's Disease: Diagnostic Biomarkers or Therapeutic Agents?

MicroRNA (miRNA) is a non-coding single-stranded small molecule of approximately 21 nucleotides. It degrades or inhibits the translation of RNA by targeting the 3′-UTR. The miRNA plays an important role in the growth, development, differentiation, and functional execution of the nervous system. Dysregulated miRNA expression has been associated with several pathological processes of neurodegenerative disorders, including Huntington’s disease (HD). Recent studies have suggested promising roles of miRNAs as biomarkers and potential therapeutic targets for HD. Here, we review the emerging role of dysregulated miRNAs in HD and describe general biology of miRNAs, their pathophysiological implications, and their potential roles as biomarkers and therapeutic agents.

Intratumour heterogeneity in microRNAs expression regulates glioblastoma metabolism

While specific microRNA (miRNA) signatures have been identified in glioblastoma (GBM), the intratumour heterogeneity in miRNA expression has not yet been characterised. In this study, we reveal significant alterations in miRNA expression across three GBM tumour regions: the core, rim, and invasive margin. Our miRNA profiling analysis showed that miR-330-5p and miR-215-5p were upregulated in the invasive margin relative to the core and the rim regions, while miR-619-5p, miR-4440 and miR-4793-3p were downregulated. Functional analysis of newly identified miRNAs suggests their involvement in regulating lipid metabolic pathways. Subsequent liquid chromatography–mass spectrometry (LC–MS) and tandem mass spectroscopy (LC–MS/MS) profiling of the intracellular metabolome and the lipidome of GBM cells with dysregulated miRNA expression confirmed the alteration in the metabolite levels associated with lipid metabolism. The identification of regional miRNA expression signatures may underlie the metabolic heterogeneity within the GBM tumour and understanding this relationship may open new avenues for the GBM treatment.

Abstract 2371: MicroRNA-99b-5p targets the mTOR/AR axis and induced autophagic cell death in prostate cancer cells

Abstract MicroRNAs are the small non-coding regulatory RNA molecules involved in a wide array of cellular and molecular processes. MicroRNAs negatively regulate gene expression via base-pairing with complementary sequences within mRNA molecules. In cancer, the dysregulation of miRNAs expression is associated with cancer development or suppression through the regulation of key gene expression followed by modulation of multiple cell signaling pathways. In the present study, we investigated the role of microRNA-99b-5p (miR-99b) on prostate cancer (PCa) cell survival, cell migration, and apoptosis. Overexpression of miR-99b in PCa cells inhibited cell proliferation, cell colony-forming capability, spheroid formation, and induced cell apoptosis. On the contrary, inactivation of miR-99b by miR-99b inhibitor promotes PCa cell proliferation, cell colony-forming capability, and cell migration. Mechanistically, miR-99b binds with the 3'UTR region of the mammalian target of the rapamycin (mTOR) gene and controls the expression of mTOR. Our preliminary data also suggest that miR-99b also inhibits androgen receptor (AR) activity in LNCaP cells and induced cell apoptosis. Further by inhibition of mTOR, miR-99b induced autophagy in PCa cells and autophagic cell death. Expression of miR-99b and inactivation of mTOR by rapamycin increased the sensitivity of PCa cells to anti-PCa drug docetaxel (DTX). Collectively the data suggest that miR-99b functions as a tumor suppressor in PCa cells, and therefore, miR-99b may be considered as novel biomarkers and therapeutic targets for PCa management in PCa patients. Citation Format: Suryakant Niture, Lucas Tricoli, Kala Hayes, Deepak Kumar. MicroRNA-99b-5p targets the mTOR/AR axis and induced autophagic cell death in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2371.

MicroRNA mediated therapeutic effects of natural agents in prostate cancer.

Several natural products, extensively studied for their anticancer activities, have been found to play an efficient role in preventing prostate cancer (PCa). Recently many natural agents have been reported to modulate microRNAs (miRNAs), that are involved in cancer cell growth. The microRNAs are endogenous small noncoding ribonucleic acid molecules that regulate various biological processes through an elegant mechanism of post-transcriptional control of gene expression. Besides being involved in cancer initiation, progression, angiogenesis, inflammation, they have been reported to be responsible for chemoresistance, and radioresistance of tumors. The dysregulated miRNA expression has been associated with many cancers including PCa. Over the past several years, it has been found that natural agents are good regulators of miRNAs and have a role in PCa also. Understanding the molecular mechanisms involving miRNAs by natural agents could result in developing useful strategies to combat this deadly disease. In order to collect research articles, the PubMed search engine was used with keywords 'prostate cancer' and 'natural agents' and 2007 papers were retrieved, further refinement with keywords 'phytochemical' and 'prostate cancer' showed 503 papers. Data was collected from research articles, published from 2010 to 2021. From these, research articles showing miRNA-mediated mechanisms were selected. In this review, we have summarized the information available on the modulation of miRNAs by natural agents, their derivatives, and various combinatorial strategies with chemo/radiation therapy for the mitigation of PCa. Based on the current review of literature, it has been found that the use of natural agents is a novel approach for altering miRNA expression strongly associated with PCa development, recurrence and resistance.

The Role of MicroRNAs in Mitochondria-Mediated Eye Diseases.

The retina is among the most metabolically active tissues with high-energy demands. The peculiar distribution of mitochondria in cells of retinal layers is necessary to assure the appropriate energy supply for the transmission of the light signal. Photoreceptor cells (PRs), retinal pigment epithelium (RPE), and retinal ganglion cells (RGCs) present a great concentration of mitochondria, which makes them particularly sensitive to mitochondrial dysfunction. To date, visual loss has been extensively correlated to defective mitochondrial functions. Many mitochondrial diseases (MDs) show indeed neuro-ophthalmic manifestations, including retinal and optic nerve phenotypes. Moreover, abnormal mitochondrial functions are frequently found in the most common retinal pathologies, i.e., glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), that share clinical similarities with the hereditary primary MDs. MicroRNAs (miRNAs) are established as key regulators of several developmental, physiological, and pathological processes. Dysregulated miRNA expression profiles in retinal degeneration models and in patients underline the potentiality of miRNA modulation as a possible gene/mutation-independent strategy in retinal diseases and highlight their promising role as disease predictive or prognostic biomarkers. In this review, we will summarize the current knowledge about the participation of miRNAs in both rare and common mitochondria-mediated eye diseases. Definitely, given the involvement of miRNAs in retina pathologies and therapy as well as their use as molecular biomarkers, they represent a determining target for clinical applications.

Expression levels of IL-17/IL-23 cytokine-targeting microRNAs 20, 21, 26, 155, and Let-7 in patients with relapsing-remitting multiple sclerosis

ABSTRACT OBJECTIVE: Although multiple sclerosis (MS) is known to be an immune-mediated disease, very little is known about its etiopathogenesis. MicroRNAs (miRNAs) are small non-coding proteins involved in the regulation of gene expression. T-cell activation potential in neurodegenerative diseases has been a research topic of interest in recent years Cytokines play an important role in the course and pathogenesis of MS, The aim of the present study was to analyze expression levels of miR-20, miR-21, miR-26, miR-155, and Let-7, which target the cytokines interleukin IL-17 and IL-23, in order to evaluate the relationship between MS and miRNAs that modulate the expression of cytokines involved in the autoimmune pathway. MATERIALS and METHODS: The study included 20 relapsing-remitting multiple sclerosis (MS) patients who were at least 18 years of age and were undergoing outpatient immunomodulatory therapy and 20 healthy, unrelated individuals who had no systemic disease and were not taking any medication as a control group. Peripheral blood samples were collected from all participants into EDTA-containing tubes and plasma was isolated for cDNA synthesis. From these cDNA samples, miRNA expression levels were quantitatively analyzed via melting curve analysis using the miScript SYBR Green kit in real-time PCR device. RESULTS: Comparison of miRNA expression levels in the peripheral blood samples and MS patients and healthy subjects revealed that the MS patients had significant upregulation of miR-20 and downregulation of miR-26 and miR-155 compared to the control group (p<0.005). CONCLUSION: Dysregulation of miRNA expression may play a role in the pathogenesis of MS.

MicroRNA expression profiling involved in doxorubicin-induced cardiotoxicity using high-throughput deep-sequencing analysis.

MicroRNAs (miRNAs/miRs) are sensitive biomarkers and endogenous repressors of gene expression by decreasing mRNA stability and interfering with mRNA translation. Despite a number of investigations revealing the dysregulation of miRNA expression associated with cardiotoxicity induced by doxorubicin (Dox), perturbation of miRNAs directly resulting from Dox at early stage in cardiomyocytes and the target gene interaction remain largely unknown. In the present study, high-throughput deep-sequencing was used to analyze changes in global miRNA expression in H9c2 cardiomyocytes exposed to 5 µg/ml Dox for 0, 12 or 24 h. Compared with the 0-h time point, the expression levels of 386 unique miRNAs were altered. Based on miRNA expression and fold-change, the target genes of 76 selected miRNAs were further analyzed using gene interaction networks and pathway enrichment analysis. These miRNAs were involved in the regulation of different pathways, whose functions included apoptosis, cell proliferation, extracellular matrix remodeling, oxidative stress and lipid metabolism. These differentially expressed miRNAs included let-7 family, miR-29b-3p, miR-378-3/5p, miR-351-3p, miR-664-3p, miR-455-3p, miR-298-3p, miR-702-5p, miR-128-1-5p, miR-671 and miR-421-5p. The present data indicated that global wide miRNA profiling in Dox-induced cardiomyocytes may provide a novel mechanistic insight into understanding Dox-induced heart failure and cardiotoxicity, as well as novel biomarkers and therapeutic targets.

MicroRNA 29 Family Serves a Key Role in Lung Development and the Prevention of Lung Pathology

Even with remarkable advances in the care of preterm infants, chronic lung disease in the form of bronchopulmonary dysplasia (BPD) continues to be a significant pathologic consequence of prematurity. BPD is caused by the interruption of physiologic lung development and exposure of the immature newborn lung to high O2 tensions. BPD is characterized by a simplified alveolar structure, arrested lung growth, impaired vascular development and lung fibrosis (1). To identify effective treatment strategies for BPD, it is important to understand the molecular mechanisms underlying this disorder. MicroRNAs (miRNA, miR) are known to regulate growth, development and repair of the developing lung; whereas, dysregulation of miRNA expression has been associated with pulmonary disease. Specifically, members of the miR-29 family have been linked to pulmonary cancers, fibrosis, and BPD. Previous studies from our laboratory indicate that developmental induction of miR-29 expression in the fetal lung near term serves a key role in promoting surfactant-producing type II cell differentiation and function through repression of TGF-β2 signaling (2). To understand the role of miR-29 in protection against BPD, in the present study, we created mice in which the entire miR-29 family (miR-29a/b1 and miR-29b2/c) (miR-29 dKO) was disrupted. Upon exposure of miR-29 dKO and WT neonatal mice to hyperoxia (95% O2) for 5 days immediately after birth, expression levels of the proinflammatory cytokines and chemokines, IL-1 β, TGF-β1, CXCL2 and IL-6, were significantly increased in the lungs of miR-29 dKO mice, compared to WT. Furthermore, lungs of miR-29 dKO adult mice manifested increased expression of their direct targets, TGF-β2 and TGF-β3. This was associated with increased collagen deposition, as evidenced by enhanced trichrome staining, suggesting the development of lung fibrosis. HDAC4 (a direct target of miR-29) and proinflammatory TNF-α, which have been implicated in pulmonary fibrosis, also were upregulated in the lungs of miR-29 dKO mice. Overall, our studies suggest a key role of the miR-29 family and its targets in prevention of inflammatory and profibrotic signaling in the neonatal lung leading to lung pathology.Supported by: NIH R01-HL050022 (C.R.M.)

MicroRNA Regulation of Breast Cancer Stemness.

Recent advances in our understanding of breast cancer have demonstrated that cancer stem-like cells (CSCs, also known as tumor-initiating cell (TICs)) are central for progression and recurrence. CSCs are a small subpopulation of cells present in breast tumors that contribute to growth, metastasis, therapy resistance, and recurrence, leading to poor clinical outcome. Data have shown that cancer cells can gain characteristics of CSCs, or stemness, through alterations in key signaling pathways. The dysregulation of miRNA expression and signaling have been well-documented in cancer, and recent studies have shown that miRNAs are associated with breast cancer initiation, progression, and recurrence through regulating CSC characteristics. More specifically, miRNAs directly target central signaling nodes within pathways that can drive the formation, maintenance, and even inhibition of the CSC population. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as biomarkers and promising clinical therapeutics, and presents a comprehensive summary of currently validated targets involved in CSC-specific signaling pathways in breast cancer.

Secreted frizzled-related protein 3 was genetically and functionally associated with developmental dysplasia of the hip.

Background: Developmental dysplasia of the hip (DDH) is the most common joint disease in child orthopedics. Secreted Frizzled-Related Protein 3 (FRZB) plays an important role in joint development. however, no direct association between FRZB and DDH has been demonstrated.Methods: Analysis of genotype distribution and allele frequency for detected single nucleotide polymorphisms (SNP) of FRZB was performed. FRZB expression was assayed in DDH joint tissues. Further experiments to identify the chondrogenic properties of FRZB were conducted. Potential upstream miRNAs for FRZB were assayed in DDH.Results: Significant difference in genotype distribution for rs3768842 (OR=1.46, P=0.0081) and rs2242040 (OR=0.65, P=0.0067) was found. DDH joint tissues showed significantly higher FRZB expression. FRZB demonstrated chondrogenic and anti-hypertrophic properties in vitro. FRZB modulated cell adhesion pathway and cell spreading by regulating integrins expressions. Upstream miRNAs regulating FRZB expression were identified in DDH synovial fluid. Experiments indicated that downregulated miRNA-454 caused FRZB upregulation in DDH joint.Conclusion: Dysregulated FRZB and its loci were associated with DDH. As a Wnt antagonist with chondrogenic properties, FRZB modulated cell adhesion pathway and cell spreading by regulating integrins expressions. FRZB in multiple DDH joint tissues might be mediated by the dysregulated miRNA expression profiles in the joint synovial fluid.

The Involvement of MicroRNAs in SARS-CoV-2 Infection Comorbid with HIV-Associated Preeclampsia.

Purpose of ReviewThis review investigated the potential role of microRNAs (miRNAs) in the synergy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, preeclampsia (PE), and human immunodeficiency virus (HIV) infection. Maternal health is a great concern when treating pregnant women fighting this triad of diseases, which is highly prevalent in South Africa. MicroRNAs are involved in fine-tuning of physiological processes. Disruptions to the balance of this minute protein can lead to various physiological changes that are sometimes pathological.Recent FindingsMicroRNAs have recently been implicated in PE and have been linked to the anti-angiogenic imbalance evident in PE. Recent in silico studies have identified potential host miRNAs with anti-viral properties against SARS-CoV-2 infection. Studies have demonstrated dysregulated expression of several miRNAs in HIV-1 infection along with the ability of HIV-1 to downregulate anti-viral host microRNAs.SummaryThis review has highlighted the significant gap in literature on the potential of miRNAs in women with HIV-associated PE in synergy with the novel SARS-CoV-2 infection. In addition, this review has provided evidence of the critical role that the epigenetic regulatory mechanism of miRNA plays in viral infections and PE, thereby providing a foundation for further research investigating the potential of therapeutic miRNA development with fewer side-effects for pregnant women.

Expression of miRNA in obesity and insulin resistance: a review

MicroRNAs (miRNAs) are part of the epigenetic mechanisms that regulate gene expression at a post-transcriptional level. This review describes some miRNAs whose expression is modified in obesity and that may be involved in the development of insulin resistance. The metabolic alterations associated with obesity are due to an adipose tissue dysfunction. miRNAs are a mechanism that regulates gene expression, one miRNA can regulate the expression up to a thousand genes, and at the same time one gene can be regulated by several miRNAs; moreover, miRNA expression is tissue specific. Obesity leads to a dysregulation of miRNA expression in adipose tissue, and changes in miRNA expression relate to changes in gene expression related to the development of insulin resistance. However, because miRNA can be exported to the extracellular medium through exosomes, proteins, and lipoproteins, miRNA can be found in extracellular fluids like blood, urine, saliva, and cerebrospinal fluid. Considering the above, miRNA have been proposed as biological markers of different diseases, and also as potential therapeutic targets.

The negative correlation between miR-140-3-p and Metadherin gene in estrogen and progesterone receptor positive–breast cancer

BackgroundBreast cancer is a complicated cancer with different etiologies including both environmental and genetic factors. Aberrant expression of many genes and proteins is essential for its development and progression. Metadherin (MTDH) gene is one of the tumor related genes that involved in tumorigenesis and metastasis. MicroRNAs (miRNAs) are widely involved in cell proliferation, tumor invasion and apoptotic processes. Dysregulation of miRNAs expression was related to carcinogenesis and tumor progression. ObjectiveThis study aimed to assess miR-140-3p expression and its possible target gene MTDH gene expression in breast tumor tissues. Moreover, we aimed to explore the correlation among their expression and different clinicopathological parameters. MethodsBioinformatics analysis was done and revealed that MTDH is a one of many target genes for miR-140-3p. Reverse Transcription-quantitative Real-Time PCR (RT-qPCR) was used to identify the expression level of miR-140-3p and MTDH in 50 breast cancer tissues and 25 normal breast tissues. Results indicated that miR-140-3p was significantly lower in breast cancer tissues than normal breast tissues (P < 0.05). Whereas MTDH expression in breast cancer was higher than in normal tissues (P < 0.05). Moreover, there was a negative association between miR-140-3p and MTDH expression levels. We found that MTDH expression was significantly higher in positive estrogen and progesterone receptors breast cancer tissues as compared to negative tissues. ConclusionThis study highlights on the innovative role of miR-140-3p as new biomarker in breast cancer. The findings reveal the potential role of miR-140-3p in breast cancer pathogenesis and prognosis through targeting MTDH expression. This may give an indication for the emerging effect for miR-140-3p as a new diagnostic and potentially a therapeutic goal in breast cancer.

Downregulation of DNA ligases in trophoblasts contributes to recurrent pregnancy loss through inducing DNA damages

IntroductionAs key components of DNA repair pathways, DNA ligases catalyze the formation of phosphodiester bonds between DNA single strands, which function as a “glue” to seal the DNA breaks. DNA ligases play important roles in almost all the normal physiological processes for maintaining the stability of genomic DNA, but their functions in recurrent pregnancy loss (RPL) are still unclear. MethodsImmunoblotting was used to determine protein level. DNA damages were examined by comet assay and cell viability was quantified by MTT assay. The cell apoptosis and cell cycle were examined by flow cytometry. The LIG4 mRNA degradation was quantified by qRT-PCR after actinomycin D treatment. The interactions between miRNAs and LIG4 were predicted by TargetScan and confirmed by dual luciferase assay. ResultsLIG1 and LIG4 were downregulated in RPL patients, while γH2AX level was upregulated. Knockdown LIG1 and LIG4 increased DNA damages in trophoblasts, which further induced apoptosis and cell cycle arrest. Serine/arginine-rich splicing factor 1(SRSF1) was reduced in RPL patients and positively correlated with LIG1. Knockdown SRSF1 increased the degradation of LIG1 mRNA which further repressed LIG1 expression. MiR-383 was upregulated in RPL patients and repressed LIG4 expression through interacting with 3′UTR of LIG4 mRNA. The level of miR-383 was found negatively correlated with LIG4 protein level in trophoblasts from RPL patients. DiscussionLIG1 and LIG4 are downregulated in patients with RPL owing to abnormal RNA degradation and dysregulated miRNA expression. LIG1 and LIG4 downregulation might contribute to the pathophysiological processes of RPL by increasing DNA damages.

Role of microRNA in pancreatic beta cell function.

MicroRNA (miRNAs) are small non-coding RNA involved in gene expression regulation. Emerging evidences identify miRNAs as key regulators of beta cell physiology. Their role in fine-tuned gene expression regulation is crucial in the differentiation of insulin-producing cells and contributes to the acquisition and management of their unique phenotype. Dysregulation of miRNA expression causes beta cell dysfunction and promotes the development of different forms of diabetes mellitus.

Identification of key miRNA signature and pathways involved in multiple myeloma by integrated bioinformatics analysis

ABSTRACT Objectives: Multiple myeloma (MM) is one of the most common types of hematologic malignancy for which the underlying molecular mechanisms remain largely unclear. Dysregulated miRNA expression has been shown to be involved in MM tumorigenesis, progression and drug response. Therefore, a comprehensive analysis based on miRNA-level integrated strategy was performed. Methods: This study aimed to elucidate key miRNA signatures and pathways in MM by integrated bioinformatics analysis. Expression profiles GSE24371, GSE49261 and GSE54156 were obtained from the Gene Expression Omnibus database, and differentially expressed miRNAs (DEMirs) with p < 0.05 were identified. The target genes of these DEMirs were obtained from ENCORI database, and functional enrichment, subpathway enrichment and protein–protein interaction network construction were performed. The key target genes were identified by random walk algorithm and survival verification was performed. Results and discussion: First, six up-regulated and four down-regulated DEMirs shared between any two GSE data sets were identified. Second, target genes (DEMirTGs) by up-regulated and down-regulated DEMirs were obtained. Functional and subpathway enrichment analysis showed that these up-regulated DEMirs are consistently involved in the Wnt signaling pathway. Moreover, enrichment of the down-regulated DEMirs is mainly in the MAPK signaling pathway. Finally, a protein–protein interaction sub-network for these DEMirTGs was constructed, the correlations between the two key genes were identified and survival in MM was evaluated using multiple independent data sets. Conclusion: We identified miRNA signatures and key target genes that were closely related to MM biology, and these genes might serve as potential therapeutic targets for MM patients.