microRNA Interactions Research Articles

Clinical significance of the long non-coding RNA NEAT1/miR-129-5p axis in the diagnosis and prognosis for patients with chronic heart failure.

Chronic heart failure (CHF) is the leading cause of death worldwide. The regulatory interactions of long non-coding RNA (lncRNAs) and microRNAs (miRs) have important roles in multiple diseases. However, the clinical significance of the nuclear-enriched abundant transcript 1 (NEAT1)/miR-129-5p axis in CHF has remained elusive. The present study explored whether the NEAT1/miR-129-5p axis may be a suitable diagnostic and prognostic marker for CHF. The expression of lncRNA NEAT1 and miR-129-5p in the serum of patients with CHF was analyzed by reverse transcription-quantitative PCR. Furthermore, inter-indicator correlations were assessed by Pearson correlation coefficient analysis. Receiver operating characteristic (ROC) curves were generated to evaluate the ability of NEAT1, miR-129-5p and brain natriuretic peptide (BNP) to identify patients with CHF. The prognostic value of the NEAT1/miR-129-5p axis was analyzed by drawing Kaplan-Meier survival curves and by Cox logistic regression analysis. Baseline data were not significantly different between CHF (n=70) and control subjects (n=62). The serum level of NEAT1 was increased and the expression level of miR-129-5p was decreased in patients with CHF (all P<0.001). The ROC curves suggested that serum NEAT1 and miR-129-5p were of diagnostic value in patients with CHF and the combined diagnostic accuracy of NEAT1, miR-129-5p and BNP was significantly improved. Kaplan-Meier and multivariate Cox regression analysis suggested that low NEAT1 and high miR-129-5p were able to predict overall survival of patients with CHF (all P<0.01). In conclusion, the present study indicated that patients with CHF had increased NEAT1 and decreased miR-129-5p expression. The deregulated NEAT1/miR-129-5p axis may provide novel non-invasive biomarkers for the diagnosis and prognosis of CHF.

Targeting lncRNA H19/miR-29b/COL1A1 Axis Impedes Myofibroblast Activities of Precancerous Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. Among these regulators, profibrotic lncRNA H19 has been found to be overexpressed in several fibrosis diseases. Here, we examined the expression of H19 in OSF specimens and its functional role in fibrotic buccal mucosal fibroblasts (fBMFs). Our results indicate that the aberrantly overexpressed H19 contributed to higher myofibroblast activities, such as collagen gel contractility and migration ability. We also demonstrated that H19 interacted with miR-29b, which suppressed the direct binding of miR-29b to the 3′-untranslated region of type I collagen (COL1A1). We showed that ectopic expression of miR-29b ameliorated various myofibroblast phenotypes and the expression of α-smooth muscle actin (α-SMA), COL1A1, and fibronectin (FN1) in fBMFs. In OSF tissues, we found that the expression of miR-29b was downregulated and there was a negative correlation between miR-29b and these fibrosis markers. Lastly, we demonstrate that arecoline stimulated the upregulation of H19 through the transforming growth factor (TGF)-β pathway. Altogether, this study suggests that increased TGF-β secretion following areca nut chewing may induce the upregulation of H19, which serves as a natural sponge for miR-29b and impedes its antifibrotic effects.

CircRNA_0005529 facilitates growth and metastasis of gastric cancer via regulating miR-527/Sp1 axis

BackgroundCircular RNAs (circRNAs) are endogenous non-coding RNAs, which are associated with various biological processes, including microRNA (miRNA) interaction, protein binding and regulatory splicing. circRNA_0005529 (circ_0005529) is derived from vacuolar protein sorting 33 homologue B (VPS33B), and its biological role in gastric cancer (GC) has not been examined. In this study, the expression and location of circ_0005529 and microRNA-527 (miR-527) were determined by qRT-PCR and fluorescence in situ hybridization (FISH). Cell proliferation and cell migration were determined by MTT, EdU incorporation, colony formation, wound scratch and transwell assays. In addition, immunohistochemistry and western blotting were performed to determine the expressions of specificity protein 1 (Sp1), PCNA, c-myc, E-cadherin and N-cadherin. Western blotting and luciferase reporter assay were performed to study the interaction between circ_0005529 and miR-527 or miR-527 and Sp1. The functional effects of circ_0005529 on GC through regulating Sp1 were further evaluated using xenograft and metastatic mouse models in vivo.ResultsOur results showed that circ_0005529 was upregulated in GC tissues and cells, and had promoting effects on cell proliferation and cell migration. Mechanism analysis suggested that circ_0005529 could bind to microRNA-527 (miR-527) and reduce its expression. The interaction between miR-527 and Sp1 in GC was systematically studied. In addition, the results indicated that Sp1 upregulation could rescue the effects on cell proliferation and migration caused by circ_0005529. Moreover, the inhibitory effects of circ_0005529 downregulation on GC growth and metastasis were evaluated in mouse models. These findings suggested that the axis of circ_0005529/miR-527/Sp1 may serve as a promising treatment target for GC diagnosis and treatment.ConclusionsThese findings suggested that the signal axis of circ_0005529/miR-527/Sp1 may has the potential to be explored as a novel therapeutic target for GC diagnosis and treatment.Graphical abstractMechanism diagram: During GC development, overexpressed circ_0005529 sponged miR-527 and then upregulated the expression of Sp1. Subsequently, epithelial-mesenchymal transition (EMT), cell proliferation and cell migration were promoted, which ultimately facilitated the tumor metastasis

A Comparison of Gene Expression Changes in the Blood of Individuals Consuming Diets Supplemented with Olives, Nuts or Long-Chain Omega-3 Fatty Acids.

Background: The Mediterranean diet, which is rich in olive oil, nuts, and fish, is considered healthy and may reduce the risk of chronic diseases. Methods: Here, we compared the transcriptome from the blood of subjects with diets supplemented with olives, nuts, or long-chain omega-3 fatty acids and identified the genes differentially expressed. The dietary genes obtained were subjected to network analysis to determine the main pathways, as well as the transcription factors and microRNA interaction networks to elucidate their regulation. Finally, a gene-associated disease interaction network was performed. Results: We identified several genes whose expression is altered after the intake of components of the Mediterranean diets compared to controls. These genes were associated with infection and inflammation. Transcription factors and miRNAs were identified as potential regulators of the dietary genes. Interestingly, caspase 1 and sialophorin are differentially expressed in the opposite direction after the intake of supplements compared to Alzheimer’s disease patients. In addition, ten transcription factors were identified that regulated gene expression in supplemented diets, mild cognitive impairment, and Alzheimer’s disease. Conclusions: We identified genes whose expression is altered after the intake of the supplements as well as the transcription factors and miRNAs involved in their regulation. These genes are associated with schizophrenia, neoplasms, and rheumatic arthritis, suggesting that the Mediterranean diet may be beneficial in reducing these diseases. In addition, the results suggest that the Mediterranean diet may also be beneficial in reducing the risk of dementia.

SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway

The hepatoprotection of histone deacetylase sirtuin 1 (SIRT1) has been identified to attenuate ischemia-reperfusion (IR)-triggered inflammation and liver damage. This study was performed to characterize the function of SIRT1 in hepatic IR injury. In in vivo assays on liver-specific knockout mice of SIRT1, we first validated the effect of SIRT1 knockout on liver damage and XBP1/NLRP3 inflammasome activation. Next, we examined whether knockdown of XBP1/NLRP3 or miR-182 agomir could reverse the effect of SIRT1 knockout. In in vitro assays, NCTC1469 cells subjected to hypoxia/reoxygenation (H/R) were transduced with small interfering RNA (siRNA)/activator of SIRT1 or miR-182 agomir to confirm the effect of SIRT1 on NCTC1469 cell behaviors as well as the regulation of miR-182 and the XBP1/NLRP3 signaling pathway. Hepatic IR injury was appreciably aggravated in SIRT1 knockout mice, and SIRT1 knockdown abolished the inhibition of XBP1/NLRP3 inflammasome activation, which was reversed by NLRP3 knockdown, XBP1 knockdown, or miR-182 agomir. Mechanistically, miR-182 expression was positively regulated by SIRT1 in hepatic IR injury in mice, and miR-182 inhibited the expression of XBP1 by binding to the 3′ untranslated region (UTR) of XBP1. The histone deacetylase SIRT1 inhibits the downstream XBP1/NLRP3 inflammatory pathway by activating miR-182, thus alleviating hepatic IR injury in mice.

ThemicroarrayidentificationcircularRNA hsa_circ_0105015up-regulated involvinginflammationpathwayin essential hypertension.

BackgroundEssential hypertension (EH) is an inflammatory disease, and endothelial dysfunction induced by chronic inflammation is one of the pathogeneses of EH. The expression of some inflammatory mediators may be regulated by the interaction of circular RNAs (circRNAs) and microRNAs (miRNAs).MethodsAn Agilent human circRNA microarray was used to identify the expression profile of circRNAs in EH. qRT‐PCR was used to evaluate the relative expression of circRNAs in 48 pairs of human whole blood samples (sex and age ± 3 years matched) and endothelial cells. TNF‐α was applied to induce endothelial cells inflammation. CircRNA‐miRNA network was predicted by MiRanda software.ResultsThere were 287 circRNAs differentially expressed in the microarray. The top 10 up‐regulated circRNAs in the EH group were hsa_circ_0014243, hsa_circ_0133228, hsa‐circRNA14116‐3, hsa_circ_0079536, hsa‐circRNA13649‐1, hsa_circ_0117886, hsa_circ_0007075, hsa‐circRNA15285‐1, hsa‐circRNA10088‐9, and hsa‐circRNA14119‐10; the top 10 down‐regulated circRNAs were hsa_circ_0100094, hsa_circ_0127342, hsa_circ_0093773, hsa_circ_0096334, hsa_circ_0131618, hsa_circ_0063886, hsa_circ_0097804, hsa_circ_0126640, hsa‐circRNA8935‐1, and hsa_circ_0039978 (fold change in descending order). Hsa_circ_0105015 has two predicted binding sites with hsa‐miR‐637. The relative expression of hsa_circ_0105015 in EH patients was significantly higher than healthy controls (P = .002), and similar results appeared in TNF‐α‐induced endothelial cells. The area under the curve after hsa_circ_0105015 combined with hsa‐miR‐637 was 0.703, P < .001.ConclusionHyperexpression of hsa_circ_0105015 is a significant risk factor of EH and its association with EH involves inflammatory pathways. Hyperexpression of hsa_circ_0105015 combined with hypoexpression of hsa‐miR‐637 indicates vascular inflammation or endothelial dysfunction and has potential as a biomarker for early diagnosis of EH.

Epigenetic interaction of miRNA-26a and P2Y12 gene DNA methylation on platelet reactivity under clopidogrel and their impact to the coronary flow after primary PCI in STEMI

Abstract Background Epigenetic factors such as miRNA-26A and P2Y12 DNA methylation play role in pathophysiology of cardiovascular disease. Clopidogrel-resistance is associated with worse cardiovascular outcome. The interactions between the expression of platelet miRNA-26a and P2Y12 DNA methylation to clopidogrel resistance and post procedural TIMI flow in STEMI patients undergoing primary PCI is unclear. Purpose To define interaction of epigenetic factors micro-RNA (miRNA)-26a expression and P2Y12 gene DNA methylation to the platelet reactivity under clopidogrel therapy, and their impact on the coronary flow after Primary PCI in patients with STEMI. Methods We studied STEMI patients who underwent primary PCI, receiving 600 mg loading dose of clopidogrel. Platelet reactivity assessed by VerifyNow P2Y12. Realtime PCR was performed to measure the expression of platelet miR-26a and DNA methylation of P2Y12 gene. Postprocedural epicardial coronary flow was assessed semi quantitatively. Results There were 100 patients were recruited. Among them, 59% have high miRNA-26a platelet expression, 60% had no methylation in their P2Y12 gene, and 27% had high platelet reactivity index under clopidogrel therapy. There was association between high miR-26a expression and reduced platelet inhibition under clopidogrel (OR 4.2, p&amp;lt;0.01), but not with DNA methylation of P2Y12 gene. High platelet reactivity index under clopidogrel therapy was associated with suboptimal coronary flow after primary PCI in STEMI patients (OR 3.3, p&amp;lt;0.05). Conclusions High miRNA-26a platelet expression, but not DNA methylation of P2Y12 gene, in patients with acute STEMI have significant association with high platelet reactivity under clopidogrel therapy. Furthermore, high platelet reactivity under clopidogrel is associated with suboptimal coronary flow in STEMI patients undergoing primary PCI. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Harapan Kita Honor Research Grant

MicroRNA in Gastric Cancer Development: Mechanisms and Biomarkers.

Gastric cancer (GC) is one of the most common and difficult diseases to treat. The study of signaling pathway regulation by microRNA provides information on the mechanisms of GC development and is the basis for biomarker creation. In this study, a circuit of microRNA interactions with signaling pathways was constructed. The microRNAs, associated with metastasis and chemoresistance, are described. In most cases, microRNAs in GC regulate the Wnt/β-catenin, PI3K/AKT/mTOR, RAS/RAF/ERK/MAPK, NF-kB, TGF-β, and JAK/STAT pathways. Part of the microRNA acts on several target genes that function in different pathways. This often leads to an intensification of the induced processes. MicroRNAs have also been described that have the opposite effect on different pathways, causing different functional consequences. By acting on several target genes, or genes associated with several pathways, microRNAs can function in a signaling network. MicroRNAs associated with metastasis most often interact with the Wnt/β-catenin pathway. MicroRNAs affecting chemoresistance, in most cases, affect the regulators of apoptosis and are associated with the PI3K/AKT/mTOR pathway. The characteristics of microRNAs proposed as candidates for GC biomarkers were analyzed. The currently developed diagnostic and prognostic panels of microRNAs are also considered.

Mutual Interaction of Clinical Factors and Specific microRNAs to Predict Mild Cognitive Impairment in Patients Receiving Hemodialysis.

Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients (mean age, 59.1 years); CDR > 0.5 included 33 patients (mean age, 64.0 years). On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest (0.897, 95% confidence interval 0.806–0.988). Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis.

Seasonal expressions of SF-1, StAR and P450scc in the scent glands of the muskrats (Ondatra zibethicus)

The steroidogenesis occurs in specific cells and tissues in the mammals which begins with the transfer and intracellular processing of cholesterol converted to pregnenolone. This study investigated the gene and protein expression levels of steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) in the scent glands of the muskrats during the breeding and non-breeding seasons. The immunohistochemical localizations of StAR and P450scc were identified in the glandular cells and epithelial cells while SF-1 was only expressed in glandular cells during the breeding and non-breeding seasons. The gene and protein expression levels of SF-1, StAR and P450scc in the scent glands were remarkedly higher in the breeding season than those of the non-breeding season. The interaction of micro RNAs (miRNAs) and transcriptome results showed that miR-762 and miR-4454 might be the genes encoding (Nr5a1, Star and Cyp11a1) in key biological processes. Taken together, these results suggested that the scent glands of the muskrats potentially owned ability to synthesize steroid hormones de novo, and the steroid hormones might affect the scent glandular functions of the muskrats during the breeding and non-breeding seasons.

Identification of Specific Circular RNA Expression Patterns and MicroRNA Interaction Networks in Mesial Temporal Lobe Epilepsy.

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson’s disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA–miRNA–mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets.

The crosstalk between bone metabolism, lncRNAs, microRNAs and mRNAs in coronary artery calcification

The association between Coronary Artery Calcification (CAC) and osteoporosis has been reported but not fully understood. Therefore, using an original bioinformatic framework we analyzed transcriptomic profiles of 20 elderly women with high CAC score and 31 age- and sex-matching controls from São Paulo Ageing & Health study (SPAH). We integrated differentially expressed microRNA (miRNA) and long-noncoding RNA (lncRNA) interactions with coding genes associated with CAC, in the context of bone-metabolism genes mined from literature. Top non-coding regulators of bone metabolism in CAC included miRNA 497-5p/195 and 106a-5p, and lncRNA FAM197Y7. Top non-coding RNAs revealed significant interplay between genes regulating bone metabolism, vascularization-related processes, chromatin organization, prostaglandin and calcium co-signaling. Prostaglandin E2 receptor 3 (PTGER3), Fibroblasts Growth Factor Receptor 1 (FGFR1), and One Cut Homeobox 2 (ONECUT2) were identified as the most susceptible to regulation by the top non-coding RNAs. This study provides a flexible transcriptomic framework including non-coding regulation for biomarker-related studies.

M6A-Atlas: a comprehensive knowledgebase for unraveling the N6-methyladenosine (m6A) epitranscriptome.

N 6-Methyladenosine (m6A) is the most prevalent RNA modification on mRNAs and lncRNAs. It plays a pivotal role during various biological processes and disease pathogenesis. We present here a comprehensive knowledgebase, m6A-Atlas, for unraveling the m6A epitranscriptome. Compared to existing databases, m6A-Atlas features a high-confidence collection of 442 162 reliable m6A sites identified from seven base-resolution technologies and the quantitative (rather than binary) epitranscriptome profiles estimated from 1363 high-throughput sequencing samples. It also offers novel features, such as; the conservation of m6A sites among seven vertebrate species (including human, mouse and chimp), the m6A epitranscriptomes of 10 virus species (including HIV, KSHV and DENV), the putative biological functions of individual m6A sites predicted from epitranscriptome data, and the potential pathogenesis of m6A sites inferred from disease-associated genetic mutations that can directly destroy m6A directing sequence motifs. A user-friendly graphical user interface was constructed to support the query, visualization and sharing of the m6A epitranscriptomes annotated with sites specifying their interaction with post-transcriptional machinery (RBP-binding, microRNA interaction and splicing sites) and interactively display the landscape of multiple RNA modifications. These resources provide fresh opportunities for unraveling the m6A epitranscriptomes. m6A-Atlas is freely accessible at: www.xjtlu.edu.cn/biologicalsciences/atlas.

Circ-SMARCA5 suppresses colorectal cancer progression via downregulating miR-39-3p and upregulating ARID4B

BackgroundCircular RNAs are crucial in tumorigenesis. However, little is known about their functions in colorectal cancer (CRC). Circ-SMARCA5 was found to be an oncogene or tumor suppresser in different types of cancers, but its exact role in CRC remains unknown. Here, we aim to identify the role of circ-SMARCA5 in CRC development. MethodsCirc-SMARCA5 expression was determined by qRT-PCR. CRC cell proliferation, migration, and invasion were detected by CCK-8, wound healing, and Transwell assays, respectively. Bioinformatics analysis was performed to predict target genes. The interaction of microRNA (miR) with circ-SMARCA5 or target genes was detected using luciferase reporter assay. Xenograft model was established to determine the effect of circ-SMARCA5 on CRC tumor growth in vivo. ResultsCirc-SMARCA5 expression was dramatically decreased in CRC cell lines and tissues. Circ-SMARCA5 overexpression inhibited CRC cell proliferation, migration and invasion. MiR-93–3p was predicted as a target of circ-SMARCA5 and its overexpression attenuated the anti-tumor effect of circ-SMARCA5 on CRC cells. Furthermore, we predicted AT-rich interaction domain 4B (ARID4B) as the target of miR-39–3p. Functional analysis showed that circ-SMARCA5 upregulated ARID4B expression via miR-39–3p. Additionally, in vivo studies demonstrated that circ-SMARCA5 suppressed CRC tumor progression. ConclusionCirc-SMARCA5 functions as a tumor suppressor by upregulating ARID4B expression via sponging miR-39–3p, and thereby inhibited CRC progression.

A SNP-mediated lncRNA (LOC146880) and microRNA (miR-539-5p) interaction and its potential impact on the NSCLC risk

BackgroundMany cancer-associated single nucleotide polymorphisms (SNPs) are located in the genomic regions of long non-coding RNAs (lncRNAs). Mechanisms of these SNPs in connection to cancer risk are not fully understood.MethodsAssociation of SNP (rs140618127) in lncRNA LOC146880 with non-small cell lung cancer (NSCLC) was evaluated in a case-control study of 2707 individuals. The mechanism of the SNP’s biologic influence was explored with in vitro and in vivo experiments, including plasmid transfection, siRNA knockdown, flow cytometry assessment, and assays of cell proliferation, migration, invasion, and colony formation.ResultsAssociation analysis showed that A allele of SNP rs140618127 was associated with low risk of NSCLC in the Chinese population. Lab experiments indicated that SNP rs140618127 contained a binding site for miR-539-5p and the binding between miR-539-5p and LOC146880 resulted in declined phosphorylation of an oncogene, ENO1. The reduced phosphorylation of ENO1 led to decreased phosphorylation of PI3K and Akt, which is further linked to the decline in cell proliferation and tumor progression.ConclusionThe study demonstrates that SNP rs140618127 in lncRNA loc146880 provides an alternate binding site for microRNA miR-539-5p which affects the phosphorylation of ENO1 and activation of the PI3K and Akt pathway.

Predicting microRNA-disease associations from lncRNA-microRNA interactions via Multiview Multitask Learning.

Identifying microRNAs that are associated with different diseases as biomarkers is a problem of great medical significance. Existing computational methods for uncovering such microRNA-diseases associations (MDAs) are mostly developed under the assumption that similar microRNAs tend to associate with similar diseases. Since such an assumption is not always valid, these methods may not always be applicable to all kinds of MDAs. Considering that the relationship between long noncoding RNA (lncRNA) and different diseases and the co-regulation relationships between the biological functions of lncRNA and microRNA have been established, we propose here a multiview multitask method to make use of the known lncRNA-microRNA interaction to predict MDAs on a large scale. The investigation is performed in the absence of complete information of microRNAs and any similarity measurement for it and to the best knowledge, the work represents the first ever attempt to discover MDAs based on lncRNA-microRNA interactions. In this paper, we propose to develop a deep learning model called MVMTMDA that can create a multiview representation of microRNAs. The model is trained based on an end-to-end multitasking approach to machine learning so that, based on it, missing data in the side information can be determined automatically. Experimental results show that the proposed model yields an average area under ROC curve of 0.8410+/-0.018, 0.8512+/-0.012 and 0.8521+/-0.008 when k is set to 2, 5 and 10, respectively. In addition, we also propose here a statistical approach to predicting lncRNA-disease associations based on these associations and the MDA discovered using MVMTMDA. Python code and the datasets used in our studies are made available at https://github.com/yahuang1991polyu/MVMTMDA/.

Biological functions, pathways of glutathione peroxidases and their expression in osteoarthritis

Purpose: To determine the biological functions of selenoprotein glutathione peroxidase (GPXs) and thier expressions in osteoarthritis (OA), and to fully explore the possible association between GPXs and OA in order to provide new insights to the study of OA pathogenesis and novel prophylactic and therapeutic strategies for OA. Methods: The biological functions of the five GPX-genes were analyzed using bioinformatics and data mining techniques. A protein-protein interaction network (PPI) was constructed to identify the core genes associated with the biological functions of GPXs. Furthermore, the expressions of the five GPX-genes in OA patients and healthy individuals were determined using gene chip datasets from public databases based on meta-analysis methods. Results: KEGG pathway enrichment analysis showed that the signalling pathways of GPXs were mainly enriched in glutathione metabolism, thyroid hormone synthesis, and amyotrophic lateral sclerosis. The PPI network of the five GPXs indicated that SOD2 was the core protein of this network (Figure 1). The microRNA interaction network of GPXs revealed 16 microRNAs for GPX1, 12 microRNAs for GPX6, and 2 microRNAs each for GPX2 and GPX4 (Figure 2). Quercetin, acetaminophen and aflatoxin B1 play important roles in the interaction between GPXs and environmental factors. Meta-analysis showed that GPX2, GPX3, GPX6 expressions showed a decreasing trend in the OA group compared with the control group (P<0.05). However, meta-analysis showed that the GPX1 and GPX4 expressions were not statistically different from those in the control group (P>0.05) (Figure 3). Conclusions: GPXs may play an important role in oxidative stress response and anti-oxidation in OA. Glutathione metabolism disorder and thyroid hormone synthesis abnormalities may increase the risk of OA. SOD2 may affect the development and progression of OA. The interaction between GPXs and MicroRNA or environmental factors provide some insights into the molecular mechanisms underlying OA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer.

MicroRNA (miRNA)–gene interactions are well-recognized as involved in the progression of almost all cancer types including prostate cancer, which is one of the most common cancers in men. This study explored the significantly dysregulated genes and miRNAs and elucidated the potential miRNA–gene regulatory network in prostate cancer. Integrative analysis of prostate cancer and normal prostate transcriptomic data in The Cancer Genome Atlas dataset was conducted using both differential expression analysis and weighted correlation network analysis (WGCNA). Thirteen genes (RRM2, ORC6, CDC45, CDKN2A, E2F2, MYBL2, CCNB2, PLK1, FOXM1, CDC25C, PKMYT1, GTSE1, and CDC20) were potentially correlated with prostate cancer based on functional enrichment analyses. MiRNAs targeting these genes were predicted and eight miRNAs were intersections between those miRNAs and the hub miRNAs obtained from miRNA WGCNA analysis. Three genes (E2F2, RRM2, and PKMYT1) and four miRNAs (hsa-mir-17-5p, hsa-mir-20a-5p, hsa-mir-92a-3p, and hsa-mir-93-5p) were key factors according to the interaction network. RRM2 and PKMYT1 were significantly related to survival. These findings partially elucidated the dysregulation of gene expressions in prostate cancer. Efficient manipulations of the miRNA–gene interactions in prostate cancer may be exploited as promising therapeutics.

MicroRNA and mRNA interactions coordinate the immune response in non-lethal heat stressed Litopenaeus vannamei against AHPND-causing Vibrio parahaemolyticus

While Vibrio parahaemolyticus (VPAHPND) has been identified as the cause of early mortality syndrome (EMS) or acute hepatopancreatic necrosis disease (AHPND) in shrimp, mechanisms of host response remain unknown. Understanding these processes is important to improve farming practices because this understanding will help to develop methods to enhance shrimp immunity. Pre-treatment of shrimp with 5-minute chronic non-lethal heat stress (NLHS) for 7 days was found to significantly increase Litopenaeus vannamei survival against VPAHPND infection. To elucidate the mechanism involved, mRNA and miRNA expression profiles from the hemocyte of L. vannamei challenged with VPAHPND after NLHS with corresponding control conditions were determined by RNA-Seq. A total of 2,664 mRNAs and 41 miRNAs were differentially expressed after the NLHS treatment and VPAHPND challenge. A miRNA-mRNA regulatory network of differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) was subsequently constructed and the interactions of DEMs in regulating the NLHS-induced immune-related pathways were identified. Transcriptomic data revealed that miRNA and mRNA interactions contribute to the modulation of NLHS-induced immune responses, such as the prophenoloxidase-activating system, hemocyte homeostasis, and antimicrobial peptide production, and these responses enhance VPAHPND resistance in L. vannamei.

Silencing lncRNA AGAP2-AS1 Upregulates miR-195-5p to Repress Migration and Invasion of EC Cells via the Decrease of FOSL1 Expression

The interaction of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs has been implicated in various types of cancers, including esophageal cancer (EC). The current study aimed to investigate the role of AGAP2-AS1/miR-195-5p/Fos-like antigen-1 (FOSL1) in EC progression. The expression of AGAP2-AS1, miR-195-5p, and FOSL1 in tumor tissues isolated from EC patients and EC cell lines was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), the results of which illustrated that AGAP2-AS1 and FOSL1 were increased while miR-195-5p was reduced in EC. Next, the ectopic expression, knockdown, and reporter assay experiments were all employed to elucidate the mechanism of AGAP2-AS1/miR-195-5p/FOSL1 in the processes of EC cell proliferation, cell cycle, apoptosis, invasion, and migration as well as tumor growth. Knockdown of AGAP2-AS1 or overexpression of miR-195-5p reduced EC cell proliferation, migration, and invasion, blocked cell cycle entry, and elevated apoptosis. FOSL1 was found to be specifically targeted by miR-195-5p. AGAP2-AS1 was observed to upregulate FOSL1 by binding to miR-195-5p. Silencing of AGAP2-AS1 was observed to restrain the development of EC both in vitro and in vivo through upregulating miR-195-5p and downregulating FOSL1. Taken together, AGAP2-AS1 knockdown exercises suppressive effects on the development of EC through miR-195-5p-dependent downregulation of FOSL1. Therefore, targeting AGAP2-AS1 could be a future direction to develop a novel molecule-targeted therapeutic strategy for EC.