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Systems biomarkers for papillary thyroid cancer prognosis and treatment through multi-omics networks.
Gulfidan, G, Soylu, M, Demirel, D, Erdonmez, HBC, Beklen, H, Ozbek Sarica, P, Arga, KY, Turanli, B
Archives of biochemistry and biophysics. 2022;:109085
Abstract
The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development of effective diagnostic and treatment strategies. Despite particular findings in this regard, a holistic analysis encompassing molecular data from different biological levels has been lacking. In the present study, a meta-analysis of four transcriptome datasets was performed to identify gene expression signatures in PTC, and reporter molecules were determined by mapping gene expression data onto three major cellular networks, i.e., transcriptional regulatory, protein-protein interaction, and metabolic networks. We identified 282 common genes that were differentially expressed in all PTC datasets. In addition, six proteins (FYN, JUN, LYN, PML, SIN3A, and RARA), two Erb-B2 receptors (ERBB2 and ERBB4), two cyclin-dependent receptors (CDK1 and CDK2), and three histone deacetylase receptors (HDAC1, HDAC2, and HDAC3) came into prominence as proteomic signatures in addition to several metabolites including lactaldehyde and proline at the metabolome level. Significant associations with calcium and MAPK signaling pathways and transcriptional and post-transcriptional activities of 12 TFs and 110 miRNAs were also observed at the regulatory level. Among them, six miRNAs (miR-30b-3p, miR-15b-5p, let-7a-5p, miR-130b-3p, miR-424-5p, and miR-193b-3p) were associated with PTC for the first time in the literature, and the expression levels of miR-30b-3p, miR-15b-5p, and let-7a-5p were found to be predictive of disease prognosis. Drug repositioning and molecular docking simulations revealed that 5 drugs (prochlorperazine, meclizine, rottlerin, cephaeline, and tretinoin) may be useful in the treatment of PTC. Consequently, we report here biomolecule candidates that may be considered as prognostic biomarkers or potential therapeutic targets for further experimental and clinical trials for PTC.
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MicroRNA-223 in gastrointestinal cancers: A systematic review and diagnostic meta-analysis.
Aalami, AH, Abdeahad, H, Mesgari, M, Sahebkar, A
European journal of clinical investigation. 2021;(2):e13448
Abstract
BACKGROUND Several studies have been conducted on the diagnostic role of miR-223 in cancers related to the digestive system. However, the diagnostic role of this microRNA in gastrointestinal (GI) cancers has not been fully elucidated. This meta-analysis aimed to accurately assess the diagnostic role of circulating miR-223 in GI cancers. METHODS A literature search was performed in PubMed/Medline, Science Direct, Web of Science, Google Scholar, Embase and Scopus, up to 1st May 2020 databases. Twelve studies were eligible and included in the analysis. Meta-Disc software was used to calculate the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the curve (AUC) and the summary receiver operating characteristic (SROC) based on true positive, true negative, false negative and false positive for each gastrointestinal cancer separately and in total. RESULTS Twelve case-control studies were included with 1859 participants (1080 cases and 779 controls). Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.77 (95% CI: 0.74-0.79), 0.75 (95% CI: 0.72-0.78), 3.04 (95% CI: 2.20-4.18), 0.31 (95% CI: 0.22-0.42) and 10.77 (95% CI: 5.96-19.47), respectively. AUC was 0.83, suggesting a high-grade diagnostic precision of miR-223 in gastrointestinal cancers. Besides, subgroup analyses were performed to assess the diagnostic power of miR-223 based on the type of gastrointestinal cancer, sample type and country via calculating pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. CONCLUSION Our meta-analysis showed the value of circulating miR-223 levels in the early diagnosis of diverse digestive system carcinomas.
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Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage.
Carotenuto, P, Amato, F, Lampis, A, Rae, C, Hedayat, S, Previdi, MC, Zito, D, Raj, M, Guzzardo, V, Sclafani, F, et al
Nature communications. 2021;(1):6738
Abstract
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.
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The Polymorphism of miR-146a (rs2910164) and Breast Cancer Risk: A Meta-Analysis of 17 Studies.
Moossavi, M, Shojaee, M, Musavi, M, Ibrahimi, R, Ibrahimi, M, Khorasani, M
MicroRNA (Shariqah, United Arab Emirates). 2020;(4):310-320
Abstract
BACKGROUND Single-Nucleotide Polymorphisms (SNPs) in genes responsible for coding microRNAs (miRNAs) are shown to be crucial in progression of Breast Cancer (BC). OBJECTIVE The purpose of this meta-analysis is to obtain more definitive and reliable results due to the ambiguity and inconsistency of the previous findings in this regard. This study aimed at clarifying the association of mir14a polymorphisms with breast cancer. METHODS We searched PubMed, EMBASE, Web of Science and Google Scholar databases for papers published before August 10, 2019. Afterward, genotypes' distribution, genotyping methods and ethnicity groups were extracted and Overall analyses were conducted. A total number of seventeen researches on 7676 subjects and 7476 controls were found to meet our criteria in this meta-analysis. RESULTS Our observations confirmed the increased risk in breast cancer with rs 2910164 polymorphism in three genetic models: allele contrast fixed genetic model, Recessive fixed genetic model and CC vs. GG genetic model (P value 0.0109, 0.0404 and 0.0019, respectively). CONCLUSION The rs2910164 polymorphism is associated with increased breast cancer risk. We suggest that more multicenter studies with larger samples investigate this matter to further clarify the association and verify our findings.
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Molecular mechanism and role of microRNA-93 in human cancers: A study based on bioinformatics analysis, meta-analysis, and quantitative polymerase chain reaction validation.
Gao, Y, Deng, K, Liu, X, Dai, M, Chen, X, Chen, J, Chen, J, Huang, Y, Dai, S, Chen, J
Journal of cellular biochemistry. 2019;(4):6370-6383
Abstract
INTRODUCTION Currently, studies have shown that microRNA-93 (miR-93) can be an oncogene or a tumor suppressor in different kinds of cancers. The role of miR-93 in human cancers is inconsistent and the underlying mechanism on the aberrant expression of miR-93 is complicated. METHODS We first conducted gene enrichment analysis to give insight into the prospective mechanism of miR-93. Second, we performed a meta-analysis to evaluate the clinical value of miR-93. Finally, a validation test based on quantitative polymerase chain reaction (qPCR) was performed to further investigate the role of miR-93 in pan-cancer. RESULTS Gene Ontology (GO) enrichment analysis results showed that the target genes of miR-93 were closely related to transcription, and MAPK1, RBBP7 and Smad7 became the hub genes. In the diagnostic meta-analysis, the overall sensitivity, specificity, and area under the curve were 0.76 (0.64-0.85), 0.82 (0.64-0.92), and 0.85 (0.82-0.88), respectively, which suggested that miR-93 had excellent performance on the diagnosis for human cancers. In the prognostic meta-analysis, dysregulated miR-93 was found to be associated with poor OS in cancer patients. In the qPCR validation test, the serum levels of miR-93 were upregulated in breast cancer, breast hyperplasia, lung cancer, chronic obstructive pulmonary disease, nasopharyngeal cancer, hepatocellular cancer, gastric ulcer, endometrial cancer, esophageal cancer, laryngeal cancer, and prostate cancer compared with healthy controls. CONCLUSIONS miR-93 could act as an effective diagnostic and prognostic factor for cancer patients. Its clinical value for cancer early diagnosis and survival prediction is promising.
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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.
Kawamura, Y, Nakaoka, H, Nakayama, A, Okada, Y, Yamamoto, K, Higashino, T, Sakiyama, M, Shimizu, T, Ooyama, H, Ooyama, K, et al
Annals of the rheumatic diseases. 2019;(10):1430-1437
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Abstract
OBJECTIVE The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.
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Replication of GWAS identified miR-137 and its target gene polymorphisms in Schizophrenia of South Indian population and meta-analysis with Psychiatric Genomics Consortium.
Sudesh, R, Thalamuthu, A, John, S, Thara, R, Mowry, B, Munirajan, AK
Schizophrenia research. 2018;:189-194
Abstract
Schizophrenia is a complex psychiatric disorder involving multiple genes each contributing a small risk. Genome-wide association studies (GWASs) have identified hundreds of risk loci for schizophrenia including miR-137, a miRNA shown to be involved in neuronal development. Several genes regulated by miR-137 were also reported as top risk genes associated with schizophrenia and has been hypothesised that the dysregulation of miR-137 and its target could be involved in the aetiology of schizophrenia. Here, we replicated the four European GWAS hits, miR-137-rs1625579 and three of its validated target gene loci SNPs (ZNF804a-rs1344706, CACNA1C-rs4765905 and TCF4-rs9960767) by genotyping in 2074 samples (schizophrenia cases-1005; controls-1069) from South Indian Population. In this study, only the CACNA1C rs4765905 showed a significant association (OR=1.24, p=0.006). Three SNPs (rs1625579, rs1344706 and rs4765905) showed a consistent direction of effect with previous studies and the polygenic risk score constructed using the weighted sum of these three SNPs showed a significant association with Schizophrenia in this population (OR=3.78, p=0.005). Further, we carried out meta-analysis combining our results with the Psychiatric Genomics Consortium (PGC2) data and observed a considerable increase in GWAS significance.
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A Meta-Analysis of the Association between Microrna-196A2 and Risk of Ischemic Stroke and Coronary Artery Disease in Asian Population.
Wang, Y, Li, Q, Mambiya, M, Zhang, K, Yang, L, Zhang, Q, Liu, S, Liu, M, Yin, J, Liu, W
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018;(11):3008-3019
Abstract
OBJECT Single nucleotide polymorphisms (SNPs) of small non-coding RNAs (sncRNAs) that affect the sncRNA function and target gene expression to mediate the risk of certain diseases. The association between the miR-196a2 rs11614913 and ischemic stroke (IS) and coronary artery disease (CAD) is still conflicting and inconclusive. This meta-analysis aimed at analysing studies which have been done so far to get a more precise assessment of the association between the mutation and these two diseases. METHODS Electronic databases dated up to April 2018 were searched, retrieved and used. Revman 5.2 software and STATA version 12.0 were used for statistical analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to identify any potential associations. Heterogeneity, publication bias and sensitivity analysis were conducted to measure the robustness of our findings. RESULTS The overall meta-analysis results showed that miR-196a2 rs11614913 T > C polymorphism was significantly associated with CAD risk in certain genetic models, as well as in subgroup analysis (CC versus TT, OR = .43, 95%CI = .39-.47, P < .00001). However, no significant association was detected between the miR-196a2 rs11614913 T > C and IS risk in all genetic models. CONCLUSIONS Our study suggests that miR-196a2 rs11614913 T > C may contribute to CAD susceptibility but further well-designed studies with larger sample size and comprehensive data are needed to confirm our findings and provide a profound conclusion.
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MiRNAs as biomarkers of myocardial infarction: a meta-analysis.
Cheng, C, Wang, Q, You, W, Chen, M, Xia, J
PloS one. 2014;(2):e88566
Abstract
BACKGROUND Recent studies have demonstrated that acute myocardial infarction induces a distinctive miRNA signature, suggesting that miRNAs may serve as diagnostic markers. Although many studies have investigated the use of miRNAs in the detection of cardiac injury, some had small sample sizes (<100 patients) or reported different results for the same miRNA. Here, the role of circulating miRNAs for use as biomarkers of myocardial infarction is summarized and analyzed. METHODS AND RESULTS Medline, SCI, Embase, and Cochrane databases were searched up to January 2013 for studies that evaluated associations between miRNAs and myocardial infarction. Relevant publications were identified by searching for combinations of "myocardial infarction," "miRNAs," and their synonyms. Methodological quality was scored using a standardized list of criteria, and diagnostic performance was assessed using estimates of test sensitivity and specificity. These values were summarized using summary receiver-operating characteristic curves. Nineteen studies met the inclusion criteria: 15 studies reported sensitivity, specificity, and AUC, but 4 studies did not. Total miRNAs: sensitivity: 0.78 (95%CI: 0.77-0.80; P = 0.0000); specificity: 0.82 (95%CI: 0.80-0.83; P = 0.0000). miR-499: sensitivity: 0.88 (95%CI:0.86-0.90; P = 0.0000); specificity: 0.87 (95%CI:0.84-0.90; P = 0.0000). miR-1: sensitivity: 0.63 (95%CI:0.59-0.66; P = 0.0000); specificity: 0.76 (95%CI:0.71-0.80; P = 0.0000). miR-133a: sensitivity: 0.89 (95%CI:0.83-0.94; P = 0.0047); specificity: 0.87 (95%CI:0.79-0.92; P = 0.0262). miR-208b: sensitivity: 0.78 (95%CI:0.76-0.81; P = 0.0581); specificity: 0.88 (95%CI:0.84-0.91; P = 0.0000). The correlation between miRNAs and other diagnostic biomarkers of myocardial infarction was obvious. CONCLUSION MiRNAs, especially miR-499 and miR-133a, may be suitable for use as diagnostic biomarkers of myocardial infarction.
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Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.
Richardson, K, Nettleton, JA, Rotllan, N, Tanaka, T, Smith, CE, Lai, CQ, Parnell, LD, Lee, YC, Lahti, J, Lemaitre, RN, et al
American journal of human genetics. 2013;(1):5-14
Abstract
Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.