Family Of Small RNAs Research Articles

Meta-analysis of Hsa-mir-499 polymorphism (rs3746444) for cancer risk: evidence from 31 case-control studies

BackgroundMicroRNAs (miRNAs) are a family of endogenous, small and non-coding RNAs that regulate gene expression negatively at the post-transcriptional level by suppressing translation or degrading target mRNAs, and are involved in diverse biological and pathological processes. Single nucleotide polymorphisms (SNPs) which are located in the miRNA-coding genes may participate in the process of development and diseases by altering the expression of mature miRNA. Recent studies investigating the association between hsa-mir-499 polymorphism (rs3746444) and cancer risk have yielded conflicting results.MethodsIn this meta-analysis, we conducted a search of case–control studies on the associations of SNP rs3746444 with susceptibility to cancer in electronic databases. A total of 31 studies involving 12799 cases and 14507 controls were retrieved and the strength of the association was estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in controls. Subgroup analyses were done by racial descent and cancer type. Publication bias of literatures was evaluated by visual inspection of funnel plots and the linear regression asymmetry test by Egger et al. Sensitivity analysis was conducted by excluding one study at a time to examine the influence of individual data set on the pooled ORs.ResultsOverall, significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models. In the stratified analyses, increased risks were found in Asians, but not in Caucasians in all comparison models tested. Moreover, significant association with an increased risk was found in Chinese population. Also, much higher significant association with increased cancer risks were found in Iranian population. In different cancer types, a decreased risk was found in esophageal cancer.ConclusionOur meta-analysis suggested that hsa-mir-499 rs3746444 T > C polymorphism is associated with the risk of cancer in Asians, mainly in Iranian and Chinese population. However, rs3746444 T > C polymorphism is negatively associated with the risk of esophageal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0126-1) contains supplementary material, which is available to authorized users.

Abstract 13269: Reduced Expression of scaRNAs Disrupts Spliceosome Function and Heart Development in Zebrafish and Infants with Tetralogy of Fallot

The splicing of messenger RNA plays a fundamental role in regulating vertebrate development and differentiation. Although it is well established that alternative splicing (AS) plays an important role in regulating mammalian heart development, a clear link between misregulated splicing and congenital heart defects has not been shown. We recently reported that more than 50% of genes associated with heart development had significant changes in splice forms in the right ventricle of infants with tetralogy of Fallot (TOF; 14M/7F; all less than 1 yr old). Moreover, there was a significant decrease (30-50%, p<0.05) in the level of 12 scaRNAs. scaRNAs are members of the large family of noncoding small RNAs that are responsible for biochemical modification of specific nucleotides in spliceosomal and ribosomal RNAs. These 12 scaRNAs target two spliceosomal RNAs, U2 and U6. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several key genes regulating human heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and 2). In addition, using available RNA-Seq data, we provide evidence that during zebrafish development, there are dynamic oscillations in scaRNAs and splice isoforms of genes that regulate heart development. We knocked down the expression of two scaRNAs; ACA35 (Scarna1) and U94 (Snord94), in zebrafish and saw a corresponding disruption of heart development. Importantly, there was an accompanying alteration in the ratios of splice isoforms of key cardiac regulatory genes. Based on these combined results, we propose that scaRNAs directly regulate the proficiency of the spliceosome by controlling spliceosomal RNA maturation. This in turn contributes to splice isoform dynamic equilibrium and ultimately heart development. These results are consistent with a failure of normal temporal and spatial splicing patterns during early embryonic development, leading to a breakdown in communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for understanding congenital cardiac malformations.

Characterization of Sus scrofa small non-coding RNAs present in both female and male gonads.

Small non-coding RNAs (sncRNAs) are indispensable for proper germ cell development, emphasizing the need for greater elucidation of the mechanisms of germline development and regulation of this process by sncRNAs. We used deep sequencing to characterize three families of small non-coding RNAs (piRNAs, miRNAs, and tRFs) present in Sus scrofa gonads and focused on the small RNA fraction present in both male and female gonads. Although similar numbers of reads were obtained from both types of gonads, the number of unique RNA sequences in the ovaries was several times lower. Of the sequences detected in the testes, 2.6% of piRNAs, 9% of miRNAs, and 10% of tRFs were also present in the ovaries. Notably, the majority of the shared piRNAs mapped to ribosomal RNAs and were derived from clustered loci. In addition, the most abundant miRNAs present in the ovaries and testes are conserved and are involved in many biological processes such as the regulation of homeobox genes, the control of cell proliferation, and carcinogenesis. Unexpectedly, we detected a novel sncRNA type, the tRFs, which are 30–36-nt RNA fragments derived from tRNA molecules, in gonads. Analysis of S. scrofa piRNAs show that testes specific piRNAs are biased for 5′ uracil but both testes and ovaries specific piRNAs are not biased for adenine at the 10th nucleotide position. These observations indicate that adult porcine piRNAs are predominantly produced by a primary processing pathway or other mechanisms and secondary piRNAs generated by ping-pong mechanism are absent.

Applied RNAi: from fundamental research to therapeutic applications

Applied RNAi: from fundamental research to therapeutic applications

Attacking c-Myc: targeted and combined therapies for cancer.

The onset of cancer is a complex process that is driven by the accumulation of multiple genetic mutations. However, the fact that inhibition of a single oncogene can impair the proliferation and survival of cancer cells due to their "oncogene addiction" provides implications for the so-called "molecular targeted therapy" in cancer treatment. The oncogenic transcription factor c-Myc is overexpressed in many types of cancers, and as a typical oncogene to which many cancers are addicted, c-Myc is necessary for the rapid proliferation of cancer cells. Strategies aimed at targeting c-Myc, including interfering with c-Myc synthesis, stability and transcriptional activity, have emerged as effective cancer treatments. We have recently shown that a natural agent, oridonin, promotes the Fbw7-mediated proteasomal degradation of c-Myc, leading to subsequent cell growth inhibition and apoptosis and demonstrating a new c-Myc-targeting strategy. Despite the effectiveness of molecular targeting in cancer treatment, failure to achieve long-lasting efficacy with a single agent is observed because cancer cells can recover from oncogene addiction as a result of their genomic instability and heterogeneity. Combined cancer therapies were therefore developed and showed better efficacies than single-agent therapy in cancer cell lines and mouse models. Combined therapy based on c-Myc targeting can be achieved through various strategies. Agents that also target c-Myc but use different mechanisms, or agents that act on other genes in the c-Myc pathway, can be selected for combination. In addition, the targeting of genes involved in different cellular processes in other pathways might also be a successful strategy. Regardless of the therapy adopted, it is important to first determine the molecular mechanisms underlying the agents to inform the therapy design. Among the various targets of therapeutic agents is a family of noncoding small RNAs, called microRNAs, that have been implicated in the anti-cancer activity of many therapeutic agents. c-Myc, as a transcription factor, regulates the expression of many microRNAs and is in turn regulated by microRNAs. Combining c-Myc-targeting agents with those that target microRNAs might provide a novel approach for cancer therapy.

Exploring microRNA-like small RNAs in the filamentous fungus Fusarium oxysporum.

RNA silencing such as quelling and meiotic silencing by unpaired DNA (MSUD) and several other classes of special small RNAs have been discovered in filamentous fungi recently. More than four different mechanisms of microRNA-like RNAs (milRNAs) production have been illustrated in the model fungus Neurospora crassa including a dicer-independent pathway. To date, very little work focusing on small RNAs in fungi has been reported and no universal or particular characteristic of milRNAs were defined clearly. In this study, small RNA and degradome libraries were constructed and subsequently deep sequenced for investigating milRNAs and their potential cleavage targets on the genome level in the filamentous fungus F. oxysporum f. sp. lycopersici. As a result, there is no intersection of conserved miRNAs found by BLASTing against the miRBase. Further analysis showed that the small RNA population of F. oxysporum shared many common features with the small RNAs from N. crassa and other fungi. According to the known standards of miRNA prediction in plants and animals, milRNA candidates from 8 families (comprising 19 members) were screened out and identified. However, none of them could trigger target cleavage based on the degradome data. Moreover, most major signals of cleavage in transcripts could not match appropriate complementary small RNAs, suggesting that other predominant modes for milRNA-mediated gene regulation could exist in F. oxysporum. In addition, the PAREsnip program was utilized for comprehensive analysis and 3 families of small RNAs leading to transcript cleavage were experimentally validated. Altogether, our findings provided valuable information and important hints for better understanding the functions of the small RNAs and milRNAs in the fungal kingdom.

Host MicroRNA Regulation of Human Cytomegalovirus Immediate Early Protein Translation Promotes Viral Latency

Reactivation of human cytomegalovirus (HCMV) is a significant cause of disease and death in immunocompromised patients, underscoring the need to understand how latency is controlled. Here we demonstrate that HCMV has evolved to utilize cellular microRNAs (miRNAs) in cells that promote latency to regulate expression of a viral protein critical for viral reactivation. Our data reveal that hsa-miR-200 miRNA family members target the UL122 (immediate early protein 2) 3' untranslated region, resulting in repression of this viral protein. Utilizing recombinant viruses that mutate the miRNA-binding site compared to the sequence of the wild-type virus results in lytic rather than latent infections in ex vivo infections of primary CD34+ cells. Cells permissive for lytic replication demonstrate low levels of these miRNAs. We propose that cellular miRNA regulation of HCMV is critical for maintenance of viral latency. Human cytomegalovirus (HCMV) is a herpesvirus that infects a majority of the population. Once acquired, individuals harbor the virus for life, where the virus remains, for the most part, in a quiet or latent state. Under weakened immune conditions, the virus can reactivate, which can cause severe disease and often death. We have found that members of a family of small RNAs, termed microRNAs, encoded by human myeloid progenitor cells are capable of repressing a key viral protein, thus enabling the virus to ensure a quiet/latent state. As these progenitor cells mature further down the myeloid lineage toward cells that support active viral replication, the levels of these microRNAs decrease. Together, our data suggest that host cell microRNA regulation of HCMV is important for the quiet/latent state of this pathogen.

Small RNA regulators in bacteria: powerful tools for metabolic engineering and synthetic biology

Small RNAs, a large class of ancient posttranscriptional regulators, have recently attracted considerable attention. A plethora of small RNAs has been identified and characterized, many of which belong to the major small noncoding RNA (sRNA) or riboswitch families. It has become increasingly clear that most small RNAs play critical regulatory roles in many processes and are, therefore, considered to be powerful tools for metabolic engineering and synthetic biology. In this review, we describe recent achievements in the identification, characterization, and application of small RNAs. We give particular attention to advances in the design and synthesis of novel sRNAs and riboswitches for metabolic engineering. In addition, a novel strategy for hierarchical control of global metabolic pathways is proposed.

MicroRNA-128 regulates the differentiation of rat bone mesenchymal stem cells into neuron-like cells by Wnt signaling

Bone marrow mesenchymal stem cells (BMSCs) are a source of multipotent stem cells ideally suited for various cell-based therapies. BMSCs can differentiate into neuron-like cells under the appropriate conditions. MicroRNAs are members of a family of noncoding small RNAs that regulate gene expression at the posttranscriptional level, either by inhibiting mRNA translation or by promoting mRNA degradation. MicroRNAs play an important role in the differentiation of BMSCs into neurons. MicroRNA-128, a brain-enriched microRNA, was recently found to be necessary in the neural differentiation of BMSCs. Studies have shown that Wnt signaling pathway is involved in regulating MSC differentiation. Our goal here was to investigate whether microRNA-128 can regulate the differentiation of BMSCs through modulation of Wnt3a, a key component of the Wnt signaling pathway. By means of dual-luciferase reporter assay, we describe for the first time that by binding to a specific site in the 3'-UTR of Wnt3a in BMSCs, downregulated microRNA-128 may lead to the neural differentiation of mesenchymal stem cells. Transfection of microRNA-128 mimic decreased the nerve cell markers and Wnt3a expression levels. On the other hand, the inhibition of microRNA-128 significantly elevated the nerve cell markers as well as the Wnt3a expression levels. This suggests that microRNA-128 acts as an endogenous attenuator of BMSCs differentiation into neurons.

Extracellular vesicles shed by Trypanosoma cruzi are linked to small RNA pathways, life cycle regulation, and susceptibility to infection of mammalian cells

The protozoan parasite Trypanosoma cruzi has a complex life cycle characterized by intracellular and extracellular forms alternating between invertebrate and mammals. To cope with these changing environments, T. cruzi undergoes rapid changes in gene expression, which are achieved essentially at the posttranscriptional level. At present, expanding families of small RNAs are recognized as key players in novel forms of posttranscriptional gene regulation in most eukaryotes. However, T. cruzi lacks canonical small RNA pathways. In a recent work, we reported the presence of alternate small RNA pathways in T. cruzi mainly represented by a homogeneous population of tRNA-derived small RNAs (tsRNAs). In T. cruzi epimastigotes submitted to nutrient starvation, tsRNAs colocalized with an argonaute protein distinctive of trypanosomatids (TcPIWI-tryp) and were recruited to particular cytoplasmic granules. Using epifluorescence and electronic microscopy, we observed that tsRNAs and the TcPIWI-tryp protein were recruited mainly to reservosomes and other intracellular vesicles including endosome-like vesicles and vesicular structures resembling the Golgi complex. These data suggested that, in T. cruzi, tsRNA biogenesis is probably part of endocytic/exocytic routes. We also demonstrated that epimastigotes submitted to nutrient starvation shed high levels of vesicles to the extracellular medium, which carry small tRNAs and TcPIWI-tryp proteins as cargo. At least a fraction of extracellular vesicle cargo was transferred between parasites and to mammalian susceptible cells. Our data afford experimental evidence, indicating that extracellular vesicles shed by T. cruzi promote not only life cycle transition of epimastigotes to trypomastigote forms but also infection susceptibility of mammalian cells.

How Do Viruses Avoid Inhibition by Endogenous Cellular MicroRNAs?

MicroRNAs (miRNAs) are an extensive family of small regulatory RNAs that function by binding to complementary mRNAs, primarily in the 3′ untranslated region (3′UTRs), and then inhibiting their expression by reducing mRNA translation and/or stability [1]. MiRNAs are initially transcribed as long pri-miRNAs, which are sequentially processed by the RNase III enzymes Drosha, in the nucleus, and Dicer, in the cytoplasm, to generate the mature, ∼22-nt miRNA [2]. This is then loaded into the RNA Induced Silencing Complex (RISC), which consists minimally of one of the four mammalian Argonaut proteins, Ago1 to Ago4, as well as a member of the GW182 protein family. MiRNAs function as guide RNAs to target RISC to complementary mRNA sequences on specific mRNA 3′UTRs. Analysis has revealed that complementarity to nucleotides 2 through 8 of the miRNA, the so-called seed region, is particularly important for effective RISC recruitment [1], although non-canonical sites, with incomplete seed complementarity, have also been reported [3]. Importantly, RISC recruitment to target sites that are occluded by RNA secondary structure or bound proteins is very inefficient [4].

SnoStrip: a snoRNA annotation pipeline

Although small nucleolar RNAs form an important class of non-coding RNAs, no comprehensive annotation efforts have been undertaken, presumably because the task is complicated by both the large number of distinct small nucleolar RNA families and their relatively rapid pace of sequence evolution. With snoStrip we present an automatic annotation pipeline developed specifically for comparative genomics of small nucleolar RNAs. It makes use of sequence conservation, canonical box motifs as well as secondary structure and predicts putative targets. The snoStrip web service and the download version is available at http://snostrip.bioinf.uni-leipzig.de/

Current State of Marek's Disease Virus MicroRNA Research

MicroRNA (miRNA) is a major family of small RNAs that posttranscriptionally regulate gene expression. Small RNA profiling studies have revealed that some viruses, particularly large DNA viruses, such as Marek's disease virus (MDV), encode their own set of miRNAs. There are currently 406 viral miRNAs in miRBase, of which 392 are encoded by herpesviruses. To date, 26 MDV-1 miRNAs, 36 MDV-2 miRNAs, and 28 herpesvirus of turkeys miRNAs have been identified. Interestingly, herpesvirus miRNAs appear to have spatial conservation, located in clusters within repeat regions, but lack sequence conservation. Two clusters of MDV-1 miRNA have been identified, one located near the MEQ gene and one within the latency-associated transcript (LAT). miRNA profiling studies have shown that MDV miRNA are differentially expressed between strains and stages of infection. For example, mdv1-miR-M4 and mdv1-miR-M2-3p are three- and sixfold higher, expressed, respectively, in vv+ strains compared to vv strains. A recent study found that deletion or seed region mutation of mdv1-miR-M4 reduces viral oncogenicity, suggesting a link between mdv1-mir-M4 and lymphoma development in MDV-infected birds. Taken together, current research suggests that viral miRNAs are a key component of MDV pathogenesis.

Small RNAs derived from structural non-coding RNAs

It has been shown in small RNA sequencing-based studies that some small RNA fragments are specifically processed from known structural non-coding RNAs, either through Dicer-dependent or Dicer-independent pathways. Although these small RNAs are often less abundant compared to microRNAs in normal mammalian tissues, they are always present in all sequenced libraries. In this paper, we use the ncPRO-seq pipeline, to describe different profiles of these small RNA fragments, and to discuss their potential processing pathways and functions. To assess whether more small RNA fragments can be detected in small RNA sequencing datasets, we decided to focus on small nuclear RNAs, abbreviated as snRNAs, which are associated with Sm ribonucleoproteins to form functional RNA–protein complexes. Here, we describe a group of small RNA fragments derived from snRNAs, which are typically highly enriched in regions bound by Sm proteins. Based on this, we propose the existence of a potential novel small RNA family associated with Sm proteins.

The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems

CRISPR-Cas is a rapidly evolving RNA-mediated adaptive immune system that protects bacteria and archaea against mobile genetic elements. The system relies on the activity of short mature CRISPR RNAs (crRNAs) that guide Cas protein(s) to silence invading nucleic acids. A set of CRISPR-Cas, type II, requires a trans-activating small RNA, tracrRNA, for maturation of precursor crRNA (pre-crRNA) and interference with invading sequences. Following co-processing of tracrRNA and pre-crRNA by RNase III, dual-tracrRNA:crRNA guides the CRISPR-associated endonuclease Cas9 (Csn1) to cleave site-specifically cognate target DNA. Here, we screened available genomes for type II CRISPR-Cas loci by searching for Cas9 orthologs. We analyzed 75 representative loci, and for 56 of them we predicted novel tracrRNA orthologs. Our analysis demonstrates a high diversity in cas operon architecture and position of the tracrRNA gene within CRISPR-Cas loci. We observed a correlation between locus heterogeneity and Cas9 sequence diversity, resulting in the identification of various type II CRISPR-Cas subgroups. We validated the expression and co-processing of predicted tracrRNAs and pre-crRNAs by RNA sequencing in five bacterial species. This study reveals tracrRNA family as an atypical, small RNA family with no obvious conservation of structure, sequence or localization within type II CRISPR-Cas loci. The tracrRNA family is however characterized by the conserved feature to base-pair to cognate pre-crRNA repeats, an essential function for crRNA maturation and DNA silencing by dual-RNA:Cas9. The large panel of tracrRNA and Cas9 ortholog sequences should constitute a useful database to improve the design of RNA-programmable Cas9 as genome editing tool.

The Trypanosoma brucei telomerase RNA (TER) homologue binds core proteins of the C/D snoRNA family

Trypanosome protozoan parasites are the causative agents of devastating diseases. Trypanosome telomeres grow in an uncontrolled manner and the variant surface glycoprotein (VSG) genes are located in subtelomeric domains. The gene encoding telomerase reverse transcriptase (TERT) was identified and in this study, we describe the Trypanosoma brucei telomerase RNA (TER). TER RNA is bound by the core proteins of the C/D small nucleolar RNA (snoRNA) family and associates with the methyltransferase-associated protein (MTAP), whose homologue binds to mammalian TER. Silencing of TbTER resulted in telomere shortening. This is the first report of a TER that binds the C/D snoRNA core proteins.

Abstract TP117: MiR-15a/16-1 Cluster Inhibits Angiogenesis In Mouse After Ischemic Stroke

Angiogenesis may occur as a natural defense response against neurological diseases. Accumulating studies have shown that post-ischemic angiogenesis promotes functional recovery after ischemic stroke and is related to longer survival time in ischemic stroke patients. MicroRNAs (miRs) have been documented as a novel family of noncoding small RNAs that negatively modulate protein expression in various organisms. Recent studies have revealed important roles for miRs in regulating angiogenesis. However, the function of miRs in the angiogenic processes after ischemic stroke is unknown. We have previously demonstrated that the miR-15a/16-1 cluster has an anti-survival role in ischemia-induced endothelial cell death. Here we further investigate the role of the miR-15a/16-1 cluster in the regulation of post-ischemic angiogenesis. We have shown that expression of the miR-15a/16-1 cluster is significantly increased in the cerebral vasculature at the penumbral area 7 days after mouse middle cerebral artery occlusion (MCAO). Accordingly, in comparison with the wild-type animals, endothelial cell (EC)-selective miR-15a/16-1 transgenic overexpression leads to reduced cerebral blood vessel formation, increased brain infarction and neurological deficits in mice 7 days post-MCAO. Mechanistically, lentivirus-mediated miR-15a/16-1 gain- or loss-of-function reduces or increases FGFR1 and VEGF mRNA or protein levels in mouse cerebral vascular endothelial cell cultures, respectively. Through the bioinformatics analysis, 3’UTR luciferase reporter assays, and immunoassays, we further found that miR-15a and miR-16-1 bind to the 3’UTR of FGFR1 or VEGF mRNA, and directly inhibit FGFR1 and VEGF activities. Our findings suggest the miR-15a/16-1 cluster can suppress post-ischemic cerebral angiogenesis through direct inhibition of endothelial FGFR1 and VEGF activities. Elucidating the molecular mechanism of miR-15a/16-1 cluster-mediated angiogenesis will provide new insights into the understanding of miR function in the post-ischemic neurovascular remodeling and neurological recovery and open a new area with potential promise for further development of neurorestorative therapies after ischemic stroke.

A load of small RNAs in the sperm - how many bits of hereditary information?

Transcriptionally silent sperm contains a variety of RNA fragments of both coding and non-coding transcripts. A recent article by Peng and colleagues reveals several new families of small RNAs enriched in sperm, which are derived from the same locus as tRNAs. The finding of these short fragments of tRNA in the sperm raises once again the question of the possible function(s) of such a miniaturized form of information carried by the spermatozoon.

SmRNAome profiling to identify conserved and novel microRNAs in Stevia rebaudiana Bertoni

BackgroundMicroRNAs (miRNAs) constitute a family of small RNA (sRNA) population that regulates the gene expression and plays an important role in plant development, metabolism, signal transduction and stress response. Extensive studies on miRNAs have been performed in different plants such as Arabidopsis thaliana, Oryza sativa etc. and volume of the miRNA database, mirBASE, has been increasing on day to day basis. Stevia rebaudiana Bertoni is an important perennial herb which accumulates high concentrations of diterpene steviol glycosides which contributes to its high indexed sweetening property with no calorific value. Several studies have been carried out for understanding molecular mechanism involved in biosynthesis of these glycosides, however, information about miRNAs has been lacking in S. rebaudiana. Deep sequencing of small RNAs combined with transcriptomic data is a powerful tool for identifying conserved and novel miRNAs irrespective of availability of genome sequence data.ResultsTo identify miRNAs in S. rebaudiana, sRNA library was constructed and sequenced using Illumina genome analyzer II. A total of 30,472,534 reads representing 2,509,190 distinct sequences were obtained from sRNA library. Based on sequence similarity, we identified 100 miRNAs belonging to 34 highly conserved families. Also, we identified 12 novel miRNAs whose precursors were potentially generated from stevia EST and nucleotide sequences. All novel sequences have not been earlier described in other plant species. Putative target genes were predicted for most conserved and novel miRNAs. The predicted targets are mainly mRNA encoding enzymes regulating essential plant metabolic and signaling pathways.ConclusionsThis study led to the identification of 34 highly conserved miRNA families and 12 novel potential miRNAs indicating that specific miRNAs exist in stevia species. Our results provided information on stevia miRNAs and their targets building a foundation for future studies to understand their roles in key stevia traits.

Hsa-miR-499 polymorphism (rs3746444) and cancer risk: A meta-analysis of 17 case–control studies

IntroductionMicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-499 rs3746444 polymorphism and cancer risk, which showed inconclusive results. Methodology/main resultsWe conducted a meta-analysis of 17 studies that included 7842 cancer cases and 8989 case-free controls and assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, hsa-miR-499 rs3746444 polymorphism was associated with higher cancer risk in heterozygote model (AG vs AA, OR=1.15, 95%CI=1.01–1.30, Pheterogeneity<0.001), dominant genetic model (GG/AG vs AA, OR=1.18, 95% CI=1.04–1.33, Pheterogeneity<0.001) and allele contrast (G vs A, OR=1.09, 95% CI=1.01–1.18, Pheterogeneity=0.021). In the stratified analyses, we observed that the GG/AG genotype might modulate breast cancer risk (OR=1.13, 95% CI=1.01–1.26, Pheterogeneity=0.111) comparing with the AA genotype. Moreover, a significantly increased risk was found among Asian populations in heterozygote model (AG vs AA, OR=1.23, 95% CI=1.06–1.43, Pheterogeneity<0.001), homozygote model (GG vs AA, OR=1.22, 95% CI=1.02–1.46, Pheterogeneity=0.319), dominant model (GG/AG vs AA, OR=1.25, 95% CI=1.06–1.39, Pheterogeneity<0.001) and allele contrast (G vs A, OR=1.14, 95% CI=1.04–1.25, Pheterogeneity=0.021). ConclusionsThese findings supported that hsa-miR-499 rs3746444 polymorphism contributes to the susceptibility of cancers.