• Infertility
• MicroRNA
• miRNA
• spermatozoa
• testis.

• CeRNA
• biological functions
• biomarker
• lung cancer

• Biomarkers, Tumor/genetics
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Lung Neoplasms/genetics
• MicroRNAs/genetics
• RNA, Circular/genetics
• RNA, Long Noncoding/genetics
• RNA, Messenger/genetics

Ovarian cancer (OVCA) is one of the most common types of cancer in women worldwide. Recent studies have focused on the presence and effect of somatic mutations in patients with OVCA; however, studies on the roles of mutations located in the untranslated regions (UTR) of genes in OVCA remain limited. In the present study, a frequent somatic mutation in the glyceraldehyde 3-phosphate dehydrogenase (GADPH) 3′UTR was identified using transcriptome sequencing of 120 pairs of OVCA tissue samples. The mutant GAPDH 3′UTR promoted tumor growth and cell motility. Furthermore, the mutation in the GAPDH 3′UTR significantly downregulated the levels of mature miR-125b by creating a new miR-125b binding site. Finally, STAT3 levels were increased in SKOV3 cells stably expressing the mutant GADPH 3′UTR, which is a critical target gene of miR-125b. In conclusion, the present study demonstrated that the mutation located in GAPDH 3′UTR promoted OVCA growth and development by sponging miR-125b and thereby affecting STAT3 expression levels.

Follicle development is characterized by the recruitment, growth, selection, and dominance of follicles, and follicle selection determines the lifetime reproductive performance. However, in birds, the molecular mechanisms underlying follicle selection still remain elusive. This study analyzed genome-wide changes in the mRNA and miRNA expression profiles in both the granulosa and theca layers of geese ovarian follicles before selection (4–6- and 8–10-mm follicles) and after selection (F5). The sequencing results showed that a higher number of both differentially expressed (DE) mRNAs and DE miRNAs were identified between 8–10-mm and F5 follicles compared with those between the 4–6- and 8–10-mm follicles, especially in the granulosa layer. Moreover, a Short Time-series Expression Miner analysis identified a large number of DE mRNAs and DE miRNAs that are associated with follicle selection. The functional enrichment analysis showed that DE genes in the granulosa layer during follicle selection were mainly enriched in five pathways related to junctional adhesion and two pathways associated with lipid metabolism. Additionally, an interaction network was constructed to visualize interactions among protein-coding genes, which identified 53 junctional adhesion- and 15 lipid regulation-related protein-coding genes. Then, a co-expression network between mRNAs and miRNAs in relation to junctional adhesion was also visualized and mainly included acy-miR-2954, acy-miR-218, acy-miR-2970, acy-miR-100, acy-miR-1329, acy-miR-199, acy-miR-425, acy-miR-181, and acy-miR-147. Furthermore, miRNA–mRNA interaction pairs related to lipid regulation were constructed including acy-miR-107, acy-miR-138, acy-miR-130, acy-miR-128, and acy-miR-101 during follicular selection. In summary, these data highlight the key roles of junctional adhesion and lipid metabolism during follicular selection and contribute to a better understanding of the mechanisms underlying follicle selection in birds.

• Anser cygnoides
• follicle selection
• granulosa layer
• junctional adhesion
• lipid metabolism
• theca layer
• transcriptome profiling

• ceRNA network
• integrated network
• ncRNA interaction
• non-coding RNA
• regulatory ncRNA

• Computational Biology
• Gene Regulatory Networks
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Sequence Analysis, RNA

Medulloblastoma is considered one of the most threatening malignant brain tumors with an extremely high mortality rate in children. In the medulloblastoma, there are several genes and mutations found to work in an unregulated manner that works together to push the cells into a cancerous state. With the discovery of non-coding RNAs such as microRNAs (miRNAs), it has been shown that a different layer of gene regulations may be disrupted which would cause cancer. This fact led scientists to put their focus on the role of miRNAs in cancer. A mature miRNA contains a seed sequence which gives the miRNA to identify and attach to the interest mRNA; this attachment may lead degradation of mRNA or suppress of translation of the mRNA. The expression of miRNAs in medulloblastoma shows that some of these non-coding RNAs are overexpressed (OncomiRs) which help cells to proliferate and keep their stemness features. On the other hand, there are other forms of these miRNAs which normally inhibit cell proliferation and promote cell differentiation (tumor suppressor). These are down-regulated during cancer progression. In this systematic review, we attempted to gather several important studies on miRNAs’ role in medulloblastoma tumors and the importance of these non-coding RNAs in the future study of cancer.

• Medulloblastoma
• Neoplasms
• Oncogenes
• Tumor suppressor genes
• microRNAs

MicroRNAs (miRs) are small non‐coding RNAs that regulate gene expression in physiological processes as well as in diseases. Currently miRs are already used to find novel mechanisms involved in diseases and in the future, they might serve as diagnostic markers. To identify miRs that play a role in glomerular diseases urinary miR‐screenings are a frequently used tool. However, miRs that are detected in the urine might simply be filtered from the blood stream and could have been produced anywhere in the body, so they might be completely unrelated to the diseases. We performed a combined miR‐screening in pooled urine samples from patients with different glomerular diseases as well as in cultured human podocytes, human mesangial cells, human glomerular endothelial cells and human tubular cells. The miR‐screening in renal cells was done in untreated conditions and after stimulation with TGF‐β. A merge of the detected regulated miRs led us to identify disease‐specific, cell type‐specific and cell stress‐induced miRs. Most miRs were down‐regulated following the stimulation with TGF‐β in all cell types. Up‐regulation of miRs after TGF‐β was cell type‐specific for most miRs. Furthermore, urinary miRs from patients with different glomerular diseases could be assigned to the different renal cell types. Most miRs were specifically regulated in one disease. Only miR‐155 was up‐regulated in all disease urines compared to control and therefore seems to be rather unspecific. In conclusion, a combined urinary and cell miR‐screening can improve the interpretation of screening results. These data are useful to identify novel miRs potentially involved in glomerular diseases.

• diagnostic marker
• glomerular diseases
• microRNA-screening
• renal cells
• urine

Competing endogenous RNA (ceRNA) are transcripts that cross‐regulate each other at the post‐transcriptional level by competing for shared microRNA response elements (MREs). These have been implicated in various biological processes impacting cell‐fate decisions and diseases including cancer. There are several studies that predict possible ceRNA pairs by adopting various machine‐learning and mathematical approaches; however, there is no method that enables us to gauge as well as compare the propensity of the ceRNA of a gene and precisely envisages which among a pair exerts a stronger pull on the shared miRNA pool. In this study, we developed a method that uses the ‘tug of war of genes’ concept to predict and quantify ceRNA potential of a gene for the shared miRNA pool in cancers based on a score represented by SoCeR (score of competing endogenous RNA). The method was executed on the RNA‐Seq transcriptional profiles of genes and miRNA available at TCGA along with CLIP‐supported miRNA‐target sites to predict ceRNA in 32 cancer types which were validated with already reported cases. The proposed method can be used to determine the sequestering capability of the gene of interest as well as in ranking the probable ceRNA candidates of a gene. Finally, we developed standalone applications (SoCeR tool) to aid researchers in easier implementation of the method in analysing different data sets or diseases.

• RNA-Seq
• SoCeR
• ceRNA
• genomics
• microRNA

• melanoma
• microRNA
• tumor suppressor

• ECM
• EMT
• LncRNAs
• cancer cells
• epithelial-mesenchymal transition
• extracellular matrix
• microRNAs
• noncoding RNAs
• tumor microenvironment

The non-coding 3′-untranslated region (UTR) of genes play an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Herein, we report that ectopic expression of XIAP 3′UTR increased human breast cancer cells proliferation, colony formation, migration, invasion and xenograft tumor growth and suppressed tumor cell death. To investigate this process, we further correlated the genome-wide transcriptional profiling with the gene expression alterations after transfecting XIAP 3′UTR in MCF-7 cells. We identified a robust, genome-wide mechanism of cell migration, motility and epithelial to mesenchymal transition by which mediated by a previously described cellular component movement factor FSCN1. Expression of XIAP and FSCN1 were up-regulated synergistically after transfecting XIAP 3′UTR in vitro and in vivo. Interactions between XIAP and FSCN1 appear to be a key determinant of these processes. Co-transfection with Dicer siRNA reversed the XIAP 3′UTR-mediated oncogenicity, suggesting the miRNAs might be involved in that process. Furthermore, we demonstrated that one miRNA, miR-29a-5p, can bind to both the XIAP and FSCN1 3′UTRs and play an important role in that interactions. We showed that the 3′UTR of XIAP was able to antagonize miR-29a-5p, and resulted in the increased translation of XIAP and FSCN1. Thus, our findings reveal important new insights into how XIAP 3′UTR works, suggesting that the non-coding XIAP 3′UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by which XIAP 3′UTR frees the target mRNAs from being repressed.

• 3'UTR
• XIAP
• breast cancer
• miRNA

Active DNA repair pathways are crucial for preserving genomic integrity and are likely among the complex mechanisms involved in the normal development of preimplantation embryos. MicroRNAs (miRNA), short non-coding RNAs, are key regulators of gene expression through the post-transcriptional and post-translational modification of mRNA. The association of miRNA expression with infertility or polycystic ovarian syndrome has been widely investigated; however, there are limited data regarding the importance of miRNA regulation in DNA repair during preimplantation embryo development. In this article, we review normal miRNA biogenesis and consequences of aberrant miRNA expression in the regulation of DNA repair in gametes and preimplantation embryos.

Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects.

• Cancer
• Cell regulation
• Heparan sulfate
• Liver
• Proteoglycans

• Agrin/metabolism
• Animals
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Glycosaminoglycans/chemistry
• Glycosaminoglycans/metabolism
• Glypicans/metabolism
• Heparan Sulfate Proteoglycans/chemistry
• Heparan Sulfate Proteoglycans/metabolism
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Liver Neoplasms, Experimental/etiology
• Liver Neoplasms, Experimental/metabolism
• Proteoglycans/chemistry
• Proteoglycans/metabolism
• Syndecan-1/metabolism
• Versicans/metabolism

• Angiogenesis
• Noncoding RNA
• Tumor

Conventional wisdom holds that only one of the two strands in a micro ribonucleic acid (miRNA) precursor duplex is selected as the active miRNA guide strand. The complementary miRNA passenger strand, however, is thought to be inactive. High levels of the oncogenic miRNA (oncomiR) guide strand called miR-17-5p is overexpressed in triple negative breast cancer (TNBC) and can inhibit ribosomal translation of tumor suppressor gene mRNAs, such as programmed cell death 4 (PDCD4) or phosphatase and tensin homolog (PTEN). We hypothesized that knocking down the oncogenic microRNA (oncomiR) miR-17-5p might restore the expression levels of PDCD4 and PTEN tumor suppressor proteins, illustrating a route to oligonucleotide therapy of TNBC. Contrary to conventional wisdom, antisense knockdown of oncomiR miR-17-5p guide strand reduced PDCD4 and PTEN proteins by 1.8±0.3 fold in human TNBC cells instead of raising them. Bioinformatics analysis and folding energy calculations revealed that mRNA targets of miR-17-5p guide strand, such as PDCD4 and PTEN, could also be regulated by miR-17-3p passenger strand. Due to high sequence homology between the antisense molecules and miR-17-3p passenger strand, as well as the excess binding sites for the passenger strand on the 3’UTR of PDCD4 and PTEN mRNAs, introducing a miR-17-3p DNA-LNA mimic to knock down miR-17-5p reduced PDCD4 and PTEN protein expression instead of raising them. Our results imply that therapeutic antisense sequences against miRNAs should be designed to target the miRNA strand with the greatest number of putative binding sites in the target mRNAs, while minimizing affinity for the minor strand.

Various non-coding regions of the genome, once presumed to be ‘junk’ DNA, have recently been found to be transcriptionally active. In particular, pseudogenes are now known to have important biological roles. Here we report that transcripts of the two tumour suppressor candidate-2 pseudogenes (TUSC2P), found on chromosomes X and Y, are homologous to the 3′-UTR of their corresponding protein coding transcript, TUSC2. TUSC2P and the TUSC2 3′-UTR share many common miRNA-binding sites, including miR-17, miR-93, miR-299-3p, miR-520a, miR-608 and miR-661. We find that ectopic expression of TUSC2P and the TUSC2 3′-UTR inhibits cell proliferation, survival, migration, invasion and colony formation, and increases tumour cell death. By interacting with endogenous miRNAs, TUSC2P and TUSC2 3′-UTR arrest the functions of these miRNAs, resulting in increased translation of TUSC2. The TUSC2P and TUSC2 3′-UTR could thus be used as combinatorial miRNA inhibitors and might have clinical applications.

Non-coding RNAs have recently emerged as crucial regulators of gene expression. Here Rutnam et al. identify a pseudogene complementary to the 3′-UTR of the TUSC2 tumour suppressor that regulates TUSC2 levels by acting as a decoy for endogenous microRNAs and thereby inhibits tumorigenesis.

• DNA repair
• Expression
• Human oocyte and blastocyst
• MicroRNA
• Preimplantation embryo development

Non-coding RNAs have gained increasing attention, as their physiological and pathological functions are being gradually uncovered. MicroRNAs are the most well-studied ncRNAs, which play essential roles in translational repression and mRNA degradation. In contrast, long non-coding RNAs are distinguished from other small/short non-coding RNAs by length and regulate chromatin remodeling, gene transcription and posttranscriptional modifications. Recently, circular RNAs have emerged as endogenous, abundant, conserved and stable in mammalian cells. It has been demonstrated that circular RNAs can function as miRNA sponges. Other possible biological functions of circular RNAs are still under investigation. In this review, the biogenesis and biological functions of the three major types of ncRNAs, including miRNAs, lncRNAs and circRNAs, are overviewed. In addition, the role of ncRNAs in human diseases and potential clinical applications of ncRNAs are discussed.

• biological functions
• circular RNA
• long-non coding RNA
• microRNA
• non-coding RNA

• cancer
• competing endogenous RNA
• microRNA

• Base Pair Mismatch
• Base Pairing
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• HeLa Cells
• Hep G2 Cells
• Humans
• Jurkat Cells
• Luciferases/genetics
• Luciferases/metabolism
• MCF-7 Cells
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Antisense/genetics
• RNA, Antisense/metabolism
• RNA, Small Interfering/genetics
• RNA, Small Interfering/metabolism
• Transgenes
• RNA, Guide, CRISPR-Cas Systems

• Competing endogenous RNAs
• PTEN
• Scale-free networks
• microRNAs

• AML immunoresistance
• PD-L1 miR-34a

• AEG-1
• Competitive endogenous RNAs (ceRNAs)
• Epithelial–mesenchymal transition (EMT)
• Lung cancer
• Snail
• Vimentin
• miR-30a

• 3′UTR
• Angiogenesis
• Breast cancer
• CYP4Z2P
• VEGF-A

• 3' Untranslated Regions
• Animals
• Base Sequence
• Blotting, Western
• Breast Neoplasms/blood supply
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line
• Cell Line, Tumor
• Chick Embryo
• Cytochrome P-450 Enzyme System/genetics
• DNA Primers
• Female
• Humans
• Neovascularization, Pathologic/genetics
• Nucleic Acid Conformation
• Pseudogenes
• RNA, Messenger/chemistry
• RNA, Messenger/genetics
• Rats
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction

MicroRNAs (miRNAs) are small RNA molecules that play important roles in gene regulation and translational repression. The mechanisms that facilitate miRNA target binding and recognition have been extensively studied in recent years. However, it is still not well known how the miRNA regulation is affected by the location and the flanking sequences of miRNA target sites. In this study, we systematically quantify the contribution of a wide spectrum of target sites on miRNA-mediated gene expression regulation. Our study investigates target sites located in four different gene regions, including 3' untranslated regions, coding sequences, 5′ untranslated regions and promoter regions. We have also introduced four additional non-canonical types of seed matches beyond the canonical seed matches, and included them in our study. Computational analysis of quantitative proteomic data has demonstrated that target sites located in different regions impact the miRNA-mediated repression differently but synergistically. In addition, we have shown the synergistic effects among non-canonical seed matches and canonical ones that enhance the miRNA regulatory effects. Further systematic analysis on the site accessibility near the target regions and the secondary structure of the mRNA sequences have demonstrated substantial variations among target sites of different locations and of different types of seed matches, suggesting the mRNA secondary structure could explain some of the difference in the miRNA regulatory effects impacted by these different target sites. Our study implies miRNAs might regulate their targets under different mechanisms when target sites vary in both their locations and the types of seed matches they contain.

• malignant melanoma
• microRNA-203
• migration
• versican

• development
• disease
• extracellular matrix
• gene expression
• microRNA

• Competing endogenous RNA
• Integrin
• Laminin
• MicroRNA
• Proteoglycan
• Therapeutics

• Atherosclerosis
• Elastic fibers
• Extracellular matrix
• Hyaluronan
• Inflammation
• Proteoglycans

• Competitive endogenous RNAs
• Posttranscriptional regulation
• ceRNAs
• miRNA decoys
• miRNA sponges
• miRNAs
• microRNAs

A mature miRNA generally suppresses hundreds of mRNA targets. To evaluate the selective effect of synthetic oligonucleotide decoys on hsa-miR-223 activity, reporters containing 3’ untranslated regions (UTR) of IGF1R, FOXO1, POLR3G, FOXO3, CDC27, FBXW7 and PAXIP1 mRNAs were constructed for the luciferase assay. The oligonucleotide decoys were designed and synthesized according to mature miR-223 sequence and its target mRNA sequence. Quantitative RT-PCR & western analysis were used to measure miR-223-targeted mRNA expression, Interestingly, apart from the antisense oligonucleotide, decoy nucleotides which were complementary to the 5’, central or 3’ region of mature miR-223 suppressed miR-223 targeting the 3’UTR of IGF1R, FOXO1, FOXO3, CDC27, POLR3G, and FBXW7 mRNAs and rescued the expression of these genes to varying degrees from miR-223 suppression at both mRNA and protein levels. All decoys had no effect on PAXIP1 which was not targeted by miR-223. The decoy 1 that was based on the sequence of IGF1R 3’UTR rescued the expression of IGF1R more significantly than other decoy nucleotides except the antisense decoy 4. Decoy 1 also rescued the expression of FOXO3 and POLR3G of which their 3’UTRs have similar binding sites for miR-223 with IGF1R 3’UTR. However decoy 1 failed to recover Sp1, CDC27 and FBXW7 expression. These data support that the sequence-specific decoy oligonucleotides might represent exogenous competing RNA which selectively inhibits microRNA targeting.

• 3' Untranslated Regions/genetics
• Apoptosis/drug effects
• Base Sequence
• Cell Proliferation/drug effects
• HEK293 Cells
• HeLa Cells
• Humans
• Luciferases/metabolism
• MicroRNAs/metabolism
• Molecular Sequence Data
• Oligonucleotides/pharmacology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptor, IGF Type 1/metabolism

• Animals
• Carcinogenesis
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Gene Expression Regulation, Neoplastic
• Male
• Mice
• Mice, Nude
• MicroRNAs/metabolism
• Neoplasm Invasiveness
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Tissue Inhibitor of Metalloproteinase-3/genetics
• Tissue Inhibitor of Metalloproteinase-3/metabolism

• MOP-102635 Canadian Institutes of Health Research
• MOP-111171 Canadian Institutes of Health Research

Angiogenesis and invasion are essential processes for solid tumor growth and dissemination. The tumor development process can be dependent on the activation of a series of signaling pathways, including growth factor-activated pathways. MicroRNAs have been shown to be critical for tumorigenesis, but their roles in cancer angiogenesis, invasion and other signaling pathways important for tumor development are still unclear in the context of tumor biology. We investigated the role of microRNA miR-98 in regulating tumor growth, invasion, and angiogenesis using a highly aggressive breast cancer model in vitro and in vitro. We found that the expression of miR-98 inhibited breast cancer cell proliferation, survival, tumor growth, invasion, and angiogenesis. Conversely, inhibition of endogenous miR-98 promoted cell proliferation, survival, tumor growth, invasion, and angiogenesis. It appeared that miR-98 inhibited angiogenesis by modulating endothelial cell activities including cell spreading, cell invasion and tubule formation. Interestingly, miR-98 reduced the expression of ALK4 and MMP11, both of which were potential targets of miR-98. Transfection of an anti-miR-98 construct increased the expression of both targets. We confirmed that mir-98 targeted the 3'-untranslated regions of ALK4 and MMP11. Finally, ALK4- and MMP11-specific siRNAs inhibited breast cancer cell proliferation, survival, and angiogenesis. Rescue experiments with ALK4 and MMP11 constructs reversed the anti-proliferative, anti-invasive and anti-angiogenic effects of miR-98. Our findings define a regulatory role of miR-98 in tumor angiogenesis and invasion through repressed ALK4 and MMP11 expression.

MicroRNAs (miRs) are key post-transcriptional regulators that silence gene expression by direct base pairing to target sites of RNAs. They have a wide variety of tissue expression patterns and are differentially expressed during development and disease. Their activity and abundance is subject to various levels of control ranging from transcription and biogenesis to miR response elements on RNAs, target cellular levels and miR turnover. This review summarizes and discusses current knowledge on the regulation of miR activity and concludes with novel non-canonical functions that have recently emerged.

Chemotherapy has been widely used in treating cancer patients. Despite the tremendous progress in cancer treatment achieved during the last decades, drug resistance still accounts for most of the tumor relapses in chemotherapy-treated patients. Emerging evidence shows that microRNAs play an important role in regulating the drug sensitivity of tumor cells. However, the mechanism of microRNA-mediated drug resistance is not fully understood. Current data suggest that microRNAs can be categorized as oncogenic or tumor-suppressive based on their functions and targets. In tumor cells undergoing drug treatment, microRNAs can function either by decreasing expression of genes associated with multiple drug resistance or by promoting escape from apoptosis and inducing tumor stem cell development. This review aims to provide an updated understanding of the role of microRNAs in regulating chemotherapy resistance and a discussion of potential therapeutic applications.