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PubMed2025

Circular RNAs orchestrating breast cancer hallmarks: bridging tumor biology and therapy resistance.

Breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide, with treatment resistance posing a significant clinical challenge. Circular RNAs (circRNAs), a class of non-coding RNAs, have gained increasing attention as key regulators of gene expression, influencing BC pathogenesis, progression, and therapeutic response. This review explores the mechanistic insights into circRNA functions in BC, focusing on their involvement in tumor proliferation, metabolic reprogramming, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, and apoptosis. Additionally, we highlight the crosstalk between circRNAs and microRNAs, emphasizing their potential as diagnostic and prognostic biomarkers. Beyond their roles in tumor biology, circRNAs are implicated in drug resistance, modulating responses to chemotherapy, targeted therapy, and endocrine treatment. Despite their promising applications, challenges remain, including the complexity of circRNA interactions, and the development of robust preclinical models. Addressing these challenges through interdisciplinary research integrating genomics, transcriptomics, and functional studies will pave the way for circRNA-based therapeutic strategies and personalized medicine approaches in BC management.

Humans↗

PubMed2006

Characterization of an abundant COL9A1 transcript in the cochlea with a novel 3' UTR: Expression studies and detection of miRNA target sequence.

EST N66408 represents one of several large unique clusters expressed in the Morton human fetal cochlear cDNA library. N66408 is 575 bp in size and initial BLAST analysis of this sequence showed no homology to any known genes or expressed sequence tags (ESTs) from other organs or tissues. Sequence of the original cochlear clone from which N66408 was derived revealed that the corresponding cDNA was about 700 bp in size, including 125 bp at its 5' end with homology to the 3' end of COL9A1 in addition to 575 bp of novel sequence. RT-PCR analysis using primers specific to COL9A1 isoforms 1 and 2 detected expression of both isoforms in human fetal cochlea. Tissue in situ hybridization using the novel 3' UTR sequence as probe showed abundant expression in spiral limbus and spiral ligament, and a moderate level of expression in the organ of Corti. dbEST analysis of ESTs specific to the 3' UTR of COL9A1 showed 19 ESTs derived from various tissues; three polyadenylation sites were identified and the majority of these ESTs were derived from overlapping polyadenylation signals at the second site (position 749-758). Comparison of the 3' UTR of human COL9A1 with its orthologs as well as with dbEST uncovered a highly conserved region around the overlapping polyadenylation signals at position 749-758 in mammals. A search of the microRNA database revealed a highly conserved target sequence for miR-9 immediately preceding the overlapping polyadenylation signals in the novel 3' UTR of COL9A1, suggesting its role in posttranscriptional regulation of COL9A1.

3' Untranslated Regions↗

PubMed2006

Frequent loss of Dab2 protein and infrequent promoter hypermethylation in breast cancer.

Disabled-2 (Dab2), a putative tumor suppressor protein, is lost in 80-90% ovarian tumors and ovarian/breast cancer cell lines. The clinical significance of Dab2 protein in breast cancer remains yet unknown. Immunohistochemical analysis of Dab2 protein showed no detectable expression in 67/91 (74%) breast tumors, while all 10 normal tissues showed presence of Dab2 protein. We hypothesized that epigenetic silencing of Dab2 may account for loss of protein in breast cancer. Methylation of Dab2 exon 1, a putative promoter, was analyzed in six breast cancer cell lines and in 54 primary breast tumors by methylation specific PCR. Methylation was observed in MDA-MB-231 and MDA-MB-157 cells and in 6 of 54 (11%) primary breast tumors that also showed loss of Dab2 protein. Expression of Dab2 transcripts was detected in all cell lines except MDA-MB-157. However, none of these six cell lines showed detectable levels of Dab2 protein by western blotting, while non-malignant mammary epithelial cell line MCF 10A showed Dab2 protein expression. To our knowledge this is the first report showing low frequency of Dab2 (putative) promoter methylation (11%) in primary breast tumors. Frequent loss of Dab2 protein (74%) suggest that hypermethylation of Dab2 promoter may only be one of the mechanisms accounting for its loss in breast cancer. Further, in silico analysis of Dab2 3'-UTR revealed existence of miRNA complimentary to this region of the gene, suggesting microRNA mediated targeting of Dab2 mRNA might account for loss of the protein in breast cancer.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Diversity of endogenous small non-coding RNAs in Oryza sativa.

Small non-coding RNAs play important roles in regulating cell functions by controlling mRNA turnover and translational repression in eukaryotic cells. Here we isolated 162 endogenous small RNA molecules from Oryza sativa, which ranged from 16 to 35 nt in length. Further analysis indicated that they represented a diversity of small RNA molecules, including 17 microRNAs (miRNAs), 30 tiny non-coding RNAs (tncRNAs) and 20 repeat-associated small interfering RNAs (rasiRNAs). Among 17 miRNAs, 13 were novel miRNA candidates and their potential targets were important regulatory genes in the rice genome. We also found that a cluster of small RNAs, including many rasiRNAs, matched to a nuclear DNA fragment that evolutionarily derived from chloroplast. These results demonstrate clearly the existence of distinct types of small RNAs in rice and further suggest that small RNAs may control gene regulation through diverse mechanisms.

Base Sequence↗

PubMed2006

Signalling between the shoot apical meristem and developing lateral organs.

A characteristic feature of plant development is the extensive role played by cell-cell signalling in regulating patterns of growth and cell fate. This is particularly apparent in the shoot apical meristem (SAM) where signalling is involved in the maintenance of a central undifferentiated stem cell population and the formation of a regular and predictable pattern of leaves, from the meristem periphery. Although these two functions occur in different regions of the meristem, their activity must be coordinated to maintain meristem integrity. The role of signalling in the SAM was first characterised over 60 years ago by elegant surgical experiments. These studies showed that existing leaf primordia determine future sites of organ formation in adjacent regions of the SAM, a finding that laid the foundation for subsequent studies into the mechanisms controlling phyllotaxy. Recent studies have identified auxin as a likely signal promoting organ formation and shown that young primordia play an important role in determining its distribution in the SAM. These pioneering surgical experiments also revealed that signals from the meristem regulate the development of organ primordia. In this case a meristem signal promotes the formation of cell types found in the top/adaxial half of the emerging leaf. While the identity of this signal remains elusive, the recent characterisation of a small family of PHABULOSA-like (PHB-like) transcription factor genes has provided important clues to its nature. These genes, which promote adaxial cell identity, are regulated by microRNAs (miRNAs) raising the exciting possibility that the meristem signal is either a miRNA or part of a pathway regulating the distribution of miRNAs.

Body Patterning↗

PubMed2006

Floral patterning defects induced by Arabidopsis APETALA2 and microRNA172 expression in Nicotiana benthamiana.

Floral patterning and morphogenesis are controlled by many transcription factors including floral homeotic proteins, by which floral organ identity is determined. Recent studies have uncovered widespread regulation of transcription factors by microRNAs (miRNAs), approximately 21-nucleotide non-coding RNAs that regulate protein-coding RNAs through transcript cleavage and/or translational inhibition. The regulation of the floral homeotic gene APETALA2 (AP2) by miR172 is crucial for normal Arabidopsis flower development and is likely to be conserved across plant species. Here we probe the activity of the AP2/miR172 regulatory circuit in a heterologous Solanaceae species, Nicotiana benthamiana. We generated transgenic N. benthamiana lines expressing Arabidopsis wild type AP2 (35S::AP2), miR172-resistant AP2 mutant (35S::AP2m3) and MIR172a-1 (35S::MIR172) under the control of the cauliflower mosaic virus 35S promoter. 35S::AP2m3 plants accumulated high levels of AP2 mRNA and protein and exhibited floral patterning defects that included proliferation of numerous petals, stamens and carpels indicating loss of floral determinacy. On the other hand, nearly all 35S::AP2 plants accumulated barely detectable levels of AP2 mRNA or protein and were essentially non-phenotypic. Overall, the data indicated that expression of the wild type Arabidopsis AP2 transgene was repressed at the mRNA level by an endogenous N. benthamiana miR172 homologue that could be detected using Arabidopsis miR172 probe. Interestingly, 35S::MIR172 plants had sepal-to-petal transformations and/or more sepals and petals, suggesting interference with N. benthamiana normal floral homeotic gene function in perianth organs. Our studies uncover the potential utility of the Arabidopsis AP2/miR172 system as a tool for manipulation of floral architecture and flowering time in non-model plants.

Arabidopsis↗

PubMed2005

Current perspectives in intronic micro RNAs (miRNAs).

MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene silencing mechanism. Intronic miRNAs, derived from introns by RNA splicing and Dicer processing, can interfere with intracellular mRNAs to silence that gene expression. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of type II RNA polymerases (Pol-II) and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in Caenorhabditis elegans, mouse and human cells; however, neither their function nor application has been reported. To this day, the computer searching program for miRNA seldom include the intronic portion of protein-coding RNAs. The functional significance of artificially generated intronic miRNAs has been successfully ascertained in several biological systems such as zebrafishes, chicken embryos and adult mice, indicating the evolutionary preservation of this gene regulation system in vivo. Multiple miRNAs can be generated from the same cluster of introns; however, non-homologous miRNAs may have different targets and functions while homologous miRNA may be derived from different intronic clusters. Taken together, the model of intronic miRNA-mediated transgenic animals provides a tool to investigate the mechanism of miRNA-associated diseases in vivo and will shed light on miRNA-related therapies.

Animals↗

PubMed2026

Circulating Biomarkers Related to Mitral Valve Prolapse: Current Evidence and Mechanistic Perspective.

PURPOSE OF REVIEW: Although imaging remains central to diagnosis and risk stratification, circulating biomarkers provide complementary information reflecting myocardial stress, fibrosis, extracellular matrix remodeling, inflammation, and metabolic dysregulation. The purpose of this review is to critically evaluate current and emerging circulating biomarkers in MVP and to assess whether these biomarkers may improve individualized management of this disease. RECENT FINDINGS: Natriuretic peptides are the most validated biomarkers in MVP, consistently predicting adverse outcomes and providing complementary prognostic information that may help inform the timing of surgical intervention, particularly in asymptomatic patients with significant mitral regurgitation. In contrast, evidence supporting fibrosis and inflammation mediators, proteomics, metabolomics, and circulating microRNAs remains emerging. In arrhythmic MVP, no circulating biomarker is currently recommended for routine risk stratification. Future research should prioritize phenotype-specific MVP registries, biomarker-CMR integration, multi-omics profiling, and biomarker-guided interventional trials.

Humans↗

PubMed2026

Emerging Therapies for Angelman Syndrome.

Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.

Humans↗

PubMed2006

An LNA-based loss-of-function assay for micro-RNAs.

MicroRNAs (miRNAs) have recently emerged as being essential for development and for the control of cell proliferation/differentiation in various organisms. However, little is known about miRNA function and mode of action at the cellular level. We have designed a miRNA loss-of-function assay, based on chemically modified locked nucleic acids (LNA) antisense oligonucleotides and usable in tissue culture cells. We show that LNA/DNA mixed oligonucleotides form highly stable duplexes with miRNAs in vitro. Ex vivo, the target miRNA becomes undetectable in cells transfected with the antisense oligonucleotide. The effect is dose-dependent, long-lasting, and specific. Moreover, using a reporter assay, we show that antisense LNA/DNA oligonucleotides inhibit short non-coding RNAs at the functional level. Thus LNA/DNA mixmers represent powerful tools for functional analysis of miRNAs.

Cells, Cultured↗

PubMed2026

Construction of circRNA-miRNA-mRNA regulatory networks in the intestine of turbot (Scophthalmus maximus) following Vibrio anguillarum infection.

Circular RNAs (circRNAs) play pivotal roles in post-transcriptional regulation by acting as molecular sponges for microRNAs (miRNAs) within the competitive endogenous RNA (ceRNA) network. However, the regulatory mechanisms in teleost immune responses remain poorly understood. In this study, circRNA-miRNA-mRNA networks were investigated in turbot (Scophthalmus maximus) following Vibrio anguillarum infection to elucidate host-pathogen interactions. Through high-throughput sequencing of intestinal tissues, a total of 50 differentially expressed circRNAs (DE-circRNAs) (18 at 2 hpi, 16 at 12 hpi, 16 at 48 hpi), 212 DE-miRNAs (11 at 2 hpi, 70 at 12 hpi, 15 at 48 hpi), and 1774 DE-mRNAs were identified. Functional enrichment analyses (GO/KEGG) revealed significant associations with immune pathways, including the MAPK signaling pathway and gap junction. An integrated circRNA-miRNA-mRNA regulatory network was constructed, highlighting key interactions including novel_circ_0002573/DE-miR-27a-3p/FGB and novel_circ_0002423/novel_347/GNE, which may regulate inflammatory and antibacterial responses. The expression patterns of selected circRNAs, miRNAs and mRNAs were validated using qRT-PCR, confirming the reliability of the sequencing results. Importantly, fibrinogen beta chain (FGB) and CXCR4/CXCL12 signaling were identified as critical immune modulators. These findings provide insights of the ceRNA regulatory networks involved in teleost intestinal immunity and provide potential molecular targets for selective breeding of disease resistance in this species.

Animals↗

PubMed2026

Functional role and regulatory network of miR-22-3p in chicken hepatic lipid metabolism.

Although microRNA-22-3p (miR-22-3p) is abundantly expressed in the avian liver, its epigenetic role in lipid homeostasis remains largely uncharacterized. To elucidate its in vivo function, 14-day-old female Qingyuan Partridge chickens were intravenously injected with lentiviral vectors to establish miR-22-3p overexpression and knockdown models. Phenotypic analysis demonstrated that miR-22-3p knockdown significantly elevated hepatic triglyceride (TG) levels (p < 0.05) and drove marked steatosis, whereas its overexpression reduced TG content. Transcriptome sequencing (RNA-Seq) revealed profound metabolic remodeling, identifying 23 core lipid-associated genes (e.g., ELOVL6, FADS2, ACSBG2, and PTGIS) heavily enriched in steroid biosynthesis, fatty acid metabolism, and elongation pathways. In conclusion, miR-22-3p functions as a bidirectional epigenetic rheostat that negatively regulates hepatic lipid deposition by orchestrating a multilayered polygenic network, providing novel molecular targets for mitigating avian metabolic disorders and optimizing production traits in indigenous poultry breeds.

Animals↗

PubMed2026

Correlative analysis of endogenous miRNA expression profiles underlying brown planthopper adaptation to resistant rice.

The brown planthopper (Nilaparvata lugens Stål, BPH) is a major insect pest threatening global rice production. However, the molecular mechanisms underlying the adaptation of BPH populations with different virulence levels to resistant rice cultivars remain poorly understood. MicroRNAs (miRNAs), as key post-transcriptional regulators, play critical roles in host adaptation in herbivorous insects. In this study, we analyzed the miRNA expression profiles of a high-virulent population (IR56p) and a low-virulence population (TN1p) after feeding on susceptible (TN1) and resistant (IR56) rice cultivars. Our findings reveal distinct miRNA-mediated regulatory strategies employed by the two populations. The IR56p population showed downregulation of miRNAs including miR-10, miR-124, and miR-316, showing an inverse correlation with increased expression of predicted target genes involved in detoxification (carboxylesterase, UDP-glycosyltransferase) and effector function (calmodulin). In contrast, several miRNAs highly expressed in IR56p, including miR-307, miR-317, and miR-275, were predicted to target rice genes associated with hormone signaling, cell wall biosynthesis, and oxidative homeostasis, suggesting a possible but unproven inter-species regulatory role that requires functional validation. Collectively, these descriptive and correlative findings provide hypothesis generating insights into insect-plant coevolution and identifies candidate molecular targets for future functional validation and RNA interference-based pest management strategies.

Animals↗

PubMed2026

Whole-transcriptome RNA sequencing and ceRNA network analyses provide novel insights into the antibacterial immune response of Hippocampus abdominalis against Vibrio harveyi.

Long non-coding RNAs (lncRNAs) stand as newly-arisen molecular types that exert regulatory effects, able to operate as competitive endogenous RNAs (ceRNAs) to engage microRNAs (miRNAs) in interaction, resulting in the recovery of target mRNA expression and activity. Increasing evidences indicate that the ceRNA network affects various biological processes in mammals, including development, cellular differentiation, metabolism, immune response, and disease pathogenesis. In teleost fish, the lncRNA-miRNA-mRNA regulatory networks have been reported occasionally. However, up to now, the roles of lncRNAs in the big-belly seahorse (Hippocampus abdominalis) remains unclear. In this study, we reported for the first time, via whole-transcriptome RNA sequencing, the lncRNA mediated ceRNA regulatory network in Vibrio harveyi-infected H. abdominalis. A total of 4197 differentially expressed mRNAs (DE-mRNAs), 1317 DE-lncRNAs, and 183 DE-miRNAs were identified. Furthermore, the crosstalk between miRNAs and lncRNAs as well as between miRNAs and mRNAs was inferred based on the negative correlations between miRNAs and their target lncRNAs/mRNAs. A core immune associated lncRNA-miRNA-mRNA putative regulatory network was thus constructed, comprising 211 lncRNA-miRNA and 224 mRNA-miRNA pairs. In conclusion, our findings provide an integrative overview of the ceRNA regulatory networks on the underlying immune responses to V. harveyi infection in the big-belly seahorse, and offer a solid theoretical foundation for the comparative immunological research of teleost fish.

Animals↗

PubMed2006

Genomic approaches to drug discovery.

Considerable progress has been made in exploiting the enormous amount of genomic and genetic information for the identification of potential targets for drug discovery and development. New tools that incorporate pathway information have been developed for gene expression data mining to reflect differences in pathways in normal and disease states. In addition, forward and reverse genetics used in a high-throughput mode with full-length cDNA and RNAi libraries enable the direct identification of components of signaling pathways. The discovery of the regulatory function of microRNAs highlights the importance of continuing the investigation of the genome with sophisticated tools. Furthermore, epigenetic information including DNA methylation and histone modifications that mediate important biological processes add to the possibilities to identify novel drug targets and patient populations that will benefit from new therapies.

Animals↗

PubMed2004

Single processing center models for human Dicer and bacterial RNase III.

Dicer is a multidomain ribonuclease that processes double-stranded RNAs (dsRNAs) to 21 nt small interfering RNAs (siRNAs) during RNA interference, and excises microRNAs from precursor hairpins. Dicer contains two domains related to the bacterial dsRNA-specific endonuclease, RNase III, which is known to function as a homodimer. Based on an X-ray structure of the Aquifex aeolicus RNase III, models of the enzyme interaction with dsRNA, and its cleavage at two composite catalytic centers, have been proposed. We have generated mutations in human Dicer and Escherichia coli RNase III residues implicated in the catalysis, and studied their effect on RNA processing. Our results indicate that both enzymes have only one processing center, containing two RNA cleavage sites and generating products with 2 nt 3' overhangs. Based on these and other data, we propose that Dicer functions through intramolecular dimerization of its two RNase III domains, assisted by the flanking RNA binding domains, PAZ and dsRBD.

Amino Acid Sequence↗

PubMed2005

RNAi: the nuts and bolts of the RISC machine.

Research on RNA interference and microRNA pathways continues to accelerate. Combinations of biochemical, genetic, and structural approaches are providing new insights into the mechanism by which small, approximately 21 nt long RNAs find their way into the RISC effector complexes and how the RISCs execute their mission of RNA-guided posttranscriptional gene silencing.

Animals↗

PubMed2005

miRNAs, cancer, and stem cell division.

MicroRNAs (miRNAs) are known to regulate the expression of genes involved in the control of development, proliferation, apoptosis, and the stress response. As a cluster of recent Nature papers now show, altered expression of specific miRNA genes contributes to the initiation and progression of cancer.

Animals↗