Search Results (2,049)

The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice. Full article

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in mammalian skeletal muscle development, moving beyond their initial characterization as transcriptional “noise”. Unlike previous reviews that focus primarily on individual IncRNA catalogues, this review systematically integrates recent advances across five dimensions: (1) molecular characteristics and multidimensional classification of muscle related lncRNAs; (2) stage-specific expression patterns spanning embryonic myogenesis, postnatal growth, adult maintenance, and regeneration; (3) underlying molecular mechanisms including chromatin remodeling, ceRNA networks, IncRNA protein interactions, and nucleocytoplasmic trafficking; (4) pathological implications in muscular dystrophy, atrophy, and neuromuscular diseases; (5) translational applications in precision animal breeding. We critically evaluate the controversial ceRNA hypothesis and highlight quantitative limitations in current evidence. By integrating existing knowledge into a multi-layer regulatory network model and addressing current technical challenges and controversies (e.g., the ceRNA stoichiometry debate), this review provides a comprehensive roadmap for future basic research and translational applications in muscle biology. Full article

This study aimed to evaluate whether serum from patients with primary antiphospholipid syndrome (APS) is associated with changes in the expression of long non-coding RNAs (lncRNAs) in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured with serum from 12 female patients with APS or 8 age-matched healthy female controls. The expression levels of HIF1A-AS1, OIP5-AS1, and GAS5 were quantified by RT-qPCR. Exposure of HUVECs to APS serum was associated with reduced expression of HIF1A-AS1 and OIP5-AS1 compared with cells stimulated with control serum. The median HIF1A-AS1 expression levels were 0.08 a.u. (interquartile range, 0.06–0.10) in APS-stimulated cells versus 0.14 a.u. (0.08–0.16) in controls (p = 0.044). Likewise, OIP5-AS1 levels were 0.09 a.u. (0.01–0.16) in APS-stimulated cells versus 2.24 a.u. (0.70–3.55) in controls (p = 0.018). In contrast, GAS5 expression did not differ significantly between groups (340 a.u. (310–3940 versus 358 a.u. (163–445); p = 0.290). In this proof-of-concept study, serum from APS patients was associated with selective downregulation of HIF1A-AS1 and OIP5-AS1 in endothelial cells. These findings support a potential link between circulating APS-related factors and endothelial lncRNA expression; however, no mechanistic or functional conclusions can be drawn. Full article

Ascosphaera apis, an obligate lethal fungal pathogen that infects bee larvae, and causes chalkbrood disease, poses a significant threat to the global beekeeping industry. Long non-coding RNAs (lncRNAs) are employed by pathogens to enhance infectivity and evade host immunity. Here, lncRNAs in A. apis spores (AaCK group) and the guts of 4-, 5-, and 6-day-old Apis cerana cerana worker larvae inoculated with A. apis spores (AaT1, AaT2, and AaT3 groups) were identified, characterized, and validated. Additionally, the expression pattern of fungal lncRNAs during infection was analyzed, followed by an investigation of the regulatory manners and roles of differentially expressed lncRNAs (DElncRNAs). A total of 1379 lncRNAs were identified in AaCK, AaT1, AaT2, and AaT3 groups using bioinformatics, involving various types such as sense lncRNAs, antisense lncRNAs, bidirectional lncRNAs, intergenic lncRNAs, and intronic lncRNAs. Additionally, 4, 9, and 75 up-regulated lncRNAs as well as 2, 1, and 15 down-regulated ones were identified in the 4-, 5-, and 6-day-old larval guts following A. apis inoculation. Fifteen DElncRNAs as potential antisense lncRNAs may interact with 15 sense-strand mRNAs in the AaCK vs. AaT3 comparison group. Cis-acting analysis identified 10, 16, and 136 upstream and downstream genes of DElncRNAs in the aforementioned comparison groups, involving a series of GO terms and KEGG pathways like metabolic process and biosynthesis of secondary metabolites. Following the trans-acting investigation, 752, 821, and 1327 co-transcribed genes with DElncRNAs were discovered, spanning an array of functional terms and pathways such as biological processes and glycerophospholipid metabolism. Analysis of a competing endogenous RNA (ceRNA) network indicated that 1 and 5 DElncRNAs in the AaCK vs. AaT1 and AaCK vs. AaT3 comparison groups potentially targeted 1 and 2 miRNAs, further targeting 208 and 286 mRNAs, respectively. Further analysis identified one ceRNA axis relevant to the MAPK signaling pathway and several ceRNA networks associated with the biosynthesis of secondary metabolites. Finally, RT-qPCR results confirmed that the expression trends of six randomly selected DElncRNAs were consistent with those in the transcriptome data. These findings not only offer a foundation for elucidating the mechanisms underlying DElncRNA-mediated A. apis infection but also enrich our understanding of honeybee host–fungal pathogen interactions. Full article

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. Methods: We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. Results: miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial–mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. Conclusions: miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed. Full article

Long non-coding RNAs (lncRNAs) have emerged as important regulators of developmental processes. Recent studies have established roles for lncRNAs in human and murine erythroid regulation, yet additional regulators remain to be discovered. To identify lncRNA candidates involved in human erythroid regulation, we established a pooled genome-editing screen strategy using human embryonic stem cells (hESCs). Long Intergenic Non-Protein Coding RNA 1089 (LINC01089) was selected for functional investigation. We found that reduced LINC01089 expression impaired erythroid differentiation. Transcriptomic profiling revealed consistent downregulation of genes related to hemoglobin assembly, heme biosynthesis, and membrane maturation, suggesting that LINC01089 supports coordinated erythroid transcriptional programs. In particular, progressive reduction of HBB expression emerged as a key transcriptional anchor. Enrichment analyses of upregulated genes identified recurrent focal adhesion signatures, suggesting a potential link between LINC01089 and focal adhesion kinase (FAK)-related signaling. Given prior evidence linking LINC01089 to FAK phosphorylation, we performed a pilot FAK-inhibition experiment, producing a partial shift toward wild-type HBB expression and supporting FAK/phosphorylated FAK (pFAK) signaling as a potential contributing axis in the impaired transcriptional programs. Together, our findings identify LINC01089 as a novel lncRNA linked to coordinated heme–globin transcriptional programs in human erythroid differentiation, with possible involvement of the FAK/pFAK axis. Full article

The oncogenic Marek’s disease virus (MDV) triggers Marek’s disease (MD), which is a substantial threat to poultry as it transforms infected T cells into tumors. Our research identified that long non-coding RNA 9802 (lncRNA-9802) exhibits increased expression in the chicken spleen following MDV infection, with its expression being strongly associated with the expression of tumor p53-binding protein 1 (TP53BP1). The function of lncRNA-9802 in T cells transformed by MDV remains unclear. Consequently, the expression levels of lncRNA-9802 were either over-expressed or knocked down in MDV-transformed T cells, MDCC-MSB1, through lentivirus-mediated over-expression and knock down experiments. Our findings demonstrate that lncRNA-9802 induces proliferation disturbances in MDCC-MSB1 cells by causing arrest in the S phase, which is accompanied by increased expression levels of TP53BP1, p53, and p21. Activation of the p53 pathway results in elevated levels of Cyclin E and Cyclin-dependent kinase 2 (CDK2), thereby facilitating the entry of MDCC-MSB1 cells into the S phase. Concurrently, the reduced levels of Cyclin A inhibit the exit of MDCC-MSB1 cells from the S phase. By modulating the TP53BP1/p53/p21 pathway, lncRNA-9802 induces S phase arrest in MDCC-MSB1 cells, characterized by upregulation of Cyclin E and CDK2 and downregulation of Cyclin A. This research enhances the understanding of the pathogenic mechanisms of MDV and provides a foundation for identifying potential targets for antiviral drug development. Full article

Triple-negative breast cancer (TNBC/18–21%) lacks targeted treatment options due to the lack of ER/PR and HER2 expression. The transport of lncRNAs via exosomes plays a role in tumor progression and metastasis and reshapes tumor-associated signaling pathways. This study aimed to compare the expression of exosomal HOTAIR, NEAT1, MALAT1, AFAP1-AS1, ANRIL, and HULC lncRNAs in primary tumor tissue and blood of patients with sporadic TNBC to evaluate their potential as biomarkers. The patients diagnosed with TNBC between the years 2021 and 2025, 21 of 62 (33.87%) with sporadic breast cancer and thirty healthy controls were included in the study. Primary tumor tissue and peripheral venous blood samples were collected from 21 patients who did not receive neoadjuvant chemotherapy. Expression levels of exosomal lncRNAs (HOTAIR, NEAT1, MALAT1, AFAP1-AS1, ANRIL, and HULC) were determined in both tissues and blood samples from the patient and control groups using Real-Time PCR method. In the patient group, HOTAIR, HULC, ANRIL, and AFAP1_AS1 gene expression was lower (downregulated) in tissue and serum compared to the control group, whereas NEAT1 and MALAT1 were higher (upregulated). Tissue and serum samples taken from the patient group were found to have statistically consistent expression levels of HOTAIR, HULC, and ANRIL genes. Furthermore, HOTAIR, HULC, and ANRIL serve as biomarkers and can be studied using exosomal RNA samples obtained from patient serum without invasive procedures. Our current study, which has different lncRNA expression profiles, reflects the biological heterogeneity of TNBC and contributes to a better understanding of its subtypes at the molecular level. Full article

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression, playing pivotal roles in diverse biological processes, including reproduction. This study identified and characterized lncRNAs located near fertility-associated genes in Retinta beef cattle, exploring their potential regulatory roles via DNA–RNA triplex formation using in silico approaches. Methods: We applied an integrative bioinformatics pipeline to identify potential triplex interactions, predicting structurally accessible regions within the lncRNAs and demonstrating the statistical enrichment of binding sites across known regulatory genomic elements. Results: Twelve protein-coding genes previously linked to female fertility or male scrotal circumference were analyzed, revealing 16 unique lncRNAs within ±50 kb windows, predominantly on BTA5. We predicted high-confidence triplex-forming oligonucleotides (TFOs) for most gene-lncRNA pairs. Our results suggest robustness and sequence specificity, as interactions were disrupted by sequence permutation or when a control background sequence was used. RNA secondary-structure analysis revealed that TFOs generally lie in exposed regions, supporting their accessibility for triplex formation. Furthermore, promoter and regulatory regions of fertility-associated genes were enriched in predicted triplex target sites (TTSs), with some overlapping CpG islands and enhancer regions, leading to the hypothesis that these lncRNAs might play a role in epigenetic regulation. Conclusions: Overall, these findings establish computationally derived hypotheses regarding the potential molecular mechanisms by which lncRNAs may modulate reproductive efficiency in cattle and highlight specific lncRNAs as promising targets for functional studies and marker-assisted breeding. Full article

Bovine mastitis causes significant economic losses in the dairy industry. Emerging evidence highlights the critical role of long non-coding RNAs (lncRNAs) in inflammation-associated epigenetic regulation through competing endogenous RNA (ceRNA) networks. In this study, we established a bovine mastitis model in three healthy primiparous Holstein cows by intramammary infection with S. aureus. Infected and control mammary tissue samples were then collected for transcriptomic profiling, which identified 2005 differentially expressed lncRNAs. Among them, BMNCR was significantly upregulated in S. aureus-infected mammary tissues and S. aureus-stimulated BMECs. We evaluated the coding potential of BMNCR and confirmed its non-coding nature. Functional studies in BMECs demonstrated that knockdown of BMNCR suppressed proliferation, promoted apoptosis, and altered the expression of inflammatory factors, including IL-2, IL-6, IL-8, and IL-12. Mechanistically, BMNCR acted as a sponge for bta-miR-145, thereby leading to the derepression of ANO6. Silencing ANO6 partly recapitulated the effects of BMNCR knockdown, impairing proliferation and increasing IL-8 expression. Collectively, these findings suggest that the BMNCR/miR-145/ANO6 axis is involved in the regulation of inflammatory responses and epithelial homeostasis during bovine mastitis, with BMNCR functioning as a protective regulator in this process. Full article

Background/Objectives: Opioid use disorder (OUD) is caused by a complex interplay between genetic and non-genetic factors. DNA methylation is an epigenetic mechanism that modulates gene expression. Data on DNA methylation and opioid addiction and treatment are limited. This association study was designed to assess the difference in genome-wide methylation patterns between individuals with OUD in methadone maintenance treatment (MMT) (n = 114) and those with OUD who achieved long-term abstinence (>10 years) without mu opioid receptor agonist treatment (n = 136). Methods: Differential DNA methylation analysis was performed in whole blood using the Illumina EPIC array. Results: A total of 135 differentially methylated probes (DMPs) reached epigenome-wide significance (p < 1 × 10⁻⁷), controlling for sex, age, estimates of blood cell proportions, and the first two principal components based on genome-wide SNP genotypes. The methylation sites were annotated to 157 genes, including 32% long non-coding RNAs. These genes are related to several systems, including cell adhesion (e.g., SAXO4), immune system and inflammation (e.g., UBTF, USP39, C10orf90, PRKCA), stress response (e.g., CRHR1, GPR19), and spermatogenesis (e.g., SPATA16, COX7B2). DMP cg11641410 is located in lncRNA ENSG00000254687, an antisense to OPRK1. Six of the DMPs were also identified in a related longitudinal study of MMT. Conclusions: At this point, it is not possible to determine whether the minor methylation differences observed in this study cause clinically relevant changes in gene expression. However, these findings have the potential to identify biomarkers and to provide new targets for treatment optimization. Full article

Background/Objectives: The androgen receptor (AR)-driven transcriptional program plays a pivotal role in the development and progression of prostate cancer. The binding of androgen dihydrotestosterone (DHT) to AR initiates transcriptional activation, thereby altering the transcriptional landscape. DHT-induced long non-coding RNAs (lncRNAs) have been recognized as crucial players in prostate cancer pathogenesis. This study aims to identify and explore the important role of such lncRNAs in prostate cancer. Methods: This study first analyzed transcriptome data from an androgen-dependent cell line, LNCaP, treated with different DHT concentrations and found a batch of lncRNAs exhibiting DHT concentration dependence. TCGA data suggested a correlation between the DHT-induced lncRNA and prostate cancer. Finally, a series of in vivo and in vitro experiments confirmed the effect and mechanism of lncRNA in prostate cancer. Results: AC092718.4 was highly expressed in AR-positive prostate cancer cell lines and tissues, and its expression in patients with Gleason scores 6–9 was significantly higher than in a normal control group. Notably, the expression level of AC092718.4 was upregulated in a concentration-dependent manner with DHT. In vitro experiments revealed that overexpression of AC092718.4 promoted cell proliferation and inhibited cell apoptosis. Conversely, knockdown of AC092718.4 suppressed tumorigenesis in vivo. Furthermore, our investigation into the pathogenetic mechanism demonstrated that AC092718.4 could act as an miRNA sponge for miR-138-5p, attenuating its inhibitory effect on downstream oncogenes, such as FERMT2, RHOC, and HIF1A. These AC092718.4/miR-138-5p/mRNA axes, in turn, facilitated the progression of prostate cancer. Conclusions: For the first time, we demonstrate that AC092718.4 may function as an oncogenic factor in prostate cancer. The AC0927.8.4/miR-138-5p/mRNA axes potentially offer promising diagnostic and therapeutic targets for prostate cancer. Full article

Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of hepatic metabolism and disease progression. The hepatocyte nuclear factor 1 alpha antisense 1 (HNF1A-AS1) lncRNA modulates liver-specific transcription factors; however, its physiological role in diet-dependent lipid homeostasis remains poorly defined. Methods: In this study, we investigated the mouse ortholog, Hnf1a opposite strand 1 (Hnf1aos1), using AAV-mediated knockdown in C57BL/6J mice fed either a chow diet (10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. Metabolic phenotyping included hepatic lipid quantification, histological analysis, serum biochemistry, and quantitative gene expression profiling. Results: Loss of Hnf1aos1 produced distinct, diet-dependent alterations in hepatic lipid handling. Under chow conditions, knockdown mice exhibited selective hepatic cholesterol accumulation (6.10 ± 2.9 mg/g tissue vs. 3.51 ± 1.1 mg/g in controls), accompanied by dysregulation of cholesterol clearance pathways. In contrast, under HFD conditions, knockdown precipitated severe macrovesicular degeneration, with hepatic triglyceride levels approximately doubled relative to HFD-fed controls (51.72 ± 19.8 mg/g vs. 26.34 ± 11.9 mg/g) and a numerically elevated triglyceride-to-cholesterol ratio (TG:TC ≈ 6.1:1; p = 0.0621, trend). Chow/Kd mice gained significantly less weight than chow-fed controls, whereas HFD/Kd mice exhibited weight gain comparable to HFD controls despite severe hepatic steatosis. This paradoxical phenotype suggests impaired metabolic feedback at the post-transcriptional level, in which compensatory upregulation of Hnf1a mRNA is insufficient to suppress lipid-associated genes such as Cd36, despite profound lipid overload; however, HNF1A protein levels were not directly measured in this study. Conclusion: Collectively, these findings identify Hnf1aos1 as a regulator of hepatic lipid homeostasis whose loss produces a phenotype consistent with inappropriate lipid accumulation during nutrient excess, without defining the underlying molecular mechanism. Our results support a role for Hnf1aos1 in shaping hepatic metabolic plasticity and provide insight into lncRNA-associated MASLD phenotypes. Full article

Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-related morbidity and mortality, and reliable biomarkers for early diagnosis and risk stratification are still lacking. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) can regulate gene expression through competing endogenous RNA (ceRNA) interactions, but OSCC-specific ceRNA axes with clinical relevance are still poorly defined. We integrated lncRNA, miRNA, and mRNA expression data from six OSCC-related datasets in the Gene Expression Omnibus with in silico interaction predictions to construct an OSCC-focused ceRNA network and examine its association with survival. The resulting network comprised 8 mRNAs, 22 miRNAs, and 12 lncRNAs. Within this network, we identified a previously unrecognized XIST–miRNA–ZNF662 axis that has not been characterized in OSCC. ZNF662 was consistently downregulated in tumors, and higher ZNF662 expression was associated with improved survival in an independent head and neck squamous cell carcinoma cohort. Components of the XIST–miRNA–ZNF662 axis also showed excellent diagnostic performance for distinguishing OSCC from normal samples across (Gene Expression Omnibus) GEO datasets, highlighting a ceRNA module with promising diagnostic and prognostic potential that could be explored further in non-invasive biofluids. Full article

Long non-coding RNAs (lncRNAs) regulate granulosa cell function, but their stage-specific dynamics across the chicken follicle hierarchy remain unclear under matched endocrine conditions. We performed Ribo-Zero RNA sequencing on granulosa cells from small yellow follicles (SYF), F5, F2, and F1 follicles collected at the preovulatory luteinizing hormone (LH) surge. A multi-predictor pipeline (CPC2, CNCI, CPAT, PfamScan) identified 26,923 stringently filtered lncRNAs together with 15,838 mRNAs. Consecutive stage comparisons detected 2094, 1085, and 4318 differentially expressed genes and 671, 267, and 2762 differentially expressed lncRNAs in F5 vs. SYF, F2 vs. F5, and F1 vs. F2, respectively, with the most extensive remodeling at the F2-to-F1 transition. The F1 vs. SYF contrast captured the cumulative transcriptional difference across the hierarchy. Enrichment and temporal clustering showed that early hierarchical stages were characterized by proliferative, metabolic, and steroidogenic programs, whereas F1 granulosa cells were enriched for extracellular-matrix remodeling, MAPK signaling, and calcium ion binding. Weighted gene co-expression network analysis identified 10 stage-associated modules and highlighted candidate lncRNAs linked to lipid metabolism, angiogenesis, extracellular-matrix remodeling, and DNA repair, including G5825–MYLIP, G66587–VEGFA, and G60212–CKS1B. qPCR validation confirmed concordant expression trends for eight representative pairs. These results define a stage-resolved lncRNA–mRNA landscape across chicken follicle development and provide candidates for mechanistic studies of follicle maturation and periovulatory remodeling. Full article