Search Results (432)

Drug repurposing refers to the systematic identification of new therapeutic uses for existing drugs. Unlike traditional de novo drug discovery, which is expensive and time-consuming, repurposing leverages compounds with already established safety, pharmacokinetic, and pharmacodynamic profiles. In this study, we propose a drug repositioning model based on low-dimensional transcriptomic representations to investigate the relationship between known anticancer drugs and non-anticancer compounds. We analyzed LINCS L1000 data (1170 drugs; 824 anticancer, 346 non-anticancer). Data were projected with UMAP, PCA, and t-SNE. For each anticancer drug and for each method, we retrieved the k = 5 nearest non-anticancer neighbors and ranked candidates by recurrence frequency across all anticancer queries. We identified Ergometrine, Mupirocin, and (S)-blebbistatin among the most frequent non-anticancer drugs with a close association with drugs known to be anticancer. In addition, we performed a local neighborhood enrichment around the three candidates. Regarding Ergometrine (DB01253), in UMAP, 44/50 neighbors were anticancer (88.0% vs. global baseline 70.5%; hypergeometric BH-adjusted p = 0.0039). Considering (S)-blebbistatin (DB01944) in UMAP, 41/50 neighbors were anticancer (82.0% vs. 70.5%; BH-adjusted p = 0.0435). Mupirocin (DB00410) in UMAP had 44/50 neighbors as anticancer (88.0% vs. 70.5%; BH-adjusted p = 0.0039). Future research should explore the three drugs with in vivo models, investigating their possible synergies. Full article

Background/Objectives: Galectin-3 (Gal-3), encoded by LGALS3, is a β-galactoside-binding lectin involved in diverse tumor-associated processes, including immune modulation, cell cycle regulation, and stress adaptation. Despite its known roles in cancer biology, the full extent of its molecular functions and prognostic relevance across tumor types remains incompletely understood. This study aimed to systematically investigate the transcriptomic impact of LGALS3 deletion and assess its clinical significance in cancer. Methods: We analyzed CRISPR-Cas9 knockout transcriptomic data from the SigCom LINCS database to characterize the consensus gene signature associated with LGALS3 loss using functional enrichment analyses. Pan-cancer survival analyses were conducted using TIMER2.0. Differential Gal-3 protein levels in ductal adenocarcinoma and normal pancreatic tissues were evaluated using the Human Protein Atlas. Finally, functional analyses were performed in pancreatic ductal adenocarcinoma (PDAC). Results: LGALS3 deletion across multiple cancer cell lines led to transcriptomic changes involving mitotic progression, stress responses, and axonal guidance pathways. High LGALS3 expression was significantly associated with worse overall survival in lower-grade glioma, PDAC, uveal melanoma, and kidney renal papillary cell carcinoma. LGALS3 knockout in YAPC cells recapitulated the pan-cancer findings, linking LGALS3 to cell morphogenesis and proliferation. Conclusions: These findings identify Galectin-3 as a key regulator of oncogenic programs and a potential prognostic biomarker in PDAC and other malignancies, with implications for therapeutic targeting. Full article

Objective: This study aimed to elucidate the regulatory mechanisms of the long intergenic non-protein coding RNA 02381 (LINC02381)/microRNA-let-7g-5p (let-7g-5p)/thrombospondin 1 (THBS1) signaling axis in osteosarcoma (OS). Methods: The expression levels of LINC02381, let-7g-5p, and THBS1 were quantified in OS and adjacent normal tissues via reverse transcription quantitative polymerase chain reaction. Their correlations with clinicopathological features were analyzed. Expression patterns were further validated in OS cell lines (143B, U-2OS, Saos-2, MNNG-HOS, MG-63) and normal osteoblast cell line hFOB1.19. The molecular interaction between LINC02381 and let-7g-5p and the targeting relationship of let-7g-5p with THBS1 were verified via dual-luciferase reporter and RNA pull-down assays. Functional effects were assessed using cell counting kit-8, colony formation, Transwell migration, and xenograft tumor models. Results: Compared to adjacent normal tissues, LINC02381 and THBS1 were upregulated in OS tissues (fold change > 3.0, p < 0.001), while let-7g-5p was downregulated (fold change ≈ 0.038, p < 0.001). Similar expression trends were observed in U-2OS cells. Knockdown of LINC02381 or overexpression of let-7g-5p reduced cell proliferation, colony formation, migration, THBS1 expression, and tumor volume (p < 0.001). These inhibitory effects were partially reversed by let-7g-5p inhibitors, restoring cell viability and migration by approximately 70%. Mechanistically, LINC02381 functioned as a competing endogenous RNA (ceRNA), directly binding to let-7g-5p and mitigating its suppression of THBS1. Conclusions:LINC02381 promotes OA progression by acting as a ceRNA for let-7g-5p, thereby upregulating THBS1 expression. This signaling axis represents a potential therapeutic target for OS. Full article

Objectives: MicroRNAs of the miR-200 family are recognized as key inhibitors of epithelial-to-mesenchymal transition (EMT). However, there is limited data on the potential regulation of miR-200 family expression by long non-coding RNAs (lncRNAs) in RCC. Methods: We conducted a comprehensive literature and database search to identify lncRNAs that had been already functionally validated as regulators of any member of the miR-200 family. We analyzed the expression levels of the miR-200 family and the identified lncRNAs by qPCR. The study included 42 samples of carcinoma and non-carcinoma tissue from 25 RCC patients. In addition, we used RNA sequencing data from The Cancer Genome Atlas (TCGA), encompassing 511 kidney RCC (KIRC) samples, to further analyze the expression of miRNAs and lncRNAs. Results: We identified 127 lncRNAs with confirmed regulatory functions, 31 of which were validated in our samples. The majority of lncRNAs, along with all members of the miR-200 family, showed consistent downregulation in carcinoma tissues compared to non-carcinoma tissues. We observed a significant correlation between the expression of at least one member of the miR-200 family and 17 lncRNAs. In particular, three lncRNAs (MALAT1, OIP5-AS1, and LINC00467) showed a correlation with the expression of all members of the miR-200 family. Our results were at least partially confirmed in KIRC samples from the TCGA dataset. Conclusions: Our results suggest that the expression of the miR-200 family in RCC might be at least partially influenced by lncRNAs. Based on our cohort of samples, MALAT1, OIP5-AS1, and LINC00467 appear to be potentially important contributors to RCC development. Full article

Long intergenic non-coding RNA 00511 (LINC00511) has been involved in the development of several types of cancer including breast cancer (BC). Several single nucleotide polymorphisms (SNPs) can be found in the genomic regions of long non-coding RNAs (lncRNAs) and are associated with the tumorigenesis of many cancers. The objective of the current study is to assess whether LINC00511 SNPs (rs11657109, rs9906859, rs17780195, rs1558535, and rs4432291) could be related with BC incidence in the Egyptian population. Five SNPs of LINC00511 were analyzed in a case–control study of 267 BC cases and 150 controls. Logistic regression analysis was used to test the association between LINC00511 SNPs and BC incidence. We found that the TT genotype of rs11657109 significantly increased BC incidence (OR: 2.177, 95%CI: 1.260–3.763) and this SNP was associated with high incidence of luminal A BC specifically using different genetic models. Haplotype (A₀₉ A₉₁ A₃₅ G₉₅ T₅₉) was strongly associated with an increased BC incidence as it was totally absent in controls. These findings suggest that LINC00511 SNP rs11657109 is associated with BC susceptibility in the Egyptian population. Full article

Cancer metastasis is responsible for most cancer-related deaths. Migration and invasion, key steps in the metastatic cascade, require nuclear pliability to traverse the physical barriers of the extracellular matrix and cell–cell junctions. The nuclear envelope (NE) contains LINC complex proteins, including nesprin-4, which regulate nuclear integrity, stiffness, and cell movement. We report that nesprin-4 expression is generally upregulated in breast cancer samples but is reduced in triple-negative breast cancer (TNBC) samples compared to other subtypes. A nesprin-4 expression analysis in 62 breast cancer cell lines showed that nesprin-4 expression correlates positively with cell lines representing less aggressive tumors, while TNBC cell lines have low or no nesprin-4 expression. To determine the role of nesprin-4, we modulated nesprin-4 expression levels in three breast cancer cell lines: MCF7, T47D (luminal A and nesprin-4-positive), and MDA-MB-231 (TNBC and nesprin-4-negative). We found that nesprin-4 promotes migration and invasion by driving cell polarization. However, we also found that nesprin-4 impedes intravasation into endothelial microvessels. Thus, we propose that nesprin-4 plays a dual role in breast cancer, promoting efficient migration and invasion, but blocking intravasation. Full article

Background: Micropeptides, encoded by non-coding RNAs, play a pivotal role in various cellular functions. While several micropeptides have already been linked to HCC, their roles remain incompletely understood. Our study identifies MP60, a conserved micropeptide strongly associated with HCC progression. Methods and Results: By analyzing The Cancer Genome Atlas (TCGA) dataset, we assessed the coding potential of long non-coding RNAs (lncRNAs) with significant expression changes in HCC. Our findings reveal that ENST0000614292, a transcript of LINC01138, exhibited the highest coding potential, encoding a putative 60-amino-acid micropeptide, which we have named MP60 and confirmed the expression of MP60 in HCC tissues, with a nuclear localization. MP60 directly interacts with RNA-binding motif protein 10 (RBM10) and downregulates its expression. Additionally, MP60 modulates EMT. Functional analyses demonstrated that MP60 promotes cellular proliferation and migration, while reducing cellular adhesion, translated by enhanced tumorigenesis in vivo. Notably, MP60 expression is markedly increased in HCC tissues and is associated with a poorer prognosis. Conclusions: These findings identify MP60 as a potential biomarker and therapeutic target in HCC, linking its oncogenic effects to EMT modulation and tumor progression. Full article

Introduction: Neuroinflammation is a common pathological hallmark of Coronavirus Disease 2019 (COVID-19) and epilepsy; however, their shared immunogenomic mechanisms remain poorly defined. This study explores shared immune-inflammatory transcriptomic signatures and identifies potential repositioning therapeutics. Methods: We integrated single-cell RNA-seq data from peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and healthy donors (GSE149689), and bulk RNA-seq data from hippocampal tissue of patients with Temporal Lobe Epilepsy with Hippocampal Sclerosis (TLE-HS) and healthy controls (GSE256068). Common Differentially Expressed Genes (DEGs) were identified and subjected to GO/KEGG enrichment, a PPI network, hub gene detection (cytoHubba), and transcriptional regulation analysis (ENCODE-based TF/miRNA networks). Drug repositioning was performed using the LINCS L1000 database. Results: We identified 25 DEGs shared across datasets, including 22 upregulated genes enriched in cytokine–cytokine receptor interaction, NF-κB, and Toll-like receptor pathways. PPI analysis revealed a CX3CR1–TLR4-centered immune module. Gabapentin emerged as a promising repositioning candidate with potential to downregulate CX3CR1, TLR4, and selectin P ligand (SELPLG). Receiver Operating Characteristic (ROC) analysis confirmed the diagnostic value of these targets (AUC > 0.90 in epilepsy). A mechanistic model was proposed to illustrate Gabapentin’s dual action on microglial polarization and cytokine suppression. Conclusions: Our results reveal a shared CX3CR1–TLR4–NF-κB inflammatory axis in COVID-19 and epilepsy, supporting Gabapentin as a potential dual-action immunomodulator. These findings reveal a previously underappreciated immunomodulatory role for Gabapentin, providing mechanistic rationale for its repositioning in neuroinflammatory conditions beyond seizure control. Full article

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks—known as vasculogenic mimicry—that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the long-range inter-chromosomal interactions between numerous developmental genes and nucleoli are changed. The aim of this work was to study the potential mechanisms behind the development of the vasculogenic mimicry phenotype in melanoma cells and whether the formation of these 3D structures is connected with the reorganization of inter-chromosomal contacts of rDNA clusters. Here, we show that after 15 h of growth on Matrigel, and following the formation of the vasculogenic mimicry phenotype, dramatic changes occur in Mel Z cells in rDNA contacts with different genomic regions that possess mainly developmental genes. Approximately 400 genes that retained stable contacts with nucleoli were co-expressed with different lincRNAs and were highly associated with H3K27me3 marks and simultaneously regulated by different transcription factors. These genes are involved in development and cell adhesion and may control the basic stage of differentiation. The genes that acquired or increased contacts with rDNA clusters during growth on Matrigel are associated with cell morphogenesis, cell junctions, and the cytoskeleton. Here, we present the first evidence that nucleoli may be involved in both the activation and repression of particular groups of developmental rDNA-contacting genes in melanoma cells forming the vasculogenic mimicry phenotype. We conclude that the inter-chromosomal interactions between developmental genes and rDNA clusters are dynamic, and that nucleoli play an important role in the development of vasculogenic mimicry and stemness phenotypes in aggressive tumor genes. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite significant advances in screening and treatment, the prognosis for advanced-stage disease continues to be poor. One thriving area of research focuses on the use of epigenetic alterations for the diagnosis, prediction of treatment response, and prognosis of CRC. In this study, we evaluated original studies and meta-analyses published within the past five years to identify the most clinically relevant epigenetic biomarkers. DNA methylation-based assays, particularly those targeting SDC2 and SEPT9 in stool and plasma, exhibit superior diagnostic accuracy compared to other epigenetic modalities. Circulating microRNAs (miRNAs), including miR-211, miR-197, and miR-21, as well as specific long non-coding RNAs (lncRNAs) such as SNHG14, LINC01485, and ASB16-AS1, also show promising diagnostic potential. Furthermore, panels combining multiple epigenetic markers, especially those incorporating DNA methylation targets, have demonstrated improved sensitivity and specificity for early-stage CRC detection. In the context of therapeutic prediction, microRNAs such as miR-140, miR-21, and miR-4442 have been associated with chemotherapy resistance and recurrence risk. DNA methylation markers like LINE-1, mSEPT9 and ERCC1 have also shown predictive value, while lncRNAs including MALAT1 and GAS6-AS1 remain less validated. Regarding prognosis, miRNAs appear to be the most promising biomarkers, with miR-675-5p and miR-150 being associated with poor survival, while miR-767-5p and miR-215 predict favorable outcomes. Methylation of NKX6.1, IGFBP3, and LMX1A has been identified as an independent negative prognostic factor, while SFRP2 hypermethylation is linked to better prognosis. Selected lncRNAs, including THOR and LINC01094, have also demonstrated significant prognostic value. Despite these advances, challenges persist, including inconsistent reporting, limited external validation, and a lack of replication by independent research groups. Full article

Background: Esophageal cancer (EC), including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), remains a lethal malignancy with limited molecularly tailored treatment options. Due to substantial histologic and transcriptomic differences between subtypes, therapeutic responses often vary, underscoring the need for subtype-stratified analysis and precision drug discovery. Methods: We integrated transcriptomic data from GEO and TCGA to identify differentially expressed genes (DEGs) specific to EAC, ESCC, and their shared profiles. Functional enrichment (GO, KEGG) and protein–protein interaction (PPI) network analyses were conducted to extract hub genes using DAVID, STRING, and Cytoscape. Survival associations were evaluated using TCGA-ESCA and UALCAN. Drug repurposing was performed using L1000FWD, L1000CDS2, and SigCom LINCS. Results: We identified 79, 59, and 17 hub genes in the DEG-EAC, DEG-ESCC, and DEG-EAC&ESCC datasets, respectively. In EAC, 16 novel hub genes including SCARB1, SERPINH1, and DSC2 were discovered, which had not been previously implicated in this subtype. These genes were significantly enriched in pathways related to extracellular matrix (ECM) remodeling and epithelial structure. In addition, shared hub genes across EAC and ESCC—such as COL1A1, SPARC, and MMP1—were enriched in ECM organization and cell adhesion processes, highlighting convergent tumor–stroma interactions. Drug repositioning analysis consistently prioritized MEK inhibitors, trametinib and selumetinib, as potential therapeutic candidates across all DEG datasets. Conclusions: This study presents a comprehensive, subtype-stratified transcriptomic framework for EC, identifying both unique and shared hub genes with potential functional relevance to ECM dynamics. Our findings suggest that ECM remodelers may serve as therapeutic targets, and highlight MEK inhibition as a promising, yet exploratory, repurposing strategy. While these results offer a molecular foundation for future precision oncology efforts in EC, further validation through proteomic analysis, functional studies, and clinical evaluation is warranted. Full article

Background/Objectives: Increasing evidence suggests that lncRNAs are core regulators in the field of tumor progression, with context-specific functions in oncogenic tumorigenesis. LINC01133, a lncRNA that has been identified as both an oncogene and a tumor suppressor, remains largely unexplored in terms of its molecular mechanisms. The purpose of this study was to conduct an in silico analysis, incorporating literature research on various cancer types, to investigate the structural and functional duality of LINC01133. This analysis aimed to identify pathways influenced by LINC01133 and evaluate its mechanism of action as a potential therapeutic target and diagnostic biomarker. Methods: In silico analyses and a narrative review of the literature were performed to predict conserved structural elements, functional internal loops, and overall conservation of the LINC01133 sequence among different vertebrate organisms, summarizing the empirical evidence regarding its roles as a tumor suppressor and tumor-promoting roles in various types of tumors. Results: LINC01133 harbors the evolutionarily conserved structural regions that might allow for binding to relevant driver signaling pathways, substantiating its specific functionality. Its action extends beyond classical tumor mechanisms, affecting proliferation, migration, invasion, and epigenetic pathways in various types of tumors, as indicated by the in silico results and narrative review of the literature we present here. Clinical outcome associations pointed to its potential as a biomarker. Conclusions: The dual character of LINC01133 in tumor biology further demonstrates its prospective therapeutic value, but complete elucidation of its mechanisms of action requires further investigation. This study establishes LINC01133 as a multifaceted lncRNA, supporting context-specific strategies in targeting its pathways, and calls for expanded research to harness its full potential in oncology. Full article

The enterovirus Coxsackievirus B3 causes a range of serious health problems, including aseptic meningitis, myocarditis, and pancreatitis. Currently, Coxsackievirus B3 has no targeted antiviral treatments or vaccines, leaving supportive care as the primary management option. Understanding how Coxsackievirus B3 interacts with and alters the blood–brain barrier may help identify new therapies to combat this often-devastating infection. We reanalyzed a previously published RNA sequencing dataset for Coxsackievirus B3-infected human-induced pluripotent stem-cell-derived brain endothelial cells (iBECs) to examine how Coxsackievirus B3 altered mRNA expression. By integrating GSEA, EnrichR, and iLINCs-based perturbagen analysis, we present a novel, systems-level approach to uncover potential drug repurposing candidates for CVB3 infection. We found dynamic changes in host transcriptomic response to Coxsackievirus B3 infection at 2- and 5-day infection time points. Downregulated pathways included ribosomal biogenesis and protein synthesis, while upregulated pathways included a defense response to viruses, and interferon production. Using iLINCs transcriptomic analysis, MEK, PDGFR, and VEGF inhibitors were identified as possible novel antiviral therapeutics. Our findings further elucidate Coxsackievirus B3-associated pathways in (iBECs) and highlight potential drug repurposing candidates, including pelitinib and neratinib, which may disrupt Coxsackievirus B3 pathology at the blood–brain barrier (BBB). Full article

Apolipoprotein E (APOE) allele 4 (APOE4), one of the robust genetic risk factors for AD, has also been associated with cognitive decline in terms of memory, executive function, language, and global cognitive function. APOE genotype-stratified analysis can help to identify additional genetic loci which might be masked due to a strong effect of APOE4. We conducted a genome-wide meta-analysis in APOE2 carriers, APOE4 carriers, and APOE 3/3 homozygote groups among 2969 non-Hispanic Whites aged ≥ 65 years using slopes of decline over time across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function. We identified novel genome-wide significant associations for decline in global cognitive function in the intergenic region between RNU7-66P/RNA5SP208 at rs116379916 (p = 1.44 × 10⁻⁹) in the APOE 3/3 group and for decline in language in the intergenic region between LINC0221/DTWD2 at rs13187183 (p = 3.79 × 10⁻⁸) in APOE4 carriers. A previously reported locus for decline in attention near RASEF at rs6559700 (p = 9.95 × 10⁻⁹) was found to be confined to the APOE 3/3 group. We also found two sub-threshold significant associations in the APOE 2 group for decline in attention (IL1RL2/rs77127114; p = 8.64 × 10⁻⁸) and decline in language (YTHDC2/KCNN2, rs116191836; p = 5.66 × 10⁻⁸). Our study points to potential biological pathways pertaining to specific domains within each APOE genotype group, and the findings suggest that immune-related pathways, plasma levels of polysaturated fatty acids, and bitter taste receptors may play roles in cognitive decline. Our findings enhance the understanding of cognitive aging and provide a framework for future studies. Full article

Uterine fibroids (leiomyomas) are benign tumors whose growth is influenced by estrogen and progesterone. This study aimed to compare the profiles of differentially expressed long non-coding RNAs (lncRNAs) in fibroids from postmenopausal and premenopausal women to identify hormone-responsive lncRNAs. RNA sequencing was performed on six pairs of fibroid (Fib) and adjacent myometrium (Myo) tissues from postmenopausal women. Out of 7876 normalized lncRNAs, 3684 were differentially expressed (≥1.5-fold), with 1702 upregulated and 1982 downregulated in Fib. Comparative analysis with a previously published premenopausal dataset identified 741 lncRNAs that were altered based on their menopausal status, including 62 lncRNAs that were uniquely dysregulated in postmenopausal samples. Overall, 9 lncRNAs were selected for validation by PCR in an expanded cohort of 31 postmenopausal and 84 premenopausal paired samples. Several lncRNAs, including LINC02433, LINC01449, SNHG12, H19, and HOTTIP, were upregulated in premenopausal Fib but not in postmenopausal ones, while ZEB2-AS1 displayed the opposite pattern. CASC15 and MIAT were elevated in Fib from both groups, although the increase was less pronounced in the postmenopausal group. LINC01117 was significantly downregulated in postmenopausal Fib, with no change observed in premenopausal samples. Additionally, analysis based on MED12 mutation status revealed that lncRNAs such as LINC01449, CASC15, and MIAT showed limited or reduced differential expression (mutation-positive vs. mutation-negative) in postmenopausal patients compared to the premenopausal group. These findings indicate that lncRNA expression in fibroids is modulated by menopausal status, likely reflecting hormonal influence. Hormone-responsive lncRNAs may play key roles in fibroid pathogenesis and represent potential targets for therapeutic intervention. Full article