Search Results (7,202)

The bone marrow tumor microenvironment (TME) is critical for acute myeloid leukemia (AML) progression, immune evasion, and treatment resistance. SRC, a non-receptor tyrosine kinase involved in multiple oncogenic pathways, has not been systematically characterized in AML in relation to prognosis and immune regulation. We integrated bulk transcriptomic and single-cell RNA-sequencing datasets from TCGA, BeatAML, and GEO. Immune-related targets were identified using xCell-based immune scoring and weighted gene co-expression network analysis (WGCNA), followed by protein–protein interaction analysis and multi-algorithm machine-learning screening. We then evaluated SRC expression patterns, prognostic associations, immune microenvironment features, predicted drug sensitivity, single-cell differentiation dynamics, intercellular communication, and in silico virtual knockout perturbation (scTenifoldKnk). SRC emerged as the most robust hub gene after integration of WGCNA, PPI analysis, machine-learning feature selection, and survival screening. SRC was significantly upregulated in AML compared with normal controls and was independently associated with poor overall survival (HR = 1.231, p = 0.037). High SRC expression was linked to adverse ELN/FAB features, increased immune checkpoint expression, enrichment of inflammatory and immunoregulatory pathways, and a higher proportion of primitive leukemia-associated cell states. Single-cell analyses further suggested that SRC was enriched in CD34⁺ progenitor compartments, associated with altered cell–cell communication, and accompanied by distinct mutation and pathway profiles. Drug-response prediction and in silico network perturbation analysis further supported the potential biological and translational relevance of SRC-centered programs. SRC is a prognostically relevant and immune-associated hub linked to AML microenvironment remodeling, and may serve as a candidate biomarker and potential therapeutic target that warrants further experimental validation. Full article

Background: Translocation morphology renal cell carcinoma (tRCC) accounts for nearly half of all pediatric RCC cases. Biological study AREN14B4-Q aimed to characterize the molecular landscape of tRCC using samples acquired from patients enrolled in the Children’s Oncology Group Risk Classification and Biobanking study AREN03B2. Methods: From 2006 to 2014, patients <30 yr old with renal tumors were prospectively enrolled in AREN03B2, a Central IRB-approved biobanking study. All pediatric RCC cases underwent a detailed central pathology review and molecular diagnostics to accurately classify RCC subtypes. Samples with confirmed tRCC and appropriate informed consent were identified with adequate tissue for RNA and DNA extraction, along with germline DNA, for whole-genome sequencing (WGS), RNA sequencing, and DNA methylation analyses. Results: From 41 patients, high-quality samples allowed for 18 tumors and non-tumor DNA to be analyzed via WGS, 19 via DNA methylation, and 36 RNA samples via transcriptome sequencing. Consistent with and extending clinical cytogenetic findings, WGS and fusion transcript analyses confirmed very few additional mutations beyond the tRCC translocation. No recurrent genomic copy number gains/losses were found. RNA and WGS analyses enabled sub-classification of tRCC, closely aligning with the different TFE3 fusion partners. DNA methylation analyses demonstrated less tRCC sub-stratification compared with RNA analyses. Pathways activated in tRCC were involved in epithelial differentiation, extracellular matrix organization, apoptosis, immune regulation, signal transduction, and angiogenesis. Conclusions: Arrested epithelial differentiation is the overarching driver in tRCC and is strongly correlated with the specific subclasses of fusion transcript generated by the genetic translocation TFE fusion partner. Negative regulation of apoptosis, increased M2 macrophage expression, and enhanced angiogenesis also appear to be functional features of tRCCs, as are increased expression of matrix metalloproteinases, PI3K-AKT/mTOR/MAPK signaling, and mitochondrial metabolism, highlighting potential therapeutic options beyond direct targeting of the oncogenic driver fusions. Full article

This study aims to investigate the potential anticancer effects of erucin, an isothiocyanate derived from Eruca sativa, in triple-negative breast cancer (TNBC) by predicting molecular targets and evaluating its in vitro effects on TNBC cell proliferation, apoptosis and cell cycle distribution. Potential protein targets of erucin were identified using SwissTargetPrediction, resulting in 117 targets, of which 84 overlapped with TNBC-related genes sourced from GeneCards, DisGeNET, and OMIM. Protein–protein interaction analysis was performed to identify key hub genes. In vitro experiments were conducted using MDA-MB-231 TNBC cells to assess dose-dependent effects on cell viability. Flow cytometry was employed to evaluate apoptotic cell populations and cell cycle distribution. Protein–protein interaction analysis identified ten hub genes, including AKT1, STAT3, EGFR, and MMP9, representing highly connected nodes within the predicted interaction network. In vitro studies showed dose-dependent reduction in MDA-MB-231 cell viability following erucin treatment, with an IC₅₀ of approximately 48.87 µg/mL. Flow cytometry revealed increased apoptotic cell population and G1 phase accumulation. These findings suggest that erucin is associated with cytotoxic and antiproliferative effects in TNBC cells and may interact with multiple cancer-related targets. However, the identified molecular targets and pathways are based on computational predictions and require further experimental validation. Overall, this study provides a preliminary integrated framework linking computational predictions with experimental observations, which may support future mechanistic and preclinical investigations of erucin in TNBC. Full article

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut–liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut–liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies. Full article

Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. While Ras GTPases are known for oncogenic signaling, emerging evidence implicates the Ras–Ral axis as a critical regulator of glucose homeostasis. This review synthesizes the distinct roles of Ras and Ral in metabolism. Ras hyperactivation promotes insulin resistance and inflammation via MAPK/PI3K pathways, whereas RalA supports GLUT4 translocation and insulin granule exocytosis. We propose a dual-pathway hypothesis: T2DM pathophysiology involves an imbalance characterized by excessive Ras signaling and insufficient Ral-mediated metabolic actions. Consequently, we explore the therapeutic potential of rebalancing this axis through combinatorial strategies, that selectively inhibit pathogenic Ras while enhancing protective Ral activity. We critically evaluate current Ras-targeted agents (e.g., farnesyltransferase inhibitors, allele-specific inhibitors) and discuss the emerging frontier of Ral-specific enhancers. Finally, we outline key translational challenges and future directions for validating this axis as a target for precision medicine in T2DM. Full article

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis that is strongly associated with chronic Clonorchis sinensis (C. sinensis, Cs) infection; however, its underlying molecular mechanisms remain elusive. Recent studies suggest that C. sinensis-derived extracellular vesicles (CsEVs) play a crucial role in host–parasite interactions and in shaping the tumor microenvironment during infection. Acting as key delivery vehicles, these CsEVs can transfer specific functional molecules, such as microRNAs (miRNAs), to host cholangiocytes, thereby modulating cellular behaviors—a process that may represent a significant pathway in parasite-induced carcinogenesis. Despite this, the specific miRNAs shuttled by CsEVs and their concrete functions and mechanisms in driving CCA proliferation and metastasis remain largely unexplored. To this end, we investigated Csi-miR-125a, a miRNA abundantly expressed in CsEVs, aiming to systematically elucidate its dual regulatory functions in CCA progression. Our findings offer novel mechanistic insights into host–parasite crosstalk, further the understanding of CCA pathogenesis, and point to potential therapeutic avenues. Using gain-and loss-of-function approaches in RBE and HuCCT1 cell lines, we demonstrated that Csi-miR-125a promotes cell proliferation by accelerating cell-cycle progression and suppressing apoptosis through direct targeting of BAK1. Concurrently, Csi-miR-125a enhances the migratory and invasive capacities of CCA cells via activation of the ERK signaling pathway. In a BALB/c nude mouse lung metastasis model, CsEVs depleted of Csi-miR-125a significantly inhibited pulmonary metastasis. Collectively, This study found that Csi-miR-125a derived from C. sinensis can regulate apoptosis and cell cycle progression by targeting BAK1, thereby promoting the proliferation of cholangiocarcinoma cells; meanwhile, it enhances cell migration and invasion by activating the ERK signaling pathway. These results suggest that Csi-miR-125a participates in and promotes the malignant progression of CCA. However, given its high homology with human endogenous miR-125a, its function may partially overlap with host endogenous miRNAs, rather than representing a completely independent carcinogenic effect. These findings provide mechanistic insights into host–parasite interactions during C. sinensis infection and lay a theoretical foundation for subsequent targeted intervention studies. Full article

Colorectal cancer (CRC) shows consistent sex-related differences in incidence, anatomic distribution, molecular subtype, immune context, and clinical outcome. However, these differences are often discussed through broad parallel themes such as hormones, genetics, or the microbiome, rather than through the biological settings in which sex meaningfully modifies tumor behavior. This review argues that sex is most informative in CRC when treated as a contextual modifier whose relevance emerges only after integrating tumor sidedness, mismatch repair status, oncogenic background, immune ecology, and age at onset. The clearest signals arise from interaction-based contexts, particularly when sex is interpreted together with tumor sidedness and dMMR/MSI-H or BRAF-linked disease states. Current evidence indicates that women are enriched for proximal or right-sided, microsatellite instability-high, mismatch repair-deficient, CpG island methylator phenotype-high, and BRAF-associated CRC, whereas men more often present with distal disease and a higher overall burden. Mechanistic studies further show that sex-related differences extend beyond hormone exposure to include KRAS–STAT4–KDM5D signaling, site-specific immune-checkpoint programs, metabolic phenotypes, epigenetic biomarker variation, and microbiota–hormone crosstalk. These effects are most evident in defined clinical niches, particularly right-sided CRC, mismatch repair-deficient disease, BRAF-mutated metastatic CRC, and early-onset CRC. A sex-aware, subtype-aware, and location-aware framework therefore offers a more clinically useful interpretation of CRC heterogeneity than descriptive male-versus-female comparisons alone. Full article

Background/Objectives: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the clonal proliferation of Langerhans-like dendritic cells and constitutive activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E), and mitogen-activated protein kinase kinase 1 (MAP2K1) variants, with BRAF V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. The use of the HistioTrak clinical assay to detect the presence of BRAF V600E mutations in peripheral blood mononuclear cells (PBMCs) has emerged as a useful diagnostic tool and biomarker. Methods: This study is a single-center retrospective study that explores the favorable outcomes of treatment with trametinib on a small number of patients with LCH. We retrospectively analyzed the records of 11 children with LCH treated with trametinib at diagnosis as front-line therapy (n = 6), due to progressive disease (n = 3) or intolerance (n = 1) to chemotherapy, or at relapse (n = 1). Results: HistioTrak identified the presence of BRAF V600E PBMCs in five patients. In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Conclusions: Prospective studies are needed before routine diagnostic or monitoring use can be recommended. Full article

Background/Objectives: Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to maintain optimal function. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616, which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Methods: Building upon this foundation, we developed and characterized a recombinant murine monoclonal antibody (referred to as 3G11) with high specificity for human DRP1-S616Ⓟ, raised against a peptide derived from the human DRP1 sequence. Results: Using diverse experimental platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels, which correlates with mitochondrial hyperfusion, while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF^V600E disease. Conclusions: 3G11 is a new recombinant antibody for detecting DRP1-S616Ⓟ and supports studies of mitochondrial division in cancer. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications. Full article

Background: The systematic identification of transcriptional repressors remains challenging, as current inference frameworks are predominantly optimized for accessible chromatin, leaving regulatory signals embedded within repressive domains undercharacterized. Methods: Here, we present NuRepress, a computational framework that predicts candidate transcriptional repressors by integrating repressive chromatin architecture, functional signatures, and transcriptional outcomes. NuRepress first identifies well-phased nucleosome arrays within repressive chromatin. These arrays are treated as discrete structural units that capture characteristic local chromatin organization associated with regulatory activity. Since distinct Tn5 cut signal patterns often imply divergent regulatory functions, the framework stratifies these arrays into potential functional subtypes. By synthesizing the quantified repressive efficacy of each subtype with spatial motif enrichment and observed transcriptional dynamics, NuRepress systematically prioritizes and ranks candidate repressors. Results: Our analysis indicated that well-phased nucleosome arrays exhibited accessibility-defined organizational patterns with distinct repressive efficacies, and that these patterns were also observed across species, suggesting that the structural principles captured by NuRepress might extend beyond one specific biological system. Positional motif analysis revealed that distinct TFs exhibited different spatial preferences relative to well-phased nucleosome arrays, suggesting scale-specific preferences for their interactions with these organized chromatin structures. When applied to pancreatic cancer progression, NuRepress identified changes in nucleosome organization associated with stage-specific transcriptional remodeling, highlighting candidate repressors of key oncogenic drivers. Conclusions: NuRepress establishes a structure-aware strategy for repressor inference that extends regulatory genomics beyond accessibility-centered paradigms. By linking well-phased nucleosome organization to transcriptional outcomes, it provides a principled framework for dissecting transcriptional repression across diverse biological settings. Full article

Breast carcinoma is a major cause of cancer-related mortality among women worldwide. Identifying novel molecular targets remains essential, particularly for aggressive triple-negative breast cancer (TNBC). Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been linked to tumor progression and angiogenesis, but its molecular mechanisms in breast cancer are poorly defined. We evaluated the effects of recombinant human LRG1 (rhLRG1) on cell viability and migration in MDA-MB-231 TNBC cells and performed transcriptomic profiling followed by functional enrichment analyses using GenArise, Cytoscape, and R-based tools. RhLRG1 treatment significantly increased cell viability and migration. Transcriptomic analysis revealed activation of key oncogenic cascades, including the PI3K/AKT, MAPK, and RAS signaling pathways. Hub-gene analysis identified upregulated genes involved in proliferation (NRAS, STAT5B, IGF2), angiogenesis (PGF, ANGPT2), and apoptosis (CASP8, BAD), whereas downregulated genes were associated with apoptotic resistance (BCL2, MCL1) and adhesion (LAMB1, ITGB4). Functional enrichment highlighted LRG1’s role in the bioinformatic analysis of differentially expressed genes that were obtained from microarray assays. LRG1 remodels the tumor microenvironment by promoting proliferation, angiogenesis, and apoptotic sensitivity while repressing resistance-related genes. These findings position LRG1 as a potential diagnostic biomarker and therapeutic target for advanced breast carcinoma. Full article

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are major risk factors for lung cancer and other diseases, acting through the aryl hydrocarbon receptor (AHR). Alveolar macrophages (AMs) help regulate the lung microenvironment by responding to inhaled toxicants and resident microbiota. Although small extracellular vesicles (sEVs, aka exosomes) released by AMs mediate intercellular communication and immune responses, the influence of lung microbiota on sEV biogenesis and the mechanisms underlying sEV dysregulation during PAH exposure remain unknown. Here, we investigated the interplay between AMs, B[a]P, and lung microbiota, focusing on sEV-associated miRNAs (exo-miRNAs). Murine AMs (MH-S) were exposed to varying B[a]P concentrations in the presence or absence of murine lung microbiota with or without an AHR antagonist. sEVs from each condition were characterized and profiled for miRNA. Distinct miRNA signatures emerged: high-dose B[a]P enriched miRNAs linked to cancer progression, whereas lung microbiota alone or with low-dose B[a]P induced tumor-suppressor miRNAs that limit proliferation and metastasis and promote apoptosis, an effect enhanced by AHR antagonism. Lung microbiota appeared to counteract high-dose B[a]P by modulating tumor-suppressive exo-miRNAs. This study demonstrates that lung microbiota-induced exo-miRNAs critically shape AM-derived sEV-miRNA signaling during PAH exposure. The identified exosomal miRNAs could serve as important exposure biomarkers and therapeutic targets for mitigating B[a]P-induced toxicity and cancer development. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article