Background Gastric cancer (GC) remains a major cause of cancer-related mortality, and biomarkers for early detection are needed. Methods Stomach and blood expression quantitative trait loci were integrated with two GC genome-wide association studies using Mendelian randomization (MR), Bayesian colocalization, and summary-data-based MR/heterogeneity in dependent instruments (SMR/HEIDI) testing. Bulk and single-cell transcriptomic analyses characterized candidate expression and lesion-associated patterns. CDC16 protein expression was evaluated by immunohistochemistry in 53 paired GC and non-neoplastic tissues, followed by paired and exploratory receiver operating characteristic analyses. Results MR prioritized PILRB , CDC16 , and GABPB1-AS1 ; SMR/HEIDI provided complementary support, while colocalization for CDC16 and GABPB1-AS1 was suggestive and model-dependent. Bulk-tissue CDC16 abundance was higher in GC, but the modest TCGA-STAD tumor–normal difference (log2FC = 0.210, FDR = 0.019) was attenuated after proliferation adjustment (log2FC = −0.002, FDR = 0.987), indicating close coupling with proliferative activity. Single-cell analysis localized CDC16 predominantly to epithelial populations, and the proportion of CDC16 -detectable epithelial cells increased across lesion categories (ρ = 0.735; permutation P = 0.031). CDC16 H-scores were higher in GC than in paired non-neoplastic tissues (161.15 ± 45.11 vs 102.15 ± 54.50; P < 0.001), with higher cancer-tissue scores in 41 of 53 cases. Exploratory AUC was 0.794 (95% CI, 0.704–0.874; sensitivity, 66.0%; specificity, 79.2%). Conclusions Convergent genetic, transcriptomic, and protein-level evidence prioritizes CDC16 as a GC-associated candidate tissue marker whose expression is closely linked to proliferative activity. Prospective validation in independent cohorts, including appropriate disease controls and blood-based evaluation, is warranted.
Background The PD-1/PD-L1 axis represents a key mechanism of tumor immune evasion. However, its expression across different immune compartments and clinical implications in DLBCL patients remain unclear. Methods This study included 67 newly diagnosed DLBCL patients and 59 healthy controls. The levels of PD-1-positive T cells in the peripheral blood (PB) and bone marrow (BM) were assessed via flow cytometry. Furthermore, this study analyzed the correlation between PD-1 expression on PB and BM T-cell subsets and the clinicopathological features of DLBCL patients to elucidate their clinical implications. Results Compared with healthy controls, DLBCL patients presented significantly elevated PD-1 expression on T cells in both the PB and BM. Elevated PD-1 expression is significantly correlated with adverse clinical outcomes and poor prognostic factors, including advanced Ann Arbor stage (III-IV), a high International Prognostic Index (IPI 3-5), elevated lactate dehydrogenase (LDH>250 U/L) and the presence of B symptoms. A strong concordance in PD-1 levels was observed between paired PB and BM samples. Conclusion Increased PD-1 expression in the peripheral blood of DLBCL patients is correlated with PD-1 expression in the bone marrow. Our results demonstrate that elevated circulating PD-1+T cells are associated with high-risk, aggressive disease features. Importantly, our data support the potential utility of peripheral blood PD-1+T cells as a minimally invasive surrogate biomarker to reflect intramedullary T cell exhaustion. DLBCL patients with abundant circulating PD-1+T cells may have greater potential to respond to PD-1/PD-L1 blockade immunotherapy, although this hypothesis requires prospective validation. These findings warrant further clinical investigation.
Background Lactylation has emerged as a crucial post-translational modification that influences oncogenesis and tumor progression. However, its intratumoral heterogeneity in osteosarcoma is not well characterized. Methods Single-cell multi-omics data were retrieved from the Gene Expression Omnibus database. Lactylation heterogeneity was assessed, cell-cell communication networks were constructed, and transcription factor activity was analyzed to delineate differences among cell populations. Bioinformatics analysis coupled with experimental validation was employed to screen for potential targets. Results The study revealed that the overall lactylation level was significantly elevated in osteosarcoma tissues compared to adjacent non-tumor tissues. At the single-cell level, osteosarcoma-derived osteoblastic cells exhibited markedly higher lactylation scores than their counterparts from adjacent non-tumor tissue. Bioinformatics analysis identified NUF2 as a potential biomarker associated with the high-lactylation malignant state. Subsequent experimental validation confirmed that NUF2 is overexpressed in osteosarcoma tissues and co-localizes with pan-Kla. Conclusion This study presents a single-cell lactylation atlas of osteosarcoma, identifies NUF2 as a potential biomarker associated with the high-lactylation malignant state, and provides a novel theoretical basis for the clinical translation of lactylation-targeted therapies.
Background Gastric cancer (GC) is a highly prevalent malignant tumor worldwide. Traditional treatment approaches have numerous limitations, and messenger RNA (mRNA)-targeted therapy offers a new direction for the treatment of GC. Objective To investigate the expression characteristics and clinical significance of miR-145-3p in GC, as well as its mechanism of action in regulating GC cell function by targeting CREB1. Methods Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-145-3p and CREB1 in GC tissues, serum, and cell lines. Cell Counting Kit-8, Transwell, and qRT-PCR assays were employed to evaluate the effects of miR-145-3p and CREB1 on GC cell proliferation, migration, invasion, and apoptosis. Bioinformatics prediction, dual-luciferase reporter assays, and rescue experiments were conducted to validate the targeted regulatory relationship between miR-145-3p and CREB1. Downstream signaling pathways were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results miR-145-3p is significantly downregulated in GC, which is closely linked with tumor malignant progression and negative prognosis. miR-145-3p mimic inhibits the proliferation, migration, and invasion of GC cells while promoting apoptosis; conversely, CREB1 OE produces the opposite effect. Bioinformatics and functional experiments confirmed that miR-145-3p targets CREB1, and CREB1 OE partially reverses the tumor-suppressive effects of miR-145-3p. GO and KEGG analyses revealed that the miR-145-3p/CREB1 axis participates in transcription regulation, metabolism, and virus-related carcinogenesis pathways. Conclusion miR-145-3p exerts effects in GC, at least in part, by targeting and inhibiting CREB1, positioning it as a potential molecular target for GC diagnosis, prognosis assessment, and mRNA-targeted therapy.
BackgroundPhosphofructokinase-platelet (PFKP) is a rate-limiting enzyme in glycolysis. PFKP is highly expressed across many cancer types including breast cancer.PurposeTo assess the extent to which PFKP can be a prognostic indicator in breast cancer and its ability to predict treatment response. To further understanding of the interaction between PFKP and key signaling pathways in cancer progression, the immune system, and epigenetics.MethodsUsing online platforms (Kaplan-Meier plotter, receiver operating characteristic curve plotter, cBioPortal, and Tumor-Immune System Interaction Database (TISIDB)), a bioinformatic analysis was conducted to establish the prognostic and predictive effects related to PFKP expression in breast cancer. A network analysis was performed using the Oncomine platform where signaling, epigenetic, and immune regulation pathways were investigated.ResultsPFKP had a poor prognostic effect in breast cancer, demonstrated at both the RNA and protein levels. This effect was prominent in advanced breast cancers. PFKP appeared to recruit hallmark cancer pathways early in the progression lifecycle, from ductal carcinoma in situ to advanced cancer. PFKP was a biomarker of resistance to chemotherapy in the short-term for luminal A breast cancer and triple-negative breast cancer, and of sensitivity to endocrine therapy over the long term for luminal B breast cancer. PFKP interacts with immune system components such tumor-infiltrating lymphocytes, chemokines, and immunomodulators.ConclusionsPFKP is overexpressed in breast cancer and has a poor prognostic effect, particularly in aggressive subtypes and advanced disease. It plays a key role in hallmark cancer pathways and interacts with the immune system in ways that could be harnessed for future therapeutic development.
Background Chronic inflammation from visceral obesity contributes to metabolic disorders and cancer through cytokine imbalance. Accurate cytokine measurement is crucial to understand these links. This study examined challenges in quantifying interleudin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin in historical biobank samples with limited volumes and varying plasma anticoagulants. Methods Luminex-MAGPIX platform was used to evaluate three analytical aspects. Single-well precision was assessed via intra- and inter-assay coefficients of variability (CVs). Plasma matrix effects were examined by pairwise comparison of analyte concentrations across citrate, heparin, and EDTA plasma from 10 volunteers. Cytokine stability was tested after one freeze-thaw cycle (analysis of variance). Results Single-well measurements showed good precision (CV <10% intra-assay, <15% inter-assay). Plasma matrix affected absolute concentrations. In particular, all analytes were lower in citrate than in EDTA and heparin, but relative relationships and subject-specific rankings remained preserved. Pearson correlation coefficients for IL-6, leptin, and adiponectin were high across matrices (r-range = 0.952–0.999), whereas correlations for TNF-α were lower (r-range = 0.897–0.972). Freeze–thaw stability was analyte- and matrix-dependent: leptin remained stable in heparin and EDTA but decreased 9.5% in citrate; adiponectin was stable in citrate but decreased in heparin (−9.0%) and EDTA (−11.8%). IL-6 and TNF-α were unaffected. Conclusion IL-6, TNF-α, leptin, and adiponectin were accurately quantified using single-well Luminex assays and showed reasonable tolerance to a single freeze–thaw cycle, offering a practical strategy for preserving valuable specimens. Although plasma anticoagulant affected absolute concentrations, the preservation of relative analyte rankings permits their use in most study designs but limit absolute value comparisons.
Liquid biopsy has emerged as a powerful approach for non-invasive cancer monitoring, with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) representing biologically distinct yet complementary analytes. Cell-free DNA (cfDNA) refers to fragmented DNA released into circulation from both normal and malignant cells, whereas ctDNA constitutes the tumor-derived fraction of cfDNA and carries cancer-specific genetic and epigenetic alterations. CTCs provide intact cellular material that enables phenotypic, transcriptomic, and functional characterization, offering unique insights into metastatic dissemination, tumor heterogeneity, and therapeutic resistance. In contrast, ctDNA enables sensitive detection of somatic mutations, copy number alterations, methylation patterns, and fragmentomic features that reflect tumor burden and clonal evolution. Clinically, ctDNA assays have achieved greater regulatory maturity, with several US Food and Drug Administration-approved tests for therapy selection, minimal residual disease (MRD) detection, and relapse monitoring, while most CTC-based platforms remain investigational or limited to specific clinical contexts. Importantly, combining CTC analysis with ctDNA profiling enhances biological resolution by integrating cellular behavior with molecular dynamics, overcoming limitations inherent to either analyte alone. Emerging advances in fragmentomics, methylation profiling, and ultra-deep sequencing are further expanding the sensitivity and clinical utility of ctDNA, particularly for early cancer detection and MRD assessment. This review critically evaluates the translational readiness, technical challenges, and clinical applications of CTCs and ctDNA, highlighting their synergistic potential in precision oncology.
Background Breast cancer is the leading cause of cancer-related mortality among women in developing nations. NFKBIA encodes the inhibitors of nuclear factor-kappaB (NF-κB), which plays a critical role in modulating inflammation and carcinogenic processes. However, no prior studies were conducted to determine the association between NFKBIA polymorphisms and breast cancer susceptibility in the Bangladeshi population. Therefore, we aimed to examine the association of the NFKBIA (rs696) polymorphism with breast cancer risk in Bangladeshi women. Methods This case-control study involved 168 breast cancer patients and 150 healthy volunteers, utilizing polymerase chain reaction-restriction fragment length polymorphism. We assessed the p -value, odds ratio (OR), and 95% confidence interval (CI) to analyze the level of risk association of rs696. Results The cancer patients exhibited a higher mutant allele frequency than the controls. Breast cancer patients who are carriers of the mutant allele demonstrated a markedly elevated risk in two genetic models, including the additive model 2 (GG vs. AA: OR = 2.09, 95% CI = 1.03–4.23, p -value=0.042) and the dominant model (AG + GG vs. AA: OR = 1.73, 95% CI = 1.07–2.78, p -value=0.025). Moreover, the analysis of allele frequency indicated that carriers of the mutant allele G among breast cancer patients exhibited a significantly elevated risk compared to carriers of the wild-type A allele (G vs. A: OR = 1.42, 95% CI = 1.04–1.96, p -value=0.029). Conclusion Our results suggest that NFKBIA (rs696) might be associated with an increased risk of breast cancer in Bangladeshi women. However, we recommend studies in the future with a larger sample size to validate these findings.
BackgroundAxillary lymph node metastasis (ALNM) serves as a critical prognostic determinant in breast cancer, yet the molecular drivers governing lymphatic dissemination remain poorly characterized. Integrating single-cell transcriptomic profiling with Mendelian-randomization (MR)-based genetic prioritization may help reveal cell type-specific mechanisms underlying metastatic progression.MethodsWe analyzed the GSE195861 single-cell RNA sequencing dataset encompassing six invasive ductal carcinoma (IDC) samples and paired ALNM specimens. t-distributed Stochastic Neighbor Embedding-based clustering and SingleR annotation delineated cellular heterogeneity, while differential expression analysis identified metastasis-associated genes in epithelial compartments. MR analysis employing five robust methods (inverse variance-weighted, weighted median, MR-Egger, simple/weighted mode) integrated genome-wide association study data (GCST90018799) to establish causal gene-breast cancer associations. CellChat reconstructed ligand-receptor networks across nine annotated cell types.ResultsUnsupervised clustering resolved 27 cell clusters into nine lineages, revealing ALNM-specific expansion of monocytes, pre-B cells, and CD34+ hematopoietic stem cells (HSCs). Epithelial cells exhibited 2421 differentially expressed genes (DEGs) between IDC and ALNM, including 12 genes whose genetically predicted expression showed significant associations with breast cancer risk in MR analysis (P < 0.05). CD53 (odds ratio (OR) = 1.110, 95% confidence interval (CI) = 1.019-1.209, P = 0.017) and TCDD-inducible poly-ADP-ribose polymerase (TIPARP) (OR = 1.153, 95% CI = 1.032-1.288, P = 0.012) were prioritized as candidate genes, as their genetically predicted expression was associated with increased breast cancer risk in weighted median MR. Cell-cell communication analysis implicated macrophage-derived midkine-nucleolin signaling and B-cell-orchestrated macrophage migration inhibitory factor-(CD74 + CXCR4) axis in metastatic crosstalk. Functional enrichment linked DEGs to extracellular matrix remodeling and MAPK/PI3K-Akt activation.ConclusionThis multi-omics integration prioritizes CD53 and TIPARP as ALNM-associated candidate genes with genetically supported associations with breast cancer risk, with macrophage-epithelial and B-cell-HSC interactions serving as potential therapeutic targets. Our findings provide a roadmap for developing metastasis-interceptive strategies through precision targeting of the ALNM-associated tumor microenvironment.
BackgroundNon-small cell lung cancer (NSCLC) patients who have mutations in their epidermal growth factor receptor (EGFR) gene respond more favorably to tyrosine kinase inhibitors (TKIs) than to standard chemotherapy. However, tissue biopsy-based EGFR testing is invasive, costly, and technically challenging. Plasma-derived circulating tumor DNA (ctDNA) offers a minimally invasive and cost-efficient alternative for mutation profiling. This study assessed the agreement between EGFR mutation status in plasma-derived ctDNA and tissue biopsy in NSCLC patients from tertiary care hospitals in Bangladesh.MethodsIn this cross-sectional analytical study, we recruited 32 patients with NSCLC before EGFR-TKI treatment. EGFR mutations in ctDNA samples were identified using the Amplification Refractory Mutation System (ARMS) polymerase chain reaction method. Tissue biopsy results were obtained from routine diagnostic procedures. Agreement between ctDNA and tissue biopsy results was assessed using kappa statistics, and diagnostic performance metrics were calculated.ResultsMost of our study participants were male (75%) and had stage IV lung adenocarcinoma (72%). We observed substantial agreement between plasma-derived ctDNA samples and tissue biopsies (kappa, κ = 0.683). This agreement was almost perfect (κ = 0.826) when calculated for patients with stage IV disease. The overall concordance was 84.4%. Compared with tissue biopsy, ctDNA testing yielded a sensitivity of 73.3% and a specificity of 94.1%.ConclusionPlasma-derived ctDNA demonstrates substantial agreement with tissue biopsy for EGFR mutation detection in patients with NSCLC, particularly those with advanced-stage disease. These findings support ctDNA as a viable alternative for molecular profiling in settings where tissue biopsy is limited or impractical.
Background Despite treatment advances, prognoses of patients with advanced colorectal cancer remain poor. The limited effectiveness of programmed cell death protein 1 (PD-1) blockade immunotherapy in a subset of patients necessitates a deeper understanding of the colorectal cancer microenvironment. This study aimed to identify new therapeutic targets and potential biomarkers by investigating CD8 + CD101hiTim3+ (CCT) T cells and their progenitors in colorectal cancer, and their association with immunotherapy response at the transcriptomic level.Methods We used single-cell sequencing data and The Cancer Genome Atlas database for comprehensive bioinformatics analysis, including single-cell sequencing data analysis, Gene Set Variation Analysis, pseudotime analysis, cell communication analysis, and construction and validation of a prognostic model.Results Key findings include the identification and annotation of various T-cell subtypes in colorectal cancer, construction of a pseudotime trajectory of CCT T cells and their progenitors showing dynamic gene expression changes, and enhanced interactions between CCT T cell progenitors and other cells in the PD-1 immunotherapy group. We developed and validated a prognostic model comprising 15 gene features with strong prognostic stratification performance, revealing that high-risk patients exhibit transcriptomic associations with potentially reduced responses to immune checkpoint inhibitors (ICIs). Pathway enrichment analysis highlighted critical pathways, including leukocyte adhesion and T cell activation, indicating complex influences on disease progression and treatment responses within the colorectal cancer immune landscape.Conclusions This study emphasizes the potential importance of targeted therapies that modulate immune interactions and functional states to improve colorectal cancer prognosis, particularly in high-risk patients who show an association at the transcriptomic level with reduced ICI responsiveness.
BackgroundOvarian cancer is a lethal malignancy with limited therapeutic options, highlighting the urgent need to identify reliable biomarkers and therapeutic targets. This study investigates the clinical and oncogenic significance of β-hydroxybutyrate dehydrogenase 1 (BDH1) as a potential therapeutic target in ovarian cancer.MethodsIntegrative genomic analyses were conducted to evaluate the oncogenic potential of BDH1 by assessing its gene amplification and expression patterns in ovarian cancer. Functional assays, including BDH1 knockdown, were performed to examine its effects on proliferation, colony formation, cell cycle, and stemness. Mechanism exploration involved assessing the Wnt/β-catenin pathway. Virtual screening was used to identify BDH1 inhibitors.ResultsBDH1 was identified as a crucial oncogene in ovarian cancer progression, characterized by frequent gene amplification and overexpression, which strongly correlated with advanced disease stage and poor patient prognosis. Functionally, BDH1 promoted tumor progression by regulating G1/S transition proteins and maintaining cancer stemness via Wnt/β-catenin signaling. BDH1 depletion suppressed malignant phenotypes, confirming its oncogenic role. BDH1 was pharmacologically targeted by centrinone, which effectively downregulated oncogenic effectors.ConclusionOur study underscores BDH1 as a multifunctional oncogenic driver in ovarian cancer. The strong association of BDH1 with aggressive disease underscores its clinical relevance as a prognostic predictor, while its functional role and pharmacological inhibition position BDH1 as a promising therapeutic target for ovarian cancer.
ObjectivesWe investigated the interactions among DHX9, phosphorylated DHX9, R-loops, and DNA damage to clarify the mechanism by which phosphorylated DHX9 inhibited lung adenocarcinoma progression.MethodsUsed PC-9 and 2BS cells divided into control, siDHX9, OE-DHX9, siDHX9 + OE-RNase H1, OE-PKA, DHX9-S279A, 6-22 Amide, and DHX9-S279A + OE-RNase H1 groups. Assays included quantitative real-time polymerase chain reaction (qRT-PCR), WB (DHX9, γH2AX, Rad51, pCtIP), EdU/CCK-8 (proliferation), TUNEL/flow cytometry (apoptosis), comet assay (DNA damage), CldU/IdU (replication), DRIP-qPCR (R-loops). Nude mice xenografts (control, siDHX9, DHX9-S279E, DHX9-S279A) assessed tumor growth, Ki67, R-loops, DNA damage, and replication.ResultsDHX9 was highly expressed in multiple cancer tissues and lung cancer cell lines, with higher messenger RNA levels in PC-9 than in 2BS cells. Compared with PC-9, siDHX9 reduced proliferation and increased apoptosis, while OE-DHX9 exerted opposite effects. siDHX9 increased DNA damage (with corresponding changes in γH2AX, Rad51, and pCtIP levels), reduced replication (rescued by OE-RNase H1), and elevated R-loops; OE-DHX9 showed opposite effects on damage and R-loops. OE-PKA increased R-loops and damage, and reduced replication, while DHX9-S279A or 6-22 Amide decreased these and 6-22 Amide also increased replication versus PC-9/OE-PKA. DHX9-S279A increased proliferation, with DHX9-S279A + OE-RNase H1 further enhancing this and reducing apoptosis. In vivo, siDHX9 and DHX9-S279E reduced tumor volume/mass and Ki67, increased R-loops, damage, and γH2AX/Rad51/pCtIP, and inhibited replication; DHX9-S279A showed opposite effects versus these groups, with no significant tumor difference versus PC-9 and higher replication versus both.ConclusionsPhosphorylated DHX9 might enhance DNA damage by suppressing R-loop resolution, ultimately inhibiting the proliferation of lung adenocarcinoma cells.
IntroductionCervical cancer represents a significant global health problem, ranking as the fourth most prevalent malignant cancer in women, particularly in low- and middle-income countries. Epigenetic silencing via aberrant methylation of tumor suppressor genes' promoters represent a second hit of cancer initializing, as well as progressing. The aim of current meta-analysis was to systematically evaluate the potential of DNA methylation-based biomarkers in non-invasive or minimal invasive samples using molecular-based approaches for cervical cancer screening and diagnosis.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was applied to perform our meta-analysis. The frequency, odds ratios, sensitivity as well as specificity with the corresponding 95% confidence intervals were used to assess the effect sizes.ResultsThere were 20 eligible articles ultimately included in the current meta-analysis. In this meta-analysis, multiple tumor suppressor genes, such as, especially, PAX1, SOX1, CDO1, GHSR, were shown to undergo hypermethylation in cervical cancer samples compared with controls. Urine samples, when combined with MSP- and qMSP-based approaches, emerged as a particularly effective non-invasive strategy.ConclusionThe current meta-analysis highlighted the important steps toward establishing DNA-methylation-based biomarkers as accessible and reliable tools for CC screening and diagnosis.
BackgroundLung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related deaths worldwide, with limited therapeutic efficacy despite advances in treatment. Our study investigated the role of LINC00578 and its regulatory interaction with miR-153-5p in LUAD progression.MethodsThe expression levels of LINC00578 and miR-153-5p were assessed in LUAD tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction. Associations between LINC00578 expression and clinicopathological features and patient prognosis were analyzed. Luciferase reporter assays, proliferation, migration, invasion, and apoptosis analyses, were conducted in LUAD cell lines (PC-9 and H1299) following modulation of LINC00578 and miR-153-5p expression.ResultsLINC00578 was significantly upregulated in LUAD tissues compared to adjacent normal tissues, whereas miR-153-5p was markedly downregulated. High LINC00578 expression was associated with lymph node metastasis, tumor-node-metastasis stage, and poor overall survival. Functional studies revealed that silencing LINC00578 inhibited LUAD cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, LINC00578 exerted its oncogenic effects by negatively regulating miR-153-5p expression. Inhibition of miR-153-5p reversed the tumor-suppressive effects induced by LINC00578 knockdown.ConclusionLINC00578 functions as an oncogenic long non-coding RNA in LUAD by promoting proliferation and metastasis through suppression of miR-153-5p. LINC00578 may serve as a novel prognostic biomarker for LUAD.
Objectives: To explore the causal associations between oxidative stress markers and the occurrence of various types of lymphomas. Methods: This two-sample Mendelian randomization (MR) study employed summary data from genome-wide association studies of oxidative stress markers and various lymphoma types. Analysis was conducted using the inverse variance weighted, with confirmation using the weighted median, weighted mode, and MR-Egger regression methods. Heterogeneity, horizontal pleiotropy, outliers, and robustness were tested using the Cochran Q, MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out methods. Results: Genetically predicted myeloperoxidase (MPO) was causally associated with follicular lymphoma (odds ratio (OR) = 1.33, P= 0.0173). Uric acid showed a causal link to diffuse large B-cell lymphoma (DLBCL) (OR = 1.003, P= 0.043). Glutathione peroxidase (GPX) was associated with follicular lymphoma (OR = 1.16, P= 0.033). Catalase (CAT) was inversely associated with non-Hodgkin lymphoma (NHL) (OR = 0.8921), non-follicular lymphoma (OR = 0.8755), and follicular lymphoma (OR = 0.8364) (all P< 0.05). Glutathione-S transferase (GST) was inversely associated with NHL (OR = 0.9248) and follicular lymphoma (OR =0.8313) (all P< 0.05). Heterogeneity was noted for uric acid and DLBCL, but no pleiotropy was detected; after outlier removal, the association with uric acid was non-significant. Conclusions: The findings suggest causal relationships between oxidative stress markers and lymphoma risk, notably MPO and GPX with follicular lymphoma, and inverse associations for GST and CAT with different lymphoma types. Limitations include heterogeneity for some markers, requiring further validation.
PurposeThis study aimed to investigate KRAB-associated protein 1 (KAP1) expression in pleural mesothelioma (PM) and its impact on the biological behavior of the human pleural mesothelioma cell line MSTO-211H, providing a specific biomarker for the early clinical diagnosis of PM.Patients and methodsKAP1 expression levels in PM tissues were detected using immunohistochemistry. Lentivirus infection was used to construct MSTO-211H mesothelioma cell lines with stable KAP1 overexpression or knockdown, and the efficiency of KAP1 overexpression or knockdown was detected using qRT-PCR(quantitative Reverse Transcription PCR) and Western blotting. The effects of KAP1 overexpression and knockdown on MSTO-211H mesothelioma cell proliferation, migration, and invasion were detected using cell counting kit-8, plate colony formation, cell scratch, and transwell invasion assays, respectively. The effects of KAP1 overexpression and knockdown on the cell cycle, related cyclins, and apoptosis were detected using flow cytometry. Gene enrichment and correlation analysis of mesothelioma were performed using bioinformatics analysis.ResultsKAP1 was significantly overexpressed in PM tissues compared with normal pleural tissues (P < 0.05). Compared to the control group, KAP1 overexpression in mesothelioma MSTO-211H cells significantly enhanced proliferation, migration, and invasion (P < 0.05), without causing cell cycle arrest, and significantly increased the mRNA and protein levels of cyclin D1 and cyclin E (P < 0.05), whereas the apoptosis rate did not significantly change (P > 0.05). Conversely, KAP1 knockdown in mesothelioma MSTO-211H cells significantly inhibited their proliferation, migration, and invasion abilities (P < 0.05), induced G0/G1 phase arrest in the cell cycle, and significantly increased the apoptosis rate (P < 0.05). Spearman correlation analysis revealed significant positive associations between KAP1 mRNA expression and TP53 and SHOX2. Conversely, KAP1 expression was significantly negatively correlated with MTAP and MSLN. GSEA reveals KAP1-associated enrichment of DNA repair, cell cycle, and proteostasis pathways in TCGA-MESO.ConclusionKAP1 is highly expressed in PM and functions as an oncogene-like regulator, enhancing tumor cell growth and aggressiveness.Clinical trial registration2023-28.
BackgroundEsophageal cancer is an aggressive malignant tumor, and its incidence rate is constantly increasing. Searching for a new biomarker is essential for the study of esophageal cancer.MethodsThe microRNA and messengerRNA expression levels were measured by employing RT-qPCR. The diagnostic value of miR-1303 in esophageal cancer was measured by the receiver operating characteristic curve. In TE-1 cells and KYSE520 cells, miR-1303 and CLDN18 were overexpressed or inhibited by transfection. The target of miR-1303 was forecasted by the TargetScan online database, which was identified by the dual-luciferase reporter system. The correlation between miR-1303 and CLDN18 in esophageal cancer was analyzed.ResultsMiR-1303 in esophageal cancer tissues increased and had a high diagnostic value in esophageal cancer. In TE-1 cells and KYSE520 cells, the overexpression of miR-1303 increased the proliferation and decreased the apoptosis, and the inhibition of miR-1303 decreased the proliferation and increased the apoptosis. The overexpression of miR-1303 significantly increased MMP2 and MMP9 and decreased E-cadherin in TE-1 cells and KYSE520 cells, and the inhibition of miR-1303 decreased MMP2 and MMP9 and elevated E-cadherin in TE-1 cells and KYSE520 cells. In esophageal cancer tissues, the expression of CLDN18 was significantly reduced, and CLDN18 was negatively correlated with miR-1303. In TE-1 cells and KYSE520 cells, the up-regulation of CLDN18 alleviated the progression of esophageal cancer caused by miR-1303.ConclusionMiR-1303 was increased in esophageal cancer tissue and had a high diagnostic value in esophageal cancer. MiR-1303 promoted the invasion and metastasis of esophageal cancer. In esophageal cancer, the inhibition of miR-1303 suppressed the development by targeting CLDN18.
PurposeAlthough human lysine oxidase-like 3 (LOXL3) is associated with various cancers, its role in pleural mesothelioma (PM) remains uncharacterized. This study investigated the expression level and prognostic association of LOXL3 in PM.MethodsTissue specimens were collected from patients with PM. The expression levels of LOXL3 were assessed using immunohistochemistry, Western blot analysis, and quantitative reverse transcription PCR. The clinical correlation analysis was conducted using R software (version 3.6.3), incorporating data from both The Cancer Genome Atlas and Chuxiong cohorts. Univariate and multivariate Cox proportional hazards regression models alongside Kaplan-Meier survival curve analysis were performed to evaluate prognostic significance. Additionally, gene expression correlation studies between LOXL3 and other members of the LOX family were performed using the Gene Expression Profiling Interactive Analysis platform. Finally, Gene Set Enrichment Analysis was conducted to identify the signaling pathways associated with LOXL3.ResultsLOXL3 exhibited significant upregulation in both sarcomatoid and biphasic PM subtypes compared to the control samples. Clinico-pathological analysis revealed the correlations between LOXL3 expression levels and cancer type, and Wilms tumor protein 1 (WT-1) status. Cox regression analysis identified cancer type as an independent prognostic factor. Kaplan-Meier analysis demonstrated obviously poorer survival rates in cohorts with high LOXL3 expression. Notably, coordinated expression patterns were observed between LOXL3 and LOXL4. The protein expression level of LOXL3 exhibits a positive correlation with CD68, CD206, and programmed death-ligand 1 (PD-L1), with this correlation being particularly pronounced in sarcomatoid mesothelioma. Functional enrichment analysis indicated that high LOXL3 expression was primarily associated with pathways related to oxidative phosphorylation, late and early estrogen response, and adipogenesis.ConclusionLOXL3 is highly expressed in PM and associated with poor prognosis, and is involved in tumor immune evasion. The expression level of LOXL3 is correlated with cancer types and the expression level of WT-1. Cancer type is an independent prognostic factor for PM. LOXL3 expression is positively associated with LOXL4, and high LOXL3 expression is enriched in oxidative phosphorylation, estrogen response, and adipogenesis pathways, while the low-expression group is enriched in apoptosis, interleukin-2/signal transducer and activator of transcription 5, mammalian target of rapamycin complex 1, and transforming growth factor-β pathways. CD68, CD206, PD-L1, and LOXL3 may collaboratively contribute to the regulation of the PM microenvironment and are closely linked to the invasion and metastasis of PM. Therefore, LOXL3 can be used as both a prognostic marker and a potential therapeutic target for PM.
Increasing evidence showed that altered histone deacetylases ( HDACs ) are involved in, and exert cell type specific roles in sarcomagenesis. Here we reviewed expression and roles of HDACs in several types of human sarcomas, providing a basic guideline for personalized therapy. In sarcomas, overexpression of HDACs was common, including a prevalence in uterine sarcomas. Class I HDAC1–3 , especially HDAC1-2 , were upregulated in most sarcomas and were often associated with poor prognosis. Class I HDACs inhibit tumor suppressor expression and lineage differentiation, but maintain chromatin integrity and oncofusion protein stability. Class II HDACs have specific functions in cellular transformation, long telomeres maintenance, drug resistance, and cytoskeletal organization, and act as negative predictors in some sarcomas; for example, HDAC4 for leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS), HDAC5 for uterine LMS, HDAC6 for ESS, chondrosarcoma (CHS) and undifferentiated endometrial sarcoma. Moreover, some HDACs play dual, cell-context or cellular localization-dependent roles. HDAC 2 and HDAC5 could promote or suppress osteosarcoma growth. HDAC4 acts as a tumor suppressor in CHS but as an oncogene in other sarcomas. Moreover, HDAC4 is the targets of several microRNAs in osteosarcoma. Cytoplasmic HDAC6 increases self-renewal and cell migration, compared with nuclear HDAC6 enhancing EWSR1-FLI1 transcription. Thus, the diverse expression and roles of HDACs in sarcoma pathogenesis will be a solid foundation to guide personalized therapeutic application of HDAC modulators in sarcomas.
