TL;DR
ADH6 and BDH1 were identified as significantly downregulated genes associated with patient survival in CRC and demonstrated promising tissue-based diagnostic discrimination between tumor and normal samples.
The expression landscape and prognostic value of N6-methyladenosine (m6A)-related genes remain largely uncharacterized in breast cancer. Here, we performed an integrative analysis of their expression profiles and clinical relevance. Utilizing multi-omics datasets and experimental validation, we conducted a systematic investigation of m6A-related genes in breast cancer. These genes exhibited pronounced differential expression in breast cancer, yet their correlation with molecular features such as promoter methylation and copy number alterations was limited. Univariate survival analysis indicated that aberrant expression of RBM15B, METTL16, HNRNPC, YTHDF1, YTHDF3, and IGF2BP1 was significantly linked to patient prognosis. Multivariate Cox regression further identified elevated YTHDF3 expression as an independent prognostic factor. Functional network analysis indicated YTHDF3 is potentially involved not only in RNA processing and metabolism but also in DNA repair, pri-miRNA processing, telomere stability, and immune infiltration. Moreover, upregulation of YTHDF3 mRNA was confirmed in clinical breast cancer specimens. Collectively, m6A-related genes are dysregulated in breast cancer and correlate with patient outcomes, highlighting their biomarker potential, with YTHDF3 warranting in-depth investigation.
Objective: This study aimed to comprehensively characterize the transcriptomic and proteomic landscape of ferroptosis-associated mRNAs, miRNAs, and proteins, elucidate subtype-specific regulatory networks, and identify potential prognostic biomarkers in triple-negative breast cancer (TNBC). Materials and Methods: Using the TCGA-BRCA cohort for discovery and the METABRIC dataset for validation, we performed differential expression and functional enrichment analyses comparing TNBC and non-TNBC subtypes. An integrated miRNA–mRNA regulatory network was constructed, and multivariable Cox proportional hazards regression analysis was performed to evaluate the prognostic value of the identified biomarkers. Results: TNBC exhibited profound transcriptional dysregulation, characterized by the marked upregulation of the iron-sequestering gene FTMT (log₂FC=5.60) and downregulation of the iron exporter SLC40A1 (log₂FC=-3.13). We identified 197 significantly dysregulated miRNAs, including the overexpressed oncomiR hsa-miR-135b and the suppressed tumor-suppressor miRNA hsa-miR-449a. Functional enrichment analyses consistently highlighted substantial disruptions in iron homeostasis and oxidative stress pathways. Network analysis identified NQO1 and SLC38A1 as central mRNA hubs. Notably, although specific mRNAs, including SLC40A1 and ALOX15, demonstrated prognostic value in univariate analyses, multivariable Cox regression analysis revealed that only hsa-miR-378c and hsa-miR-449a remained significant as independent prognostic factors. Conclusion: This multi-omics integration maps the ferroptosis-related regulatory landscape of TNBC. Although specific mRNAs serve as key structural hubs, hsa-miR-378c and hsa-miR-449a emerge as robust independent prognostic biomarkers, providing important insights into TNBC risk stratification and potential targeted therapeutic strategies.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide. Although screening has reduced CRC in older adults, cases in younger individuals are rising, highlighting the need for early biomarkers. Emerging research highlights the role of estrogen metabolism in CRC progression, with enzymes such as hydroxysteroid (17-beta) dehydrogenase (HSD17B) being increasingly implicated. In this study, we performed a bioinformatics analysis using publicly available datasets, including The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort and two independent Gene Expression Omnibus (GEO) cohorts (GSE40967 and GSE41258), to investigate the role of HSD17B enzymes in CRC. Our results suggest that HSD17B2 is frequently downregulated in precancerous lesions and early-stage CRC, which may contribute to elevated estradiol levels and a tumor-promoting microenvironment. In advanced stages, higher HSD17B2 expression levels are associated with poorer survival outcomes in retrospective cohorts. Other HSD17B enzymes also exhibit significant expression changes, further complicating the hormonal landscape of CRC. In addition, estrone, traditionally considered a weaker estrogen, emerges as a potential driver of CRC progression. Our in-silico analyses indicate that HSD17B2 and HSD17B11 warrant further investigation as candidate biomarkers for distinguishing CRC from benign and precancerous conditions, with the combination showing strong discriminatory power in Receiver Operating Characteristic (ROC) analyses. Overall, these findings highlight the potential role of estrogen metabolism in CRC and suggest that HSD17B enzymes may hold value as candidate prognostic and diagnostic indicators, though their clinical utility remains hypothetical at this stage. Experimental and clinical validation is strictly required to confirm these in silico observations and to clarify their mechanisms in CRC.
Triple-negative breast cancer (TNBC) remains one of the most therapeutically resistant breast cancers and often displays pronounced immune heterogeneity. This study integrates multi-omics datasets to identify candidate biomarkers that may influence TNBC progression and modulate therapeutic response. Transcriptomic, DNA methylation, microRNA (miRNA), and single nucleotide polymorphism (SNP) datasets from public repositories were analyzed using differential expression and correlation pipelines. Expression, mutation, and regulatory metrics were then integrated to prioritize key genes. Top candidates, including CCND2 and KIF1A, were preliminarily validated using qPCR and Kaplan—Meier plots. CIBERSORT was applied to examine tumor immune cell infiltration and to assess the immune-related expression of candidate genes. Multi-omics integration highlighted CCND2 and KIF1A as highly ranked candidates associated with TNBC proliferation and cell cycle regulation. Literature and pathway analysis suggested potential involvement of these genes in key oncogenic and immune-related signaling pathways. Preliminary qPCR results supported their differential expression relative to normal breast tissue. These findings nominate CCND2 and KIF1A as candidate biomarkers and potential therapeutic targets in TNBC. Continued pathway and functional validation will clarify how these genes contribute to tumor progression and may inform precision treatment strategies for TNBC. n/a Translational and Interventional Immunology (TI)
Background Glutathione metabolism plays an important role in redox homeostasis, oxidative stress responses, and metabolic adaptation in cancer. However, its prognostic significance in lung adenocarcinoma (LUAD) remains incompletely understood. This study aimed to develop a glutathione metabolism-related prognostic signature and investigate its associations with immune characteristics, genomic alterations, and biological pathways in LUAD. Methods Transcriptomic, clinical, and somatic mutation data from TCGA-LUAD were analyzed, and GSE50081 was used as an independent validation cohort. Glutathione metabolism-related genes were identified through differential expression and Cox regression analyses, followed by least absolute shrinkage and selection operator (LASSO) Cox regression to construct a prognostic signature. Survival analysis, time-dependent receiver operating characteristic (ROC) analysis, Cox regression, immune infiltration analysis, Gene Set Enrichment Analysis (GSEA), mutation profiling, tumor mutation burden (TMB) analysis, and drug-sensitivity prediction were subsequently performed. Results A glutathione metabolism-related signature stratified patients into high- and low-risk groups with significantly different overall survival in both the TCGA training cohort and the GSE50081 validation cohort. The risk score remained an independent prognostic factor in multivariable Cox regression analysis. High-risk tumors exhibited reduced B-cell and dendritic-cell infiltration, enrichment of cell-cycle- and metabolism-related pathways, higher frequencies of TP53 and KEAP1 mutations, and elevated tumor mutation burden. Computational drug-sensitivity analysis identified differences in predicted responses to several therapeutic agents between risk groups. Conclusions The proposed glutathione metabolism-related signature demonstrated prognostic value in both training and validation cohorts and was associated with immune characteristics, pathway enrichment patterns, genomic alterations, and tumor mutation burden in LUAD. These findings provide additional insights into glutathione metabolism-related heterogeneity in LUAD and warrant further biological and clinical validation.
Hepatocellular carcinoma (HCC) poses a significant global health burden with limited therapeutic options, particularly for non-viral etiologies. The mitochondrial solute carrier SLC25A43 is implicated in cellular redox homeostasis, yet its role in HCC remains unclear. This study aimed to comprehensively investigate the expression pattern, clinical significance, biological function, and potential mechanisms of SLC25A43 in HCC. Utilizing multi-omics data from public databases (TCGA-LIHC, GEO, and HPA), we performed integrated bioinformatic analyses. SLC25A43 was consistently upregulated in HCC tissues compared with non-tumorous liver tissues and demonstrated strong diagnostic value (AUC = 0.861). High SLC25A43 expression was significantly associated with advanced tumor stage, metastasis, and adverse clinicopathological features. Survival analyses identified SLC25A43 as an independent prognostic risk factor for overall survival, progression-free interval, and disease-specific survival. Functional enrichment analyses suggested that SLC25A43 is involved in mitochondrial oxidative phosphorylation, energy metabolism, and immune-related pathways. Immune infiltration analyses using ssGSEA, xCell, and TIMER consistently revealed negative correlations between SLC25A43 expression and multiple antitumor immune cell populations, particularly CD8 + T cells. Experimental validation confirmed that SLC25A43 was significantly upregulated in HCC tissues at both mRNA and protein levels. Functional assays in Huh-7, Hep-LM3, MHCC97H, and LO2 cells demonstrated that SLC25A43 knockdown inhibited, whereas overexpression promoted, cell proliferation and migration. Rescue experiments further verified the specificity of these effects. Mechanistically, SLC25A43 regulated intracellular ATP production, ROS accumulation, and glutathione metabolism, indicating a role in redox homeostasis and energy metabolism. In addition, PBMC co-culture experiments showed that SLC25A43 suppressed CD8 + T-cell cytotoxic activity by reducing Granzyme B expression. A prognostic nomogram incorporating SLC25A43 exhibited favorable predictive performance and was successfully validated in two independent GEO cohorts. SLC25A43 is a novel diagnostic and prognostic biomarker for HCC. Its upregulation promotes tumor progression through metabolic reprogramming, redox homeostasis remodeling, and suppression of antitumor immune responses. These findings highlight SLC25A43 as a promising therapeutic target and provide new insights into the metabolic-immune regulatory network in hepatocellular carcinoma.