Functional enrichment analysis reveals that SLC25A39 is commonly associated with immune-related pathways and cell cycle-related pathways in the pan-cancer dataset.
Abstract
Solute carrier family 25 member 39 (SLC25A39) is crucial for regulating mitochondrial oxidative metabolism and homeostasis, linking to various physiological and pathological processes. Its expression landscape and mechanistic roles across cancer types remain largely unexplored. This study systematically profiled SLC25A39 in pan-cancer and assessed its prognostic relevance, molecular associations, and therapeutic potential. Multi-omics database resources were utilized to perform an integrated analysis of SLC25A39, including its expression profiles, prognostic value, molecular mechanisms, and associations with the immune microenvironment across diverse tumors. The oncogenic role of SLC25A39 was confirmed through in vitro gene knockdown in hepatocellular carcinoma. SLC25A39 was predominantly over expressed in nearly all types of cancer. SLC25A39 serves as an unfavorable prognosis marker. Its expression was primarily linked to immune cell infiltration, the cancer immunity cycle, major histocompatibility complex, immune checkpoints, tumor mutation burden, microsatellite instability, and RNA modifications like m1A, m5C, m6A, as well as DNA methylation sites. Functional enrichment analysis reveals that SLC25A39 is commonly associated with immune-related pathways and cell cycle-related pathways in the pan-cancer dataset. Knockdown of SLC25A39 in Huh-7 and HepG2 cells significantly inhibited hepatocellular carcinoma cell proliferation. SLC25A39 induces pro-tumorigenic effects across various cancer types. It serves as a potential biomarker.
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.
Dunzhen Chen, Li Yu, Xichang Zhou et al.· Scientific Reports· 0 citations
MEX3A is an evolutionarily conserved RNA-binding protein characterized by two KH RNA-binding domains and a C-terminal RING domain, suggesting potential roles in both post-transcriptional regulation and protein modification. Although MEX3A has been implicated in several individual cancer types, its shared and cancer-specific roles across human cancers remain incompletely understood. In this study, we performed a comprehensive pan-cancer analysis of MEX3A by integrating publicly available datasets, including TCGA, GTEx, CPTAC, and other external resources. We systematically evaluated MEX3A expression, genetic alterations, phosphorylation status, clinical relevance, RNA modification-related associations, immune-related features, and functional enrichment profiles across multiple tumor types. MEX3A was significantly upregulated in most cancers and showed associations with advanced pathological stage in several tumor types. Survival analyses indicated that elevated MEX3A expression was correlated with poor overall survival and disease-specific survival in cancers such as ACC, LIHC, MESO, and SARC, supporting its potential value as a prognostic biomarker. Genetic alteration analysis revealed frequent copy number amplification of MEX3A in several cancers, whereas these alterations were not consistently associated with survival outcomes. Proteomic analyses further identified altered phosphorylation levels at S338 and S462 in tumor tissues, suggesting that post-translational modification may contribute to the regulation of MEX3A activity in a cancer-type-specific manner. Correlation analyses showed that MEX3A expression was associated with RNA modification-related genes, immune modulators, immune checkpoint genes, tumor-infiltrating immune cells, tumor mutational burden, and microsatellite instability across different cancers. These findings suggest that MEX3A may participate in RNA regulatory networks and tumor-immune microenvironment interactions. Functional enrichment analysis revealed that MEX3A-associated proteins are involved in pathways related to transcriptional dysregulation, mRNA stability, and translational regulation. However, as these findings are primarily based on bioinformatic and correlation-based analyses, they should not be interpreted as evidence that MEX3A is a validated therapeutic or immunotherapy target. Overall, this study provides a systematic pan-cancer characterization of MEX3A and supports its potential role as a prognostic biomarker and a hypothesis-generating candidate for future mechanistic and clinical validation.
Xuezhong Zhang, Yongxin Pan, Ning Li et al.· Discover Oncology· 0 citations
Ubiquitin-conjugating enzyme E2A (UBE2A), a member of the ubiquitin-conjugating E2 enzyme family, has been implicated in tumor development; however, its role across human cancer types remains incompletely understood. The present study aimed to systematically characterize the expression pattern, prognostic importance and immune relevance of UBE2A in a pan-cancer context. Public datasets, including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, were integrated to evaluate UBE2A expression, clinical importance, molecular characteristics, immune associations and biological functions across cancer types. Single-cell RNA sequencing data were analyzed to investigate the cellular distribution of UBE2A. Functional validation was performed through UBE2A knockdown in breast cancer cell lines. Results indicated that UBE2A was significantly upregulated in a number of cancer types and was associated with unfavorable overall and progression-free survival. UBE2A expression exhibited significant correlations with immune cell infiltration and immune checkpoint-associated genes across cancer types. Functional enrichment analyses indicated that UBE2A was primarily involved in cell cycle regulation and proliferative processes. Single-cell analysis revealed preferential UBE2A expression in proliferative T-cell populations. Furthermore, in vitro experiments demonstrated that UBE2A knockdown significantly suppressed breast cancer cell proliferation, migration and invasion. Overall, UBE2A was shown to be a promising prognostic biomarker associated with tumor progression, cell cycle activity and immune-associated characteristics across cancer types. Its preferential expression in proliferative T-cell populations and oncogenic role in breast cancer suggest that UBE2A may serve as a potential therapeutic target and a candidate biomarker for evaluating tumor prognosis and the tumor immune microenvironment.
Yunjie Wen, Pengfei Luo· Molecular Medicine Reports· 0 citations
Preclinical evidence suggests that KIF23 is a molecule with significant translational potential, demonstrating promising prospects in disease diagnosis, prognostic assessment, and targeted therapy, and further in-depth research on KIF23 will significantly advance precision medicine.
Yi Liu, Yu Luo, Pinghong Hu et al.· Cancer Cell International· 0 citations
Hematological malignancies are highly heterogeneous diseases characterized by dysregulated signaling pathways and limited durable therapeutic responses. Calcium homeostasis has emerged as a critical regulator of cancer cell fate, yet the role of the sodium/calcium exchanger 1 (NCX1/SLC8A1) in leukemogenesis remains poorly defined. In this study, we comprehensively investigated the biological significance and therapeutic potential of NCX1 across major hematological malignancies by integrating transcriptomic analyses, protein-protein interaction networks, experimental validation, and in silico drug repurposing strategies. NCX1 was highly expressed in HL-60, K-562, and Jurkat cells compared to HaCaT controls. Network analyses revealed that NCX1 interacts with key regulators of calcium signaling, immune response, and signal transduction. In AML and CML patient datasets, a strong positive correlation was observed between NCX1 expression and immune-related pathways, while a negative correlation was observed with translation-related processes. Molecular docking analyses demonstrated that several clinically approved compounds, particularly imatinib and nilotinib, interact with NCX1. Molecular dynamics simulation was performed to evaluate the binding stability and safety of imatinib. Remarkably, the comprehensive analysis showed that imatinib exhibited a stable molecular dynamics profile. All these findings have demonstrated NCX1 as a biologically informative marker of myeloid differentiation and a promising therapeutic weak point within calcium signaling networks in hematological malignancies, providing a rationale for future functional and single-cell validation studies.
Sema Mısır, S. Yaman, Nina Petrović et al.· Biochemical and Biophysical...· 0 citations
Objective Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, therapeutic resistance, and marked metabolic adaptability. Disulfidptosis is a recently described form of regulated cell death associated with glucose deprivation and disulfide stress. This study aimed to identify disulfidptosis-related genes associated with HCC progression and to investigate the potential biological role of SLC5A6. Methods Single-cell RNA sequencing and TCGA-LIHC transcriptomic data were integrated. A literature-derived, non-directional disulfidptosis-related gene-set enrichment score was calculated using ssGSEA, and copy-number alterations were inferred using inferCNV. WGCNA, differential expression analysis, and the SLC-family gene list were integrated to identify candidate genes. Bayesian deconvolution, ESTIMATE, TIDE, and GSVA were used to evaluate tumor-microenvironment-related features and pathway signatures. The biological effects of SLC5A6 silencing were assessed using proliferation, migration, invasion, apoptosis, and xenograft assays. Glucose-deprivation-induced disulfide stress was further evaluated by measuring protein disulfide content, the NADP+/NADPH ratio, and FLNA and FLNB band patterns under non-reducing conditions. Results Single-cell analysis showed that malignant hepatocytes with higher inferCNV-derived CNV scores exhibited greater enrichment of the disulfidptosis-related gene signature. Integration of glucose-deprivation-associated DEGs, WGCNA modules, and SLC-family genes identified SLC5A6 as a candidate disulfidptosis-related gene that was upregulated in HCC and associated with poor prognosis. Bayesian deconvolution, ESTIMATE, TIDE, and GSVA analyses linked elevated SLC5A6 expression to advanced disease, stromal and immunosuppressive cell enrichment, higher T-cell exclusion scores, and activation of Wnt/mTOR-related signaling signatures. In SLC7A11-high HCC cells, glucose deprivation increased protein disulfide content and the NADP+/NADPH ratio and altered non-reducing FLNA and FLNB band patterns, whereas these changes were partially attenuated by SLC5A6 silencing. Under conventional culture conditions, SLC5A6 silencing inhibited proliferation, migration, invasion, and xenograft growth and increased apoptosis. Conclusion SLC5A6 is a candidate disulfidptosis-related gene and prognostic biomarker associated with malignant progression in HCC. The findings suggest that SLC5A6 may participate in glucose-deprivation-induced disulfide stress, while its direct role in regulating disulfidptotic cell death remains to be established. Its associations with immune-exclusion-related features also require further functional validation.
Chong Fu, Zemin Fang, Yanping Zhang et al.· Frontiers in Oncology· 0 citations