Jing Zhang

Liver hepatocellular carcinoma (LIHC) represents a common and aggressive malignancy characterized by an unfavorable clinical outcome, highlighting an urgent need to discover reliable prognostic indicators and novel therapeutic targets. The present investigation centers on the JAMM family genes, with a specific emphasis on PSMD14, to delineate their functional contributions in the context of LIHC. We utilized an integrated analytical framework, incorporating bulk RNA sequencing data from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing (scRNA-seq) datasets, to systematically investigate the expression profiles, prognostic significance, and underlying functional roles of JAMM family deubiquitinases in LIHC. A prognostic risk score model was developed through least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. To elucidate the biological functions and signaling pathways linked to PSMD14, we performed comprehensive functional enrichment analyses, encompassing Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The landscape of immune cell infiltration within the tumor microenvironment was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA). Furthermore, scRNA-seq data were leveraged to dissect cellular heterogeneity and examine the expression patterns of PSMD14 across distinct cell populations. Finally, immunohistochemical staining was applied to validate PSMD14 protein expression levels in clinical tissue samples. Our findings demonstrated that PSMD14 and EIF3H were markedly upregulated in LIHC tissues, with PSMD14 emerging as a critical prognostic indicator. A risk stratification model constructed from JAMM family genes effectively categorized patients into distinct high- and low-risk cohorts, where the high-risk group displayed significantly shorter overall survival. The dysregulated expression of PSMD14 is partly attributable to copy number alterations and DNA methylation patterns, showing associations with multiple DNA methyltransferases. Functional enrichment analyses indicated that elevated PSMD14 expression is involved in metabolic pathways and oncogenic signaling cascades. Moreover, PSMD14 expression was linked to an immunosuppressive tumor microenvironment, exhibiting a positive correlation with Th2 cells and an inverse relationship with cytotoxic immune cells. scRNA-seq validated the predominant expression of PSMD14 in malignant epithelial cells. A nomogram incorporating PSMD14 expression and clinical variables was developed to predict patient survival probabilities at 1 and 5 years. Additionally, immunohistochemical analysis of 55 clinical samples revealed that PSMD14 protein levels were substantially higher in LIHC tissues compared to adjacent non-tumorous tissues. These results indicate that PSMD14 may serve as a promising prognostic biomarker and therapeutic target for LIHC, highlighting the need for further exploration of its underlying molecular mechanisms and therapeutic applications.

Background: Colorectal cancer (CRC) remains a significant global health challenge, marked by high incidence and mortality rates, as well as ongoing limitations in current diagnostic and therapeutic strategies. Accurate prognostic evaluation and the customization of treatment to meet the individual requirements of patients are of paramount importance. gamma-aminobutyric acid type A receptor subunit delta (GABRD) plays a role in the progression of a number of different cancers, such as glioma, breast cancer, and stomach cancer. However, its function in CRC was rarely reported. In this study, we aimed to evaluate the diagnostic, prognostic and immune infiltration value of GABRD in CRC. Methods: Transcriptomic data and clinical records of CRC patients were retrieved from The Cancer Genome Atlas (TCGA). A prognostic signature based on neurotransmitter receptor-associated genes (NRGs) was developed using the least absolute shrinkage and selection operator (LASSO) Cox regression model. Functional enrichment analyses were performed. Immune cell infiltration was assessed via single-sample Gene Set Enrichment Analysis (ssGSEA). The correlation between GABRD expression and clinicopathological characteristics was analyzed, and prognostic significance was evaluated using univariate and multivariate Cox regression models, supplemented by Kaplan-Meier survival analysis. Immunohistochemical (IHC) validation of GABRD protein expression was performed on 115 CRC tissue samples. In vitro validation was conducted using reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, and functional assays in CRC cell lines. Results: GABRD was significantly overexpressed in CRC tissues, with elevated levels correlating with advanced disease stages and poorer survival outcomes. Further analysis revealed that GABRD contributes to the establishment of an immunosuppressive tumor microenvironment. Functional assays highlighted GABRD’s involvement in key signaling pathways, including Hedgehog, Wnt/β-catenin, and TGF-β, which are pivotal in CRC progression. Knockdown of GABRD significantly inhibited CRC cell proliferation and migration. Molecular docking simulations suggested promising drug repurposing avenues, particularly with afatinib and crizotinib, for GABRD inhibition. Conclusions: GABRD gene may serve as a novel biomarker in the diagnosis, prognosis and immune infiltrates of CRC patients.

Background: PI3K/Akt/mTOR pathway is crucial in some cancers, but its relation with tumor-infiltrating immune cells in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is unanalyzed. This study aimed to determine if ACTR3 overexpression affects CC survival and explore its impact on the tumor immune microenvironment. Methods: Research investigated ACTR3 expression levels related to PI3K/Akt/mTOR pathway and its influence on tumor immunology and clinical outcomes. Methods included RNA-seq data analysis, immune cell infiltration evaluation, survival analysis, gene enrichment analysis, and single-cell RNA-seq data integration. ACTR3 expression in cervical cancer specimens was evaluated by immunohistochemistry. Results: Least absolute shrinkage and selection operator (LASSO) Cox regression identified ten key genes including ACTR3 with prognostic value. High ACTR3 expression correlated with poor outcomes, suggesting it as a prognostic biomarker. The prognostic model was validated by time-dependent receiver operating characteristic (ROC) curves for 1-, 3-, and 5-year survival. A nomogram combining ACTR3 expression and clinical parameters estimated patient survival. Single-cell RNA sequencing showed ACTR3-expressing immune cells in CESC include dendritic cells (DCs), T cells, and tissue stem cells. Conclusion: This research elucidated a distinct signature linked to the PI3K/Akt/mTOR signaling pathway, particularly focusing on ACTR3, which plays a role in both the onset and advancement of CESC. Moreover, ACTR3 has the potential to act as a prognostic biomarker for patients diagnosed with CESC, thereby offering novel perspectives for the development of clinical therapeutic approaches.

Background: Glioma, a highly aggressive brain tumor, presents significant challenges in prognosis and treatment. This study investigates the role of PTX3 expression in glioma and its correlation with patient outcomes, addressing a gap in current research regarding its molecular mechanisms. Materials and Methods: RNA sequencing data and clinical information for glioma patients were obtained from The Cancer Genome Atlas (TCGA). A multigene prognostic signature based on IL-18 signaling-related genes (ISRGs) was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression method. The functional roles of PTX3 were analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Single-sample GSEA (ssGSEA) was used to assess the association between PTX3 expression and immune cell infiltration. The relationship between PTX3 expression and clinicopathological features was also examined. Prognostic relevance was evaluated using univariate and multivariate Cox regression models, and Kaplan–Meier survival analysis was performed. PTX3 protein expression was validated via immunohistochemistry in 56 glioma specimens. Results: The LASSO Cox regression model identified a nine-gene prognostic signature, including BMP2, NCF1, HSPB1, PIGT, PTX3, CCNA2, CCNB2, CCN4, and DES. Functional enrichment analysis revealed that PTX3-associated differentially expressed genes were significantly enriched in pathways such as cytokine–cytokine receptor interaction and PI3K-Akt signaling, which are critical for immune response and cell proliferation in glioma. PTX3 expression showed a strong correlation with immune cell infiltration, particularly macrophages, neutrophils, T cells, and natural killer cells, suggesting a role in modulating the tumor microenvironment. Pan-cancer analysis indicated that PTX3 is markedly upregulated in various cancers, especially gliomas, highlighting its potential as a biomarker. PTX3 expression was also associated with clinical features such as WHO grade, IDH mutation status, and 1p/19q co-deletion, with higher PTX3 levels linked to poorer survival outcomes. Immunohistochemistry confirmed elevated PTX3 protein expression in both lower-grade glioma and glioblastoma multiforme. Conclusions: These findings highlight the critical role of PTX3 in glioma and suggest its potential as both a prognostic biomarker and therapeutic target. This study provides a foundation for future research into targeted therapies involving PTX3.