Expression of PSMD2 gene in hepatocellular carcinoma and its correlation with immune checkpoints and prognosis.

Hepatocellular carcinoma (HCC) is a prevalent and fatal tumor globally, characterized by a complex pathogenesis and poor prognosis. Despite significant advancements in the application of immune checkpoint inhibitors (ICIs) for cancer treatment, the efficacy of immunotherapy in HCC remains suboptimal. PSMD2, a crucial regulator of the ubiquitin-proteasome system, has attracted increasing attention for its involvement in various cancers; however, its functions and mechanisms in HCC are still poorly understood. This study aims to investigate the expression of PSMD2 in HCC, its association with prognosis, and its interaction with immune checkpoints, thus establishing a foundation for further exploration of its role in immune evasion in HCC. We analyzed the expression levels of PSMD2 in HCC and adjacent normal tissues utilizing the GEPIA and TIMER databases. Cox regression analysis was performed using R software to evaluate the relationship between PSMD2 expression and prognosis. Furthermore, we assessed the correlation between PSMD2 and immune cell infiltration, as well as immune checkpoints, including PD1, PD-L1, and CTLA-4, using R tools. Additionally, we examined the association between PSMD2 expression and immune therapy response through Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Finally, we constructed a protein-protein interaction (PPI) network using the STRING database and Cytoscape software, followed by Gene Set Enrichment Analysis (GSEA). PSMD2 was significantly overexpressed in HCC and was closely correlated with poor prognosis (HR = 1.61, P = 2.0e-4). Immune infiltration analysis demonstrated that PSMD2 was positively correlated with several immune checkpoint genes, including PD1, PD-L1, and CTLA-4, as well as various immune cell types. TIDE analysis indicated that elevated PSMD2 expression was significantly associated with increased immune evasion potential and a poor response to immunotherapy. Furthermore, GSEA enrichment analysis revealed that PSMD2 is primarily enriched in the p53 signaling pathway, the ubiquitin-mediated proteolysis pathway, and other cancer-related pathways. The elevated expression of PSMD2 in HCC is not only correlated with poor prognosis but may also play a role in immune evasion by modulating tumor immunity, thereby affecting patient responses to immunotherapy. Consequently, PSMD2 presents a promising novel therapeutic target and potential biomarker for immunotherapy in HCC.

Gu MY ，Ma WL ，Ma ZM ，Ma LN ，Ding XC ... -  《Scientific Reports》

Multiomics analysis reveals the involvement of NET1 in tumour immune regulation and malignant progression.

Neuroepithelial cell transforming gene 1 (NET1) is a member of the Ras homologue family member A (RhoA) subfamily of guanine nucleotide exchange factors and a key protein involved in the activation of Rho guanosine triphosphatases, which act as regulators of cell proliferation, cytoskeletal organization, and cell movement and are crucial for cancer spread. Research has shown that NET1 can regulate the malignant biological functions of tumour cells, such as growth, invasion, and metastasis, and it is closely related to the progression of pancreatic cancer, gastric cancer, and liver cancer. However, the comprehensive role and mechanistic function of NET1 in other types of cancer remain largely unexplored. A deeper understanding of the role of NET1 may provide new insights into the molecular mechanisms of cancer progression and metastasis. This study aims to fill this knowledge gap and provide a more comprehensive understanding of the role of NET1 in cancer biology. The Cancer Genome Atlas and Genotype-Tissue Expression databases were utilized to analyse the differential expression of NET1 in normal and cancer tissues. The prognostic value of NET1 in cancer was evaluated through log-rank tests and Cox regression models. Further analysis was conducted to assess the relationships between NET1 expression and clinical features, as well as its diagnostic value. We investigated potential factors contributing to genetic alterations in NET1 to elucidate the role of NET1 in cancer progression. We also explored the relationships between NET1 and genes associated with epigenetic modifications, oncogenes, and tumour characteristics, such as RNA stemness scores (RNAss), DNA stemness scores (DNAss), the tumour mutation burden (TMB), and microsatellite instability (MSI). Additionally, we analysed the associations between NET1 expression and immune cell infiltration, immunoregulatory genes, and sensitivity to therapeutic drugs. We conducted gene set enrichment analysis to further investigate the signalling pathways that might be affected by changes in NET1. The prognostic value of NET1 in triple-negative breast cancer (TNBC) was further validated using real-world and Gene Expression Omnibus (GEO) data. Finally, through both in vivo and in vitro experiments, we confirmed that the overexpression of NET1 contributed to the malignant progression of TNBC cells, and we explored the potential mechanism by which NET1 regulates malignant biological behaviour through cellular experiments. Our study revealed a higher expression level of NET1 in 18 types of tumour tissues than in their corresponding normal tissues. Specifically, we observed high expression of NET1 in LIHC, LUSC, PAAD, and BRCA tumour tissues, which was associated with a poor prognosis. In terms of gene alterations, "amplification", "mutation", and "deep deletion" were identified as the main types of changes occurring in NET1. Among these, "amplification" was predominantly observed in LIHC, LUSC, PAAD, and BRCA. Furthermore, a significant positive correlation was found between copy number variations and the NET1 expression level in various tumours, including LIHC, LUSC, PAAD, and BRCA. We also discovered that NET1 expression was positively correlated with the expression of genes related to epigenetic modification in almost all types of cancer and was related to the expression levels of numerous oncogenes. In certain tumours, a significant positive correlation was noted between the expression of NET1 and TMB, MSI, DNAss, and RNAss. Intriguingly, in most tumours, NET1 expression was strongly negatively correlated with the levels of infiltrating natural killer cells and M1 macrophages. Moreover, NET1 expression was significantly positively correlated with the expression of immune genes in nearly all types of cancer. An analysis of single-cell data revealed that NET1 was expressed primarily in malignant tumour cells in most tumours, with little to no expression in immune cells. Additionally, the expression level of NET1 was associated with sensitivity to various therapeutic drugs. Data from GEO and real-world studies indicated high expression of NET1 in TNBC tissues, which was correlated with a poor prognosis. Cellular experiments indicated that NET1 could regulate the proliferation, invasion, cell cycle, and apoptosis of TNBC cells. Furthermore, NET1 may mediate the malignant proliferation of tumour cells through the AKT signalling pathway. NET1 can serve as a potential prognostic marker for LIHC, LUSC, PAAD, and BRCA tumours. Real-world data further suggest that NET1 can also serve as a prognostic indicator for TNBC. High expression of NET1 may contribute to the malignant proliferation of TNBC cells, potentially through the AKT signalling pathway. Moreover, NET1 may contribute to the formation of an immunosuppressive microenvironment that can promote tumour progression. Therefore, targeting NET1 may represents a promising approach for inhibiting tumour progression.

Pang J ，Huang X ，Gao Y ，Guan X ，Xiong L ，Li L ，Yin N ，Dai M ，Han T ，Yi W ... -  《Scientific Reports》

TMEM101 expression and its impact on immune cell infiltration and prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer caused by inflammation, which affects the immune response and treatment outcomes. Finding new immune-related targets could improve HCC immunotherapy. New research suggests that TMEM family proteins can act as either tumor suppressors or oncogenes, but the role of TMEM101 in HCC development is unclear. This study conducted an analysis of TMEM101 mRNA expression and its correlation with clinical outcomes in HCC patients using RNA sequencing data from various open databases. Additionally, differences in TMEM101 expression in HCC cell lines and HCC tissue microarrays were examined using RT-qPCR, western blotting, and in situ hybridization staining. The findings presented herein offer initial evidence indicating a significant upregulation of TMEM101 mRNA expression in HCC, which is linked to a poorer prognosis. Furthermore, TMEM101 expression was found to be positively associated with the histological grade and clinical stage of HCC patients. Moreover, a notable reduction in promoter methylation of TMEM101 was observed in HCC patients. Cox regression analysis indicated that TMEM101 was an independent prognostic factor for overall survival (OS) in HCC patients. A nomogram incorporating TMEM101 and tumor stage was constructed and assessed. Comparative analysis with four established HCC diagnostic biomarkers (AFP, EFNA3, MDK, and SMYD5) using ROC curve and time-dependent ROC curves demonstrated the diagnostic potential of TMEM101 in HCC. Gene set enrichment analysis (GSEA) revealed a correlation between TMEM101 and the cell cycle, DNA replication, and repair signaling pathways, which were differentially enriched in the TMEM101 high expression phenotype. The findings from CIBERSORT analysis suggest that TMEM101's pro-tumor effect may be due to decreasing the number of anti-tumor immune cells (M1 macrophages and resting memory CD4+ T cells) and promoting M0 macrophage infiltration in the tumor microenvironment (TME). Overall, our study indicates that TMEM101 could serve as a promising diagnostic and prognostic biomarker for HCC.

Kuang L ，Pang Y ，Fang Q 《Scientific Reports》

FLT3 is associated with dendritic cell infiltration, tertiary lymphoid structure construction, and predict response to checkpoint inhibitors immunotherapy in solid cancers.

The crosstalk between cancers and the immune microenvironment plays a critical role in malignant progression. FMS-like tyrosine kinase 3 (FLT3) is a frequently mutated gene in acute myeloid leukemia (AML). However, its role in solid cancers remains poorly understood. We analyzed the frequency of FLT3 alterations, its mRNA expression levels, and its prognostic implications across multiple cancer types. Additionally, we explored genes co-expressed with FLT3 and performed gene ontology analysis to identify associated biological processes. We also examined the relationship between FLT3 expression and markers of various immune cells, tertiary lymphoid structures (TLSs), and epithelial-mesenchymal transition. Furthermore, we validated these findings in our own cohort of hepatocellular carcinoma (HCC) patients. We found that FLT3 alteration and expression were both significantly upregulated in AML and were associated with poor prognosis, which is opposite to its role in solid cancers. The genes co-expressed with FLT3 in solid cancers were correlated with the regulation of the immune microenvironment. FLT3 was positively correlated with the formation of TLSs in only solid cancers, which was especially relevant to central memory T cells. We also found that FLT3 was positively correlated with the infiltration of NK cells, B cells, and DCs. It also positively correlated with the occurrence of apoptosis in solid cancers, but exhibited opposite roles in AML. The structural factors of the TLSs were positively correlated with FLT3 in solid cancers, but exhibited a negative correlation in AML. Meanwhile, we further validated the above conclusions in our own HCC cohort and demonstrated that FLT3 could serve as a predictive indicator of PD-1 treatment efficacy in HCC. In summary, the role of FLT3 is different in AML and solid cancers. FLT3 is associated with dendritic cell infiltration, tertiary lymphoid structure construction, and predict response to checkpoint inhibitors immunotherapy in HCC.

Tang Y ，Wang H ，Zhang J ，Yang C ，Xu F ，Song Y ，Li T ，Zhang Q ... -  《-》

Study of TRAF3IP3 for prognosis and immune infiltration in hepatocellular carcinoma.

Tumor necrosis factor receptor-associated factor 3 (TRAF3)-interacting protein 3 (TRAF3IP3) expressed in various tumor cell. However, its role in hepatocellular carcinoma (HCC) was unclear. We aimed to demonstrate the relationship between TRAF3IP3 and HCC and explore the potential role of TRAF3IP3 in HCC. The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), KM-Plotter, University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and Xiantao Academic Online Website were utilized for the systematic analysis of TRAF3IP3. This analysis included mRNA expression, protein expression, prognostic value, enrichment analysis, and immune cell infiltration in HCC. Subsequently, immunohistochemistry was performed to assess the expression levels of TRAF3IP3 in both cancer and non-cancer tissues of patients with HCC. Analysis of public databases and immunohistochemical staining on 20 pairs of samples confirmed a decrease in TRAF3IP3 expression in HCC. Both the TCGA database and GSE14520 indicated that patients with high TRAF3IP3 expression had a more favorable prognosis in terms of overall survival (OS) and progression-free interval (PFI), as shown by KM curve results. Multivariate Cox regression analysis further demonstrated that high TRAF3IP3 expression was an independent protective factor for HCC prognosis (hazard ratio (HR): 0.619, 95% confidence interval (CI) [0.399-0.959]; p < 0.05). In the high TRAF3IP3 expression group, various immune response-related molecular pathways, particularly B lymphocyte-mediated pathways, were activated. The level of TRAF3IP3 expression showed a significant correlation with the presence of tumor-infiltrating CD8+ T cells. Additionally, a positive correlation was observed between immunophenoscore (IPS) and TRAF3IP3 expression. Notably, the half-maximal inhibitory concentration (IC50) of commonly used chemotherapeutic drugs, such as lapatinib and mitomycin, was inversely associated with TRAF3IP3 expression in HCC patients. TRAF3IP3 may be as a novel and promising biomarker for prognosis prediction and immunological evaluation of HCC.

Wang X ，Gao X ，Liu A ，Qin Y ，Ni ZY ，Zhang XL ... -  《PeerJ》