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》

CD161, a promising prognostic biomarker in hepatocellular carcinoma, correlates with immune infiltration.

CD161, encoded by the killer cell lectin-like receptor B1 (KLRB1) gene, exhibits varied roles among different tumors. This study aimed to explore both the potential value of CD161 as a prognostic biomarker for hepatocellular carcinoma (HCC) and its association with immune cell infiltration. A total of 109 HCC patients who underwent surgery were retrospectively analyzed. Immunohistochemistry, bioinformatic analyses, and statistical measurements were used to investigate the associations between CD161 expression, immune cell infiltration, and clinical outcomes in both public databases and in-house cohorts. CD161 was highly expressed at both protein and mRNA levels in adjacent normal tissues compared to tumor tissues of HCC patients. Meanwhile, CD161 was enriched in HCC cases characterized by smaller tumor sizes (≤5 cm) and the absence of portal vein tumor thrombus. Individuals with high CD161 expression showed extended overall survival (OS) and relapse free survival (RFS) compared to those with lower CD161 levels. CD161 was identified as an independent prognostic indicator for both OS and RFS. In addition, the enrichment analysis indicated a close correlation between CD161 and immune response, as well as between CD161 and the signaling pathways of cytokines and chemokines, implying its role in immune regulation during cancer development. Specifically, CD161 expression was positively associated with immunomodulators and tumor-infiltrating immune cells, especially CD8+T cells, CD4+T cells, and dendritic cells. Multiple public databases showed that patients with high CD161 expression were more likely to derive benefits from immunotherapy. CD161 was identified as a promising prognostic biomarker for HCC, as its expression indicates a favorable prognosis. Additionally, CD161 is closely linked to high infiltration of immune cells, participates in the regulation of the tumor immune microenvironment, and holds promise as a potential biomarker for predicting the efficacy of immunotherapy.

Wang J ，Wang X ，Shi J ，Wang Y ，Mi L ，Zhao M ，Han G ，Yin F ... -  《PeerJ》

To construct and validate a risk score model of angiogenesis-related genes to predict the prognosis of hepatocellular carcinoma.

Gao D ，Lu Y ，Jiang T ，Duan Q ，Huang Z ... -  《Scientific Reports》

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》

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》