Jul 2026· Technology in Cancer Research and Treatment· Vol 25· 0 citations· 20 references
Medicine
TL;DR
SYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses, and its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies.
Abstract
Introduction Hepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment and limited therapeutic options. Synaptogyrin-2 (SYNGR2), a transmembrane protein, has been implicated in cancer but its comprehensive role in HCC prognosis, immune regulation, and treatment response remains unclear. Methods Multiomics bioinformatics analysis was performed via RNA-seq data from the TCGA-LIHC cohort. Prognostic value was assessed via Cox regression and Kaplan‒Meier analysis. Immune cell infiltration was estimated via CIBERSORT, and drug sensitivity was predicted via the oncoPredict R package. In vitro validation was conducted using Hep3B and Huh7 cell lines. To establish causality, isogenic gain- and loss-of-function experiments were performed, followed by RT–qPCR, and CCK-8 assays. Results SYNGR2 expression was significantly elevated in HCC tissues and correlated with advanced tumor stage, poor differentiation, and poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (all P<0.05). It served as an independent prognostic biomarker (AUC=0.923). High SYNGR2 expression was associated with an immunosuppressive microenvironment characterized by increased numbers of M0 macrophages and Tregs and strongly positively correlated with immune checkpoint genes (PD-1, CTLA-4, and PD-L1). Bioinformatic predictions revealed that SYNGR2-high tumors were more sensitive to MK-1775 (DNA damage inhibitor) and paclitaxel, whereas SYNGR2-low tumors were sensitive to JAK1/IAP inhibitors. In vitro, Hep3B cells (high endogenous SYNGR2) displayed a markedly lower IC50 for MK-1775 than Huh7 cells (low endogenous SYNGR2). Critically, plasmid-mediated overexpression of SYNGR2 in Huh7 cells significantly sensitized them to MK-1775, while siRNA-mediated knockdown of SYNGR2 in Hep3B cells conferred significant resistance, establishing a causal role for SYNGR2 in modulating sensitivity to this WEE1 inhibitor. Conclusion SYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses. Its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies, particularly in selecting patients for DNA damage-targeting agents.
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
To investigate the role of Intermediate Filament Family Orphan Protein 2
(IFFO2) in Liver Hepatocellular Carcinoma (LIHC), we systematically evaluated mRNA expression
and analyzed the correlation between IFFO2 expression and clinicopathological information, patient
prognosis, and the immune microenvironment. In this study, the influence of IFFO2 on LIHC proliferation,
clone formation, migration, and invasion was demonstrated using in vitro experiments. This
will provide a theoretical basis for IFFO2 to be developed into a biomarker and therapeutic target for
LIHC.
IFFO2 expression in pan-cancer and LIHC tissues was analyzed in the Cancer
Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. For assessing diagnostic
value, Receiver Operating Characteristic (ROC) curves were used, and Kaplan-Meier (KM)
and Cox regression were used for Prognostic analysis. The single-sample Gene Set Enrichment Analysis
(ssGSEA) algorithm was used to examine the relationship between IFFO2 expression and immune
cell infiltration. In vitro experiments used siRNA to knock down IFFO2 in HUH7 and HepG2
cells, followed by CCK-8 proliferation assays, clone formation, scratch wound-healing assays,
transwell invasion assays, and other experiments to examine changes in cellular behavior.
IFFO2 expression was obviously upregulated in the LIHC tissues (p < 0.05). The results of
the ROC analysis showed a high diagnostic ability, with an Area Under the Curve (AUC) of 0.790.
Increased IFFO2 is associated with high pathological stages, high levels of Alpha-Fetoprotein (AFP),
prolonged prothrombin time, and shortened overall survival (OS) (p < 0.05). Functional enrichment
analysis revealed that IFFO2 is significantly associated with immune regulation, cell cycle, and complement
activation pathways. Immune infiltration analysis demonstrated the presence of various immune
cell subtypes that exhibited both positive and negative correlations with IFFO2. In vitro experiments
have demonstrated that IFFO2 knockdown remarkably diminishes the proliferation, clone
formation, migration, and invasion capacities of LIHC cells (p < 0.05).
The findings suggest that IFFO2 functions as an oncogene in LIHC. Its strong association
with adverse prognosis and its potential to modulate the immune microenvironment underscore
its dual potential as a diagnostic biomarker and a promising therapeutic target, warranting further
mechanistic and clinical investigation.
IFFO2 is significantly upregulated in LIHC and promotes tumor progression; its expression
is associated with unfavorable prognostic outcomes, suggesting its potential utility as a biomarker
for diagnosis and a therapeutic target.
Qi Li, Shengke Wen, Hong Chen et al.· Current Cancer Therapy Revie...· 0 citations
BACKGROUND
Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear.
METHODS
RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays.
RESULTS
In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk.
CONCLUSION
FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.
BACKGROUND
SH3 Domain Binding Glutamate Rich Protein Like 3 (SH3BGRL3) plays a crucial part in regulating tumor necrosis factor (TNF)-induced effects and was involved in the onset and progression of various cancers. However, its role at pan-cancer level remains unclear.
METHODS
Firstly, SH3BGRL3 expression and its correlation with patients' survival, and other clinical variables were explored in our clinical cohort of 370 kidney neoplasm patients. Subsequently, differential expression analysis, competing endogenous RNA and protein-protein interaction network analysis, correlation analysis with clinical characteristics, tumor purity, gene alteration, immune landscape and signaling pathways were performed to evaluate the role of SH3BGRL3 in pan-cancer. Drug sensitivity analysis, molecular docking and in vitro experiments were also conducted to explore its possible pharmaceutical significance.
RESULTS
In our clinical cohort of kidney neoplasms, SH3BGRL3 was downregulated in tumor tissues (p < 0.001). Higher tumor SH3BGRL3 was linked to decreased overall survival (p = 0.022), advanced stages and was an independent risk factor for progression-free survival (hazard ratio = 2.11, 95%confidence interval = 1.05-4.2, p = 0.037). Further pan-cancer analysis revealed that SH3BGRL3 expression was upregulated in most tumors, and correlated with unfavorable outcomes and advanced tumor stages of various cancers. It was also associated with tumor purity, tumor genomics, tumor immunity, pathway enrichment, and drug sensitivity at pan-cancer level. Dasatinib was found to effectively suppress SH3BGRL3.
CONCLUSIONS
SH3BGRL3 was an independent prognostic factor in our kidney neoplasm cohort. At the pan-cancer level, it served as a promising prognostic and immunological biomarker exhibiting cancer-type-specific variations.
Yuntao Yao, Zihui Zhao, Bingnan Lu et al.· Discover Oncology· 0 citations
Objective Triosephosphate isomerase 1 (TPI1) is aberrantly overexpressed and exerts a critical oncogenic role in the development and progression of various human cancers by regulating multiple malignant biological phenotypes. However, the biological functions of TPI1 and the molecular mechanisms underlying its regulatory effect on ferroptosis sensitivity in head and neck squamous cell carcinoma (HNSCC) remain not fully elucidated. Methods TPI1 expression was analyzed across 33 cancer types using The Cancer Genome Atlas pan-cancer dataset, and validated in 6 paired HNSCC tumor/adjacent normal tissues via Western blotting and immunohistochemistry. Clinical correlations were assessed using the Wilcoxon rank-sum test, and prognostic value was evaluated by Kaplan-Meier analysis and multivariate Cox regression. A prognostic nomogram integrating TPI1 and clinical covariates was constructed and validated by calibration curves. Single-cell RNA-sequencing (3 independent cohorts: GSE103322, GSE150321, GSE172577) and spatial transcriptomics (4 patient samples) were employed to map TPI1 cellular distribution in the tumor microenvironment. Gain- and loss-of-function assays were performed in FaDu (overexpression) and TU177 (knockdown) cell lines using lentiviral vectors. Cell proliferation was measured by CCK-8 and colony formation assays; migration and invasion were evaluated by wound healing and Transwell assays. Ferroptosis sensitivity was assessed by RSL3 dose-response curves, malondialdehyde (MDA) assay, BODIPY 581/591 C11 lipid peroxidation staining, and intracellular Fe2+ quantification. Results TPI1 was significantly upregulated in HNSCC at both mRNA and protein levels, with an AUC of 0.914 for distinguishing tumor from normal tissues. High TPI1 expression correlated with male sex, high histologic grade, advanced pathologic stage, and T3-T4 stage, and independently predicted poor overall survival. The nomogram integrating TPI1, age, gender, stage, and grade showed robust prognostic performance with well-calibrated 1-, 3-, and 5-year survival predictions. Single-cell and spatial transcriptomics confirmed that TPI1 was predominantly and specifically expressed in malignant epithelial cells, with minimal expression in stromal and immune cells. Functionally, TPI1 overexpression significantly enhanced FaDu cell proliferation, migration, and invasion, while TPI1 knockdown markedly suppressed these phenotypes in TU177 cells. Mechanistically, TPI1 conferred ferroptosis resistance by attenuating RSL3-induced lipid peroxidation, reactive oxygen species accumulation, and intracellular Fe2+ elevation; conversely, TPI1 silencing sensitized HNSCC cells to ferroptotic cell death. Conclusion This study identifies TPI1 as a key tumor-promoting factor and independent prognostic biomarker in HNSCC. TPI1 promotes malignant progression by enhancing ferroptosis resistance, providing a promising therapeutic target for overcoming ferroptosis evasion in HNSCC.
Rui Ye, Zhihua Xu, Yehai Liu· Frontiers in Genetics· 0 citations
In vitro findings suggest a potential association among SRM, IL‐8 expression, and pathways related to tumor progression and immune modulation, although further in vivo studies are required to confirm these observations.
Bo-Wen Wu, Feng-Hong Wang, Lei Zhang et al.· Mediators of Inflammation· 0 citations