Aug 2026· Frontiers in Genetics· Vol 17· 0 citations· 38 references
Medicine
TL;DR
This study identifies TPI1 as a key tumor-promoting factor and independent prognostic biomarker in HNSCC, providing a promising therapeutic target for overcoming ferroptosis evasion in HNSCC.
Abstract
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.
Background Glycolipid transfer protein (GLTP) is a key regulator of glycosphingolipid distribution between intracellular membranes. Although aberrant GLTP expression has been implicated in various cancers, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods HNSCC samples from The Cancer Genome Atlas (TCGA) were stratified based on GLTP expression levels. A comprehensive bioinformatic analysis was conducted to investigate GLTP’s expression, functional networks, and impact on the tumor immune microenvironment. To construct a prognostic model, a signature based on genes associated with GLTP expression was developed using univariate Cox and LASSO regression analyses, and its robustness was validated in the independent GSE41613 cohort. The role of GLTP in cell migration was further verified using wound-healing assays in HSC-3 and SCC-9 cell lines with GLTP overexpression or knockdown. Results GLTP was significantly downregulated in HNSCC tissues. Functional analysis linked GLTP to epidermal differentiation, muscle contractile processes, and immunomodulatory mechanisms, with involvement in key pathways such as the chemokine, Ras, and PI3K-Akt signaling pathways. Immune infiltration analysis revealed that, compared to the low GLTP expression group, the high GLTP expression group exhibited increased plasma cell infiltration, decreased levels of resting CD4+ memory T cells and M1 macrophages, and generally lower expression of immune checkpoint genes. Based on these findings, a GLTP-related risk score model was constructed, which stratified patients into distinct prognostic groups and was validated in an independent cohort. Functional experiments demonstrated that GLTP overexpression inhibited cell migration, whereas its knockdown promoted migration, suggesting that GLTP regulates HNSCC cell motility. Conclusions This study developed and validated a GLTP-based prognostic model that stratifies HNSCC patients into distinct risk groups. Functional experiments demonstrated that GLTP overexpression inhibited HNSCC cell migration, while its knockdown enhanced migration. These findings indicate that GLTP is involved in HNSCC progression and provide a rationale for further investigation.
Lu Zeng, Yi-Hong Hu, Ziwei Ma et al.· PeerJ· 0 citations
Abstract Background/Aim: Endoplasmic reticulum resident protein 44 (ERP44), a protein disulfide isomerase family member, has been implicated in tumor biology, but its role in lower-grade glioma (LGG) remains unclear. This study investigated the prognostic significance and biological function of ERP44 in LGG, focusing on proliferation and temozolomide (TMZ) resistance. Materials and Methods: ERP44 expression, clinicopathological associations, and prognostic value were analyzed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets. Time-dependent receiver operating characteristic (ROC) curves, Cox regression, and a prognostic nomogram were constructed. Differential expression, Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) enrichment, immune infiltration, and drug sensitivity analyses were performed. Functional validation was conducted in SW1088 and SW1783 cells using shRNA-mediated ERP44 knockdown, followed by RT-qPCR, western blotting, CCK-8, colony formation, and TMZ IC50 assays. Subcutaneous xenograft models with or without TMZ treatment were used for in vivo validation. Results: ERP44 was markedly upregulated in LGG and associated with higher WHO grade, IDH wildtype status, 1p/19q non-codeletion, and poor survival in TCGA and CGGA cohorts. ERP44 showed strong prognostic performance and improved risk stratification in a multivariable nomogram. Enrichment analyses linked high ERP44 expression to immune/inflammatory pathways and reduced neuronal functional signatures. ERP44 positively correlated with immune infiltration, proliferation/stemness markers, and predicted TMZ resistance, while its knockdown inhibited proliferation and colony formation, reduced TMZ IC50, suppressed xenograft growth, enhanced TMZ efficacy, and decreased Ki67 positivity. Conclusion: ERP44 is a prognostic biomarker that promotes LGG proliferation and TMZ resistance, suggesting its potential as a therapeutic target.
Ling-Min Shao, Jia Liu, Mohammad Rohul Amin et al.· Cancer Genomics & Proteomics· 0 citations
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer; however, its prognosis remains poor, and the underlying molecular mechanisms have yet to be fully elucidated. In this study, a prognostic model was constructed based on manganese metabolism-related genes, which effectively stratifies patients with LUAD with different prognoses and drug sensitivity. Mendelian randomization analysis identified glutathione peroxidase 3 (GPX3) as a key prognostic gene, which was downregulated in LUAD and significantly correlated with favorable outcomes. Functionally, GPX3 was found to inhibit LUAD cell proliferation, invasion, and metastasis while promoting apoptosis. Mechanistically, GPX3 binds to heat shock protein β-1 (HSPB1), induces its ubiquitination, and facilitates its degradation, thereby activating the Hippo signaling pathway and suppressing malignant phenotypes in LUAD cells. In summary, this study not only established a robust prognostic model based on manganese metabolism-related genes but also uncovered the critical regulatory role of the GPX3/HSPB1/yes-associated protein (YAP) axis in LUAD progression, underscoring the therapeutic potential of targeting GPX3.
Si-Xuan Wu, He Huang, Junfan Pan et al.· Cell Reports· 0 citations
BACKGROUND
Lung adenocarcinoma (LUAD) is a predominant and lethal subtype of non-small cell lung cancer, with a lack of reliable prognostic biomarkers to guide clinical management. Basigin (BSG) has been implicated in tumor progression across multiple cancers, yet its expression pattern, prognostic significance, and underlying mechanisms in LUAD remain incompletely elucidated.
METHODS
We integrated multi-omics data from TCGA, GTEx, CCLE, and GEO databases to analyze BSG expression profiles. Clinical correlations were assessed via Kruskal-Wallis tests. Prognostic value was determined using Kaplan-Meier survival analysis, univariate/multivariate Cox regression, and nomogram construction with calibration curves. Functional enrichment (GO/KEGG) and immune infiltration analyses were performed to explore BSG-related mechanisms, followed by immunohistochemical (IHC) validation in A549 cells and clinical LUAD tissue microarrays.
RESULTS
BSG was significantly upregulated in LUAD tissues versus normal/paired adjacent tissues, correlating with advanced T/N/pathologic stages. High BSG expression predicted worse survival outcomes in TCGA-LUAD, which was validated in GEO datasets. Multivariate Cox regression identified BSG as an independent prognostic factor, with a well-calibrated nomogram for survival prediction. Functional exploration indicated that BSG mainly participated in tumor-associated and immunological pathways. Immune infiltration analysis indicated that BSG was significantly correlated with the infiltration of various immune cells. Moreover, BSG exhibited a strong association with immune checkpoint proteins, chemokines, chemokine receptors, and MHC genes. IHC further confirmed its cytoplasmic/membranous localization and prognostic relevance.
CONCLUSION
BSG serves as an independent prognostic biomarker and potential therapeutic target in LUAD, shedding light on its regulatory roles in tumor progression and immune microenvironment remodeling.
Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in lung adenocarcinoma.
Hui Xie, Cai-Xia Xu, Bing-Han Zhou et al.· British Journal of Cancer· 0 citations
Objective
Esophageal cancer has a poor prognosis and limited treatment options. Ferroptosis, an iron-dependent cell death pathway, is a promising therapeutic target; however, its significance in esophageal cancer remains largely unexplored. Here, we investigated the prognostic significance of ferroptosis-related genes in esophageal cancer and identified a key functional regulator that may serve as a therapeutic target.
Methods
We analyzed ferroptosis-related gene expression profiles with The Cancer Genome Atlas-Esophageal Carcinoma (TCGA-ESCA) cohort and constructed a prognostic risk model using LASSO Cox regression analysis. Among the genes in this model, GTP cyclohydrolase 1 (GCH1) was selected for functional investigation, based on its established role in antioxidant defense. Subsequently, in vitro experiments were performed to assess the effects of GCH1 knockdown on cell proliferation, migration, clonogenicity, and ferroptosis-related biochemical indicators. The role of GCH1 in antitumor immunity was evaluated through co-culture of esophageal cancer cells with activated T cells, and drug sensitivity was assessed using cytotoxicity assays.
Results
A prognostic model consisting of nine ferroptosis-related genes (STC2, TRIB3, HMGB3, CXCL8, GCH1, PARP10, APOE, MTIM, and GPER1) with reliable risk stratification was constructed. The prognostic model could reflect the differences in drug responses and immune cell infiltration. GCH1 knockdown suppressed esophageal cancer cell proliferation, migration, and clonogenicity. Furthermore, GCH1 knockdown increased the intracellular levels of reactive oxygen species, lipid peroxidation, and ferrous iron (Fe2+). Co-culture assays demonstrated that GCH1 knockdown in tumor cells increased the production of granzyme B and interferon-γ by CD8+ T cells. Moreover, GCH1 silencing sensitized esophageal cancer cells to both sorafenib and cisplatin.
Conclusions
This study established a ferroptosis-related prognostic model for esophageal cancer and identified GCH1 as a critical regulator that contributes to esophageal cancer progression and drug resistance. These findings suggest that targeting GCH1 may be a promising strategy to improve drug sensitivity and clinical outcomes in esophageal cancer.
Yu Xue, Wen-Ting Huang, Si-Jia Liu et al.· Chinese journal of cancer re...· 0 citations
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