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PubMed2026

Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.

BACKGROUND: Enhanced glycolysis is a hallmark of metabolic reprogramming in cervical cancer and plays a key role in tumor progression. Hypoxia-inducible factor-1α (HIF-1α), a core regulator of glycolytic metabolism, remains incompletely characterized in cervical cancer. This study aimed to investigate the expression pattern and clinical significance of HIF-1α in cervical cancer, and to explore its association with malignant biological behavior and lactate dehydrogenase A (LDHA)-related glycolytic metabolism in cervical cancer cells. METHODS: The expression level, clinicopathological features, immune infiltration correlation, and prognostic value of HIF-1α in cervical cancer were analyzed based on the The Cancer Genome Atlas (TCGA) database. HIF-1α overexpression and knockdown models were established in HeLa and Caski cells. Cell viability and invasive ability were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect changes in LDHA expression. Lactate production was measured using a lactate assay kit, and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry. RESULTS: Bioinformatics analysis showed that HIF-1α was highly expressed in cervical cancer and was closely associated with patient age, menopausal status, immune cell infiltration, and poor prognosis. Kaplan-Meier survival analysis demonstrated that patients with high HIF-1α expression had significantly worse overall survival (OS) than those with low expression. In vitro functional experiments further confirmed that HIF-1α overexpression significantly enhanced the viability and invasive ability of HeLa and Caski cells, whereas HIF-1α knockdown produced the opposite effects. HIF-1α overexpression was associated with increased messenger RNA (mRNA) and protein expression levels of LDHA, a key glycolytic molecule, along with increased lactate production and elevated intracellular ROS levels. CONCLUSIONS: HIF-1α is aberrantly highly expressed in cervical cancer and may enhance glycolytic activity by upregulating LDHA expression, thereby promoting the proliferation and invasion of cervical cancer cells. These findings suggest that HIF-1α could serve as a potential diagnostic, prognostic, and therapeutic target biomarker for cervical cancer.

Hypoxia-inducible factor-1α (HIF-1α)↗
PubMed2026

Non-small cell lung cancer and tumor-educated platelets: screening of biomarkers and construction of a prognostic model.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, emphasizing the urgent need for effective early detection strategies. Traditional Chinese medicine (TCM) provides a unique perspective on tumor pathogenesis, focusing on concepts such as "long-term stasis leading to accumulation". Tumor-educated platelets (TEPs) offer potential as biomarkers due to their ability to reflect cancer heterogeneity and facilitate less invasive diagnostic approaches. This study aims to identify TEP-related prognostic biomarkers for non-small cell lung cancer (NSCLC) and to construct and validate a multigene prognostic model by integrating platelet transcriptomic data with tumor tissue datasets. METHODS: We performed comprehensive analysis of gene expression datasets obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories to characterize transcriptomic differences among lung cancer specimens, normal tissue samples, and TEPs. Using R software, we identified Differentially expressed genes (DEGs) and subsequently applied a multi-stage analytical pipeline to TEP-associated DEGs, incorporating univariate Cox proportional hazards regression, least absolute shrinkage and selection operator (LASSO) regression, multivariate Cox regression, and stepwise regression modeling to pinpoint genes with prognostic significance. These prognostically relevant genes served as the foundation for developing a risk stratification model. We computed individual risk scores across both training and validation cohorts, enabling patient stratification into high- and low-risk categories. Model robustness was assessed through internal cross-validation and external validation procedures, while predictive performance was quantified using risk calibration metrics and receiver operating characteristic (ROC) curve analysis. RESULTS: Through systematic bioinformatics screening, we identified a four-gene prognostic signature comprising NELL2, C4orf48, PRAM1, and KLHL35, which served as the foundation for developing our risk stratification algorithm. Rigorous internal cross-validation and external cohort validation substantiated the moderate predictive performance of this signature. Comprehensive clinicopathological correlation analysis revealed that elevated risk indices, advanced pathological staging (stage III-IV), increased primary tumor dimensions, regional lymph node metastasis, and distant organ dissemination each demonstrated statistically significant associations with diminished overall survival (OS) outcomes in lung cancer patients. The clinical nomogram exhibited acceptable calibration, with calibration plots showing reasonable concordance between predicted and observed survival probabilities across all time points. Discriminative capacity assessment via time-dependent ROC analysis yielded area under the curve (AUC) values consistently surpassing 0.6, confirming moderate prognostic discrimination. Furthermore, decision curve analysis (DCA) demonstrated that our integrated multi-gene model conferred potential net clinical benefit compared to individual prognostic variables across the full spectrum of clinically relevant threshold probabilities (0-1 range), thereby establishing its potential utility for risk-informed clinical decision-making. CONCLUSIONS: This study identified NELL2, C4orf48, PRAM1, and KLHL35 as candidate TEP-related prognostic biomarkers for non-small cell lung cancer (NSCLC). The developed prognostic model shows preliminary potential for patient stratification, but its clinical application, particularly as a platelet-based liquid biopsy tool, requires further validation in independent TEP-based cohorts.

Tumor-educated platelets (TEPs)↗
PubMed2026

Microplastics and nanoplastics-related genes signature predicts prognosis in pancreatic ductal adenocarcinoma and functional validation of interleukin 1 alpha.

BACKGROUND: Microplastics and nanoplastics (MNPs), as emerging environmental pollutants, have garnered significant attention from the global scientific community due to their potential threats to human health, particularly their association with the occurrence and development of cancer. The goal of our study is to create a predictive marker for pancreatic ductal adenocarcinoma (PAAD) based on MNPs-related genes, with the purposes of predicting survival outcomes and assessing the tumor immune microenvironment. METHODS: Using multi-cohort data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC), we assessed the association between MNPs and PAAD prognosis through the Xiantao Academic (https://www.xiantao.love/). The development of a prognostic signature was followed by an assessment of its significance through the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and decision curve analysis (DCA). The validity of the risk model was confirmed through the ICGC and GSE71729 cohorts. The model was then assessed for levels of tumor immune infiltration. To explore MNPs-related genes expression characteristics within immune cells in PAAD, we performed single-cell RNA sequencing and spatial transcriptomics analysis through the Sparkle Platform (https://grswsci.top/). Finally, in vitro experiments were conducted to investigate the biological function of interleukin 1 alpha (IL1A). RESULTS: A four-gene signature comprising XDH, IL1A, KIF20A, and ASPM, based on MNPs, was developed to stratify PAAD patients into two distinct risk groups. The high-risk group showed a significantly poorer prognosis. A similar trend was verified in the external cohorts ICGC and GSE71729. The signature risk score affected immune cell infiltration in the PAAD microenvironment. The infiltration of B cells, CD8+ T cells, cytotoxic cells, immature dendritic cells (iDCs), mast cells, plasmacytoid dendritic cell (pDC), T cells, Tem cells, T follicular helper (TFH) cells, and T helper 17 (Th17) cells had a positive correlation with the low-risk group. In contrast, high-risk patients tended to have increased number of T helper (Th2) cells and higher expression of SIGLEC15, CD274, IGSF8. Knockdown of IL1A in PAAD cells inhibited their tumor proliferation ability in vitro. CONCLUSIONS: Using MNPs-related genes, we built a prognostic model for PAAD, revealing that patients with high-risk scores are likely to have a worse prognosis. This model is designed to develop personalized treatment strategies tailored to the specific needs of each patient, thereby improving clinical outcomes for PAAD patients. Furthermore, IL1A could be a promising therapeutic candidate for PAAD.

Microplastics↗
PubMed2026

A three-gene radioresistance signature predicts tumor progression in cervical cancer.

BACKGROUND: As a primary curative treatment for locally advanced cervical cancer, radiotherapy is frequently undermined by radioresistant tumor cells that evade cell death and subsequently drive post-treatment tumor progression. This study aimed to identify candidate genes associated with radioresistance in cervical cancer and to explore their potential in predicting unfavorable outcomes among radioresistant patients, thereby providing a reference for future research. METHODS: We screened for co-expressed genes using transcriptomic data from radiation non-complete response (NCR) cervical cancer patients in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Cox regression analyses were conducted to identify the most significant radioresistance-associated genes for constructing a prognostic model. The predictive performance of this model was further validated through logistic regression, weighted gene co-expression network analysis (WGCNA), and pan-cancer analyses. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify the expression levels of key genes in cervical cancer tissue samples from radiosensitive and radioresistant patients. RESULTS: The resulting prognostic model comprised three genes: MTMR11, VANGL1, and CD46. This gene panel was significantly associated with the prognosis of cervical cancer patients receiving radiotherapy and showed acceptable predictive performance across multiple cancer types. qRT-PCR analysis revealed that the expression patterns of MTMR11 and VANGL1 were generally consistent with radioresistance of cervical cancer, whereas CD46 exhibited an unexpected expression trend. CONCLUSIONS: Our findings indicate that MTMR11, VANGL1, and CD46 are associated with radioresistance and prognosis in cervical cancer. Their potential clinical utility, especially in predicting radiotherapy response at the individual patient level, requires further validation in larger, independent, and prospective cohorts.

Cervical cancer↗
PubMed2026

Genetic insights into lung squamous cell carcinoma: how TP53 and CSMD3 co-mutations shape prognosis and immune response.

BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of lung cancer cases and is often associated with smoking and various environmental factors. The prognostic and immunologic implications of TP53 and CSMD3 co-mutations in LUSC remain poorly understood. This study aimed to investigate the role of TP53/CSMD3 co-mutations in LUSC using comprehensive bioinformatics analyses. METHODS: Data from 487 LUSC patients were obtained from The Cancer Genome Atlas (TCGA) database, with external validation performed using the combined cohort. Patients were stratified into TP53/CSMD3 co-mutation, single-mutation, and wild-type (WT) groups. Prognostic analysis was conducted using Kaplan-Meier survival curves. Tumor mutational burden (TMB) was calculated, and immune cell infiltration was assessed using multiple algorithms. Differentially expressed genes (DEGs) between co-mutated and WT groups were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A nomogram incorporating mutation status, gender, age, and tumor stage (T stage) was developed for individualized prognostic prediction. RESULTS: The TP53/CSMD3 co-mutated group exhibited significantly better overall survival (OS) compared to single-mutation and WT groups. TMB scores were markedly higher in co-mutated patients, suggesting potential sensitivity to immune checkpoint inhibitors. Immune infiltration analysis revealed distinct profiles, including elevated CD8 T cells and reduced immunosuppressive components, in the co-mutation group. A total of 403 DEGs were identified between co-mutated and WT groups, with significant enrichment in immune-related pathways. Mechanistically, the co-mutation was associated with distinct downregulation of complement negative regulators (CFH/CFI), indicating complement hyperactivation independent of TMB. The constructed nomogram provided accurate individualized prognostic assessments. CONCLUSIONS: The co-mutation of TP53 and CSMD3 identifies a distinct LUSC subtype with favorable survival, marked by high TMB and an immune-activated microenvironment. Beyond TMB-driven neoantigen generation, the significant downregulation of complement negative regulators (CFH/CFI) reveals an independent complement hyperactivation pathway associated with CSMD3 loss. The constructed nomogram provides accurate individualized survival prediction. These findings establish TP53/CSMD3 co-mutation as a promising prognostic biomarker and offer mechanistic insights for personalized immunotherapy strategies. Future prospective cohorts are warranted to validate its predictive value.

Lung squamous cell carcinoma (LUSC)↗
PubMed2026

PSMA6 drives non-small cell lung cancer progression by stabilizing NEDD8 and activating NF-κB signaling.

BACKGROUND: Non‑small cell lung cancer (NSCLC) is a major cause of cancer‑associated death globally. Elucidating novel molecular drivers is essential for targeted therapy development. This study sought to investigate the function and regulatory mechanism of proteasome 20S subunit alpha 6 (PSMA6) in NSCLC. METHODS: Proteasome 20S subunit alpha 6 (PSMA6) expression in NSCLC tissues and cells was analyzed using The Cancer Genome Atlas (TCGA) datasets, immunohistochemistry, and Western blotting. Gain- and loss-of-function assays were performed to evaluate its biological functions. Protein interaction assays and functional rescue experiments were conducted to investigate the underlying mechanisms. RESULTS: We found that PSMA6 was significantly upregulated in NSCLC tissues and cell lines and was associated with poor patient prognosis. Functional experiments demonstrated that PSMA6 promoted NSCLC cell proliferation and migration. Mechanistically, PSMA6 activated nuclear factor kappa B (NF-κB) signaling by enhancing p65 nuclear translocation and IκBα phosphorylation. Further investigation revealed that PSMA6 directly interacted with neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) and increased its protein stability without affecting its mRNA level. Importantly, NEDD8 knockdown abolished PSMA6-induced NF-κB activation and malignant phenotypes, confirming that PSMA6 exerts its oncogenic effects through the NEDD8/NF-κB axis. CONCLUSIONS: Our findings identify a novel PSMA6/NEDD8/NF-κB regulatory axis that promotes NSCLC progression and suggest PSMA6 as a potential therapeutic target.

Proteasome 20S subunit alpha 6 (PSMA6)↗
PubMed2026

GCH1, identified by a ferroptosis-related prognostic model, contributes to progression and drug resistance of esophageal cancer.

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.

Esophageal cancer↗
PubMed2026

Identification of JAML as an Immune-Associated Prognostic Marker in Non-Small Cell Lung Cancer.

INTRODUCTION: Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, and the identification of novel prognostic biomarkers associated with tumor immunity is urgently needed. Junctional adhesion molecule-like (JAML), a member of the junctional adhesion molecule family, participates in leukocyte adhesion, migration, and T-cell activation. Although JAML has been implicated in immune regulation and tumor progression in other cancers, its expression pattern, prognostic significance, and association with the immune microenvironment in NSCLC remain unclear. This study aimed to investigate the clinical and immunological significance of JAML in NSCLC. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to evaluate JAML expression patterns in NSCLC subtypes. The prognostic value of JAML was assessed using Kaplan-Meier survival analysis and Cox regression models. The association between JAML expression and immune cell infiltration was investigated using TIMER2.0, CIBERSORT, and TISIDB analyses. Functional enrichment analyses were performed to explore potential biological pathways associated with JAML expression. In addition, JAML expression was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paired NSCLC and adjacent normal tissues. RESULTS: JAML expression was significantly decreased in NSCLC tissues compared with normal tissues (P < 0.005), with the lowest expression observed in lung squamous cell carcinoma (LUSC) and reduced expression in lung adenocarcinoma (LUAD). Survival analysis demonstrated that patients with high JAML expression had significantly improved overall survival compared with those with low expression (univariate HR = 0.68, 95% CI: 0.54-0.86, P = 0.001; multivariate HR = 0.76, 95% CI: 0.57-1.00, P = 0.049). Immune infiltration analysis revealed that JAML expression was significantly associated with multiple immune cell populations, including CD8+ T cells (r = 0.42, P < 0.001), suggesting a close relationship between JAML expression and the tumor immune microenvironment. qRT-PCR validation confirmed that JAML expression was approximately 2.3-fold higher in adjacent normal tissues than in NSCLC tissues (P < 0.05). CONCLUSION: JAML is downregulated in NSCLC and its high expression is associated with favorable overall survival and distinct immune infiltration patterns. These findings indicate that JAML may serve as a potential prognostic biomarker and provide insights into the relationship between JAML expression and the tumor immune microenvironment in NSCLC.

JAML protein↗
PubMed2026

Prognostic Role of Global DNA Methylation in Renal Cancer Reveals Decitabine Treatment Benefit.

BACKGROUND: Renal cancer presents a significant global health challenge due to its rising incidence and mortality rates. Often undetected in early stages, it complicates diagnosis and treatment. Current therapies face resistance and limited effectiveness, especially in advanced stages. The diverse subtypes of renal cancer highlight the need for new biomarkers and risk assessment tools for targeted treatments. OBJECTIVE: This study aims to assess the prognostic significance of global DNA methylation (GM) levels in renal cancer, identify new biomarkers, and evaluate the therapeutic potential of the DNA methyltransferase inhibitor decitabine. METHODS: Data on RNA sequencing, gene mutations, DNA methylation, and clinical outcomes were collected from TCGA and GEO databases. We calculated global DNA methylation scores (GMS) and categorized patients into high, intermediate, and low GMS groups. Survival analysis and genomic analyses were conducted to explore the relationships between GMS, clinical outcomes, and tumor characteristics. RESULTS: Higher GMS was identified as an independent prognostic factor associated with worse outcomes in renal cancer. Patients with elevated GMS showed increased mutations, copy number variations, and a more aggressive tumor phenotype. Treatment with decitabine was observed to reduce tumor hypermethylation and downregulate cell cycle pathway activity, indicating potential therapeutic benefits. CONCLUSION: Global DNA methylation plays a significant role in renal cancer prognosis. GMS may serve as valuable biomarkers for prognosis and personalized treatment strategies. Decitabine shows potential efficacy for high GMS patients, particularly through its impact on cell cycle regulation, underscoring the importance of personalized approaches in cancer treatment.

Humans↗
PubMed2026

NPLOC4 Constructs Tumor Immunosuppressive Microenvironment in Pan-cancer and Hepatocellular Carcinoma.

INTRODUCTION: NPLOC4 (nuclear protein localization 4 homolog) is mainly involved in DNA damage, cell cycle, and ubiquitination promotion. Nonetheless, the role of NPLOC4 in the tumor immune microenvironment (TIME) and its potential as a promising tumor therapeutic target remains unclear. METHODS: Therefore, analyses of NPLOC4 mRNA and protein expression, RNA subcellular localization, and patient prognosis associated with NPLOC4 expression were conducted across multiple tumor types. Additionally, the correlations between NPLOC4 and immune cells, non-immune cells, and immune molecules within the tumor immune microenvironment (TIME) were investigated. These analyses utilized data from various public resources, including the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), The Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), TIMER2.0, KM-Plotter, The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), and Tumor Immune Single-cell Hub 2 (TISCH2). Subsequently, we utilized hepatocellular carcinoma (HCC) patients' cancer and adjacent tissues plus tumor cell lines to verify the differential RNA and protein expression of NPLOC4 via qRT-PCR and immunohistochemistry (IHC). Then, the relationship of NPLOC4 expression level with immune infiltration score, infiltration of effector immune cells, suppressive immune cells, and several vital immune checkpoints was analyzed in HCC immune microenvironment. Furthermore, the distribution of expression of NPLOC4 in various cells in the HCC microenvironment was determined through single-cell sequencing analysis. RESULTS: We discovered that NPLOC4 was up-regulated in a variety of tumors and was correlated with poor prognosis. NPLOC4 not only had the potential as a tumor prognostic marker and therapeutic target but also was strongly linked to immune cells, immune checkpoints, and immune-related molecules and pathways in HCC immune microenvironment. CONCLUSION: In summary, NPLOC4 may serve as a promising target for immunotherapy.

Humans↗
PubMed2026

Development and Validation of a Prognostic Signature Based on Transcription Factors Associated with Endoplasmic Reticulum Stress in Pancreatic Adenocarcinoma.

BACKGROUND: Endoplasmic reticulum stress (ER stress) plays a crucial role in influencing the malignant behaviors of various tumors. Targeting the expression or degradation of transcription factors (TFs) offers a promising avenue for cancer treatment. However, a detailed understanding of how ER stress affects TF function and their interactions remains limited. This study aims to develop a prognostic model and identify TFs associated with ER stress in pancreatic ductal adenocarcinoma (PDAC). METHODS: We obtained gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA). To develop a prognostic signature, we performed several analyses, including unsupervised clustering, enrichment analysis, immune infiltration assessment, as well as univariate, LASSO, and multivariate Cox regression analyses. Four transcription factors-STAT1, IRF6, NRF1, and RXRA-were incorporated into a risk model, which was subsequently validated using the GSE dataset. Additionally, we examined IRF6 through quantitative PCR, western blotting, flow cytometry, and immunohistochemistry in vitro using pancreatic cancer cell lines and a tissue microarray. RESULTS: The high-risk group identified by the model exhibited significant associations with immune cell infiltration and poorer survival outcomes, though there was no significant correlation with tumor purity (p = 0.19). Furthermore, IRF6 downregulation in vitro was found to inhibit pancreatic cancer cell proliferation and promote apoptosis. IRF6 depletion also increased the expression of key molecules involved in ER stress at both the transcriptional and translational levels. Immunohistochemical analysis revealed marked differences in IRF6 expression between tumor and adjacent non-tumor tissues (59.29&#xb1;29.88 vs. 95.22&#xb1;40.80, p<0.001). CONCLUSION: This study provides evidence that the constructed risk model can effectively predict prognosis in PDAC patients. Transcription factors related to ER stress, such as IRF6, show promise as both prognostic biomarkers and potential therapeutic targets for PDAC.

Humans↗
PubMed2026

CDC20B Dysregulation: Links to Tumor Prognosis and Immunity.

OBJECTIVE: This study aimed to clarify the pan-cancer expression pattern, upstream regulatory mechanisms, prognostic relevance, and immune associations of CDC20B. METHOD: Using public databases (GTEx, GEO, and TCGA), we examined CDC20B expression and its associations with prognosis and tumor immunity across multiple cancers. Immunohistochemistry (IHC) on an independent clinical cohort was performed to validate CDC20B upregulation in tumor tissues. Promoter methylation, genetic alterations, and immune infiltration were analyzed using bioinformatics tools (cBioPortal, UALCAN, TIMER2.0, ESTIMATE). Functional enrichment was assessed by GSEA and single-cell state analysis (CancerSEA). RESULTS: CDC20B was markedly upregulated in most tumor types (p < 0.001), with strong diagnostic efficiency (AUC > 0.7 in 15 cancers) and potential regulation by promoter hypomethylation. IHC confirmed its overexpression in clinical tumor tissues. However, the prognostic impact of CDC20B was cancer-type-specific: high expression correlated with poor overall survival in UCS, LGG, KIRC, and OV, but with favorable survival in BRCA, LUAD, and PAAD. CDC20B expression was associated with immune infiltration patterns, showing negative correlations with ImmuneScore in most cancers but positive correlations with CD8+ T cells in PAAD. Functional analyses indicated involvement in EMT, KRAS/NF-&#x3ba;B signaling, and DNA damage response pathways. DISCUSSION: The dual prognostic role of CDC20B suggests context-dependent functions, likely influenced by tumor microenvironment composition and underlying oncogenic programs. Promoter hypomethylation emerges as a potential epigenetic driver of overexpression. The associations with immune modulation and genomic instability suggest that CDC20B is a candidate biomarker, though causal relationships require experimental validation. CONCLUSION: CDC20B may contribute to tumor progression in a context-dependent manner, with its prognostic impact varying across cancer types. Its role in tumor immunity and oncogenic pathways warrants further investigation, particularly in stratified patient populations.

CDC20B↗
PubMed2026

KLK6 is Associated with a Neutrophil-Dominant Immunosuppressive Microenvironment and Epigenetic Deregulation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer and is associated with poor survival despite advances in targeted therapies. Kallikrein-related peptidase 6 (KLK6) has been implicated in several malignancies, but its expression pattern, clinical relevance, and biological function in LUAD remain incompletely characterized. This study aimed to evaluate KLK6 expression and its associations with prognosis, epigenetic regulation, immune infiltration, and migratory phenotypes in LUAD. METHODS: RNA-seq expression and clinical data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. KLK6 expression was analyzed in relation to clinicopathological parameters, survival outcomes, promoter methylation status (via UALCAN), and tumor-infiltrating immune cell abundance (via TIMER2.0). In vitro, KLK6 was knocked down using shRNA in A549 and H1299 LUAD cell lines. Cell migration was assessed by transwell assays, and the expression of Epithelial-Mesenchymal Transition (EMT)- and Wnt signaling-related markers was examined by qRT-PCR and Western blotting. RESULTS: KLK6 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. High KLK6 expression was associated with poorer overall survival (HR = 1.52, P = 0.009) and disease-specific survival (HR = 1.55, P = 0.03). ROC analysis showed that KLK6 discriminated stage I LUAD from normal tissues with an AUC of 0.73. Promoter hypomethylation was observed in LUAD tumors and correlated with increased KLK6 expression. Immune infiltration analysis revealed that KLK6-high tumors exhibited reduced B-cell infiltration and increased neutrophil infiltration. Functional experiments demonstrated that KLK6 knockdown significantly suppressed cell migration, accompanied by increased E-cadherin and decreased N-cadherin, Vimentin, Wnt5a, and &#x3b2;-catenin expression. DISCUSSION: These findings suggest that KLK6 overexpression in LUAD is driven in part by promoter hypomethylation and is closely linked to a neutrophil-dominant immunosuppressive microenvironment. Furthermore, KLK6 appears to promote LUAD cell migration through EMT- and Wnt-related signaling pathways. Collectively, these multi-layered data position KLK6 as a potential driver of aggressive tumor behavior and a candidate biomarker for risk stratification. CONCLUSION: KLK6 is aberrantly overexpressed in LUAD and is associated with poor prognosis and enhanced migratory capacity. It may serve as a promising prognostic biomarker and a potential therapeutic target for LUAD.

KLK6↗
PubMed2026

Identification of Drug-resistant Cell Subpopulations in Colorectal Cancer Through Single-cell Analysis and Exploration of Potential Therapeutic Strategies.

INTRODUCTION: The therapeutic efficacy of Colorectal Cancer (CRC) is often compromised by resistance to the standard chemotherapy agent oxaliplatin. METHODS: This study obtained single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database. Differentially Expressed Genes (DEGs) between resistant and sensitive epithelial subpopulations were identified, followed by enrichment analysis. Pseudotemporal trajectory and cell-cell communication were analyzed using Monocle2 and CellChat, respectively. The candidate drug was predicted by Connectivity Map (cMAP) analysis. External validation included assessment of the EpC2 signature in an oxaliplatin-resistant cell line dataset (GSE76092), survival analysis using The Cancer Genome Atlas (TCGA) cohorts, and re-analysis of the GSE179784 dataset to assess the reproducibility of EpC2-like subpopulations and their DNA Damage Repair (DDR) scores. RESULTS: Cell subpopulations were divided into 10 clusters. Among them, epithelial cells comprised 5 subpopulations, with EPC2 identified as a potential oxaliplatin-resistant subset. DEGs were enriched in the TNF and IL-17 pathways. External validation confirmed the enrichment of EpC2 in resistant cell lines and its association with poor survival. Pseudotemporal trajectory revealed that epithelial cells underwent state transitions, forming two distinct branches. The resistant group exhibited enrichment in RNA splicing and NF-&#x3ba;B pathways. Cell-cell communication analysis revealed interactions involving MDK- NCL and PPIA-BSG. Dasatinib was predicted as a candidate drug. DISCUSSION: We identified an oxaliplatin-resistant subpopulation of Epithelial Cells (EpC2) in CRC, elucidated its multi-layered resistance mechanisms, and integrated multi- omics and cMAP database analyses to predict a potential intervention drug. CONCLUSION: This study provided potential therapeutic possibilities for oxaliplatin resistance, contributing to CRC treatment.

Humans↗
PubMed2026

ARL6IP1 Inhibits Breast Cancer Tumor Progression by Targeting OLFM4 to Regulate Glycolysis.

INTRODUCTION: ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear. AIMS: This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target. OBJECTIVE: The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism. METHODS: Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated. RESULTS: ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown. CONCLUSION: ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

Humans↗
PubMed2026

KLHL17 as a Prognostic Indicator and Therapeutic Target in Cervical Cancer: A Comprehensive Analysis.

INTRODUCTION: This study aims to clarify the role of kelch like family member 17 (KLHL17) in cervical cancer (CESC) is unclear. OBJECTIVE: To clarify this uncertainty, our research employed bioinformatics analysis coupled with experimental corroboration. METHODS: We utilized the Cancer Genome Atlas (TCGA) database to assess the expression of KLHL17 in various cancers, specifically CESC, and to explore its association with clinical characteristics, diagnostic utility, and prognostic significance in CESC. The current investigation delved into the potential regulatory pathways related to KLHL17, examining its connection with the infiltration of immune cells, the expression of immune checkpoint genes, the status of microsatellite instability (MSI), and the efficacy of diverse therapeutic agents in CESC. The research analyzed KLHL17 expression patterns using single-cell sequencing data from CESC samples and investigated the genetic variations of KLHL17 within this context. KLHL17 expression was validated using GSE145372. The presence and levels of KLHL17 in different cell lines were validated through quantitative real-time PCR (qRT-PCR) assays. RESULTS: KLHL17 exhibited irregular expression profiles across various cancer types, including CESC. Furthermore, increased KLHL17 levels in CESC patients were significantly associated with a lower progression-free survival (PFS) rate (hazard ratio: 1.62; 95% confidence interval: 1.01-2.60, p = 0.044). Moreover, KLHL17 expression emerged as a distinct prognostic indicator for CESC patients (p = 0.031). It has been associated with various biological pathways, such as cytokine-cytokine receptor interaction, primary immunodeficiency, cell adhesion molecules (CAMs), chemokine signaling pathway, steroid hormone biosynthesis, and others. The expression levels of KLHL17 were found to correlate with the presence of immune cells, the expression of immune checkpoint genes, and the status of MSI within CESC. Furthermore, KLHL17 expression exhibited a significant and inverse correlation with XMD15-27, rTRAIL, Paclitaxel, tp4ek, and tp4ek-k6. Furthermore, KLHL17 was found to be significantly positively regulated in CESC cell lines. DISCUSSION: The findings suggest that KLHL17 is involved in the progression of CESC and may serve as a potential prognostic marker and therapeutic target. KLHL17's association with immune cell infiltration and immune checkpoint genes indicates a role in immuneevasion. Future research should focus on validating these findings through independent datasets and experimental studies to elucidate the molecular mechanisms underlying KLHL17's role in CESC progression and immune regulation. CONCLUSION: KLHL17 is a promising prognostic marker and potential therapeutic target in CESC.

Humans↗
PubMed2026

ZUP1 as a Novel Potential Oncogenic Driver and Prognostic Biomarker in Breast Cancer.

INTRODUCTION: Breast cancer is one of the main causes of cancer death in women globally. Identifying new predictive markers and therapeutic targets is important for improving patient outcomes. Zinc finger-containing U-rich RNA-binding protein 1 (ZUP1) is an RNA-binding protein containing a zinc finger structure that has not been systematically analyzed in breast cancer research. MATERIALS AND METHODS: The study used data from 1,231 samples from the Cancer Genome Atlas (TCGA) database. The ZUP1 expression in tumor tissues and normal tissues was compared. Its predictive value was assessed using survival analysis and regression models. Its biological role was explored through gene functional analysis. The immune cell analysis method was used to study the tumor immune environment, and the drug susceptibility database was used to predict drug responses. Predictive models were also built and validated. RESULTS: ZUP1 expression was significantly higher in breast cancer tissues than in normal tissues. High expression of ZUP1 is related to advanced tumor stage and is an independent indicator of poor survival prognosis in univariate and multivariate analyses. Functional enrichment revealed that ZUP1 is closely linked to cell cycle progression, DNA replication, and the Fanconi anemia (FA) pathway. Immune infiltration analysis demonstrated a significant negative link between ZUP1 levels and the abundance of resting mast cells and activated NK cells. Furthermore, high ZUP1 expression was associated with increased sensitivity to several targeted therapies, including Nutlin-3a and PD-0325901. A clinically applicable nomogram combining ZUP1 expression with key clinical factors (age, stage, T, N, M) was developed to predict 3- and 5-year OS with good calibration and discrimination. DISCUSSION: Our study identifies ZUP1 as a potential oncogenic factor and a robust independent prognostic biomarker in breast cancer. Its involvement in critical cellular processes and modulation of the tumor immune microenvironment highlights its potential as a novel therapeutic target. Functional experiments, including immunohistochemical staining and CCK8 proliferation assays, further supported the oncogenic role of ZUP1. The established nomogram provides a valuable tool for personalized risk assessment and clinical decision-making. CONCLUSION: Our findings suggest that ZUP1 is a novel multifaceted biomarker with significant implications for personalized treatment strategies in breast cancer.

ZUP1↗
PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗