Translational cancer research最新文献

Background: Prognosis in elderly colorectal cancer (CRC) patients is generally poor, predominantly attributable to the interrelated phenomena of immunosenescence and malnutrition. Current prognostic assessment tools typically evaluate nutritional and immune status in isolation, potentially overlooking the synergistic effects of these interconnected factors on patient outcomes. Therefore, this investigation aims to establish a comprehensive immuno-nutritional biomarker, integrating lymphocyte subset profiles and the Geriatric Nutritional Risk Index (GNRI), to prognosticate postoperative outcomes in elderly CRC patients.

Methods: A retrospective cohort of 201 elderly CRC patients undergoing curative resection at our institution between October 2018 and July 2020 was analyzed. Immunological and nutritional parameters were selected via least absolute shrinkage and selection operator (LASSO) regression to formulate a novel composite biomarker, designated as lymphocyte subsets-GNRI (LS-GNRI). Survival analyses employing Kaplan-Meier estimators and Cox proportional hazards models assessed the correlation of LS-GNRI with overall survival (OS) and disease-free survival (DFS). A prognostic nomogram integrating LS-GNRI and variables identified through multivariate Cox regression was constructed, with predictive accuracy and practicality evaluated via area under the curve (AUC), calibration plots (CAL), decision curve analysis (DCA), and clinical impact curves (CIC).

Results: Results indicated that the LS-GNRI biomarker demonstrated independent prognostic significance for elderly CRC patients [hazard ratio (HR): 0.323, 95% confidence interval (CI): 0.217-0.480, P<0.001]. Patients with elevated LS-GNRI exhibited significantly improved OS and DFS, with AUCs for 1-, 3-, and 5-year survival predictions of 0.763, 0.82, and 0.753, respectively. The nomogram incorporating LS-GNRI, age, carcinoembryonic antigen (CEA), tumor staging, RAS gene and BRAF gene exhibited high predictive performance (AUC: 0.872, 95% CI: 0.807-0.936) and demonstrated clinical utility.

Conclusions: In conclusion, LS-GNRI constitutes a robust composite biomarker for postoperative prognostication in elderly CRC patients. Furthermore, a prognostic nomogram incorporating LS-GNRI, patient age, CEA levels, tumor staging, RAS gene and BRAF gene enhances the accuracy of survival prognostication in elderly individuals diagnosed with CRC.

Background: Early-stage oral squamous cell carcinoma (OSCC) frequently poses a risk of occult lymph node metastasis, complicating neck management decisions. Elective neck dissection (END) is a critical strategy for mitigating this risk, though its criteria for selection continue to be debated. This study evaluated whether tumor differentiation can guide END decisions in early-stage OSCC.

Methods: Patients with stage I/II OSCC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox regression analyses assessed cancer-specific survival (CSS) and overall survival (OS), comparing END and no END groups across tumor differentiation grades. Stratified analyses further examined the influence of tumor site and size on survival.

Results: Among 10,396 early-stage OSCC patients, END did not improve survival in well-differentiated tumors but significantly improved CSS and OS in moderately and poorly differentiated/undifferentiated tumors. Interaction analyses revealed that tumor site and size significantly modified END's survival benefit. Stratified analyses highlighted that END benefits patients with moderately or poorly differentiated/undifferentiated tumors, but provides limited benefit for well-differentiated, small tumors, or those located in the floor of mouth.

Conclusions: Tumor differentiation is a critical determinant of END's survival benefit in early-stage OSCC. END should be considered for patients with moderately or poorly differentiated/undifferentiated tumors but may be unnecessary in well-differentiated cases.

Background: Breast cancer (BC) remains one of the most harmful malignancies in women, characterized by high heterogeneity, frequent recurrence, and metastasis. The competitive endogenous RNA (ceRNA) mechanism is crucial in tumor biology. While cuproptosis, a novel copper-induced cell death, shows therapeutic promise in BC, its ceRNA-associated regulatory network is largely unknown. This study aimed to identify and characterize a specific ceRNA axis involved in BC progression and to investigate its functional relationship with cuproptosis.

Methods: To explore this, we identified a potential ceRNA axis, WT1-AS/miR-206/BCL11A in BC. Its role was investigated using copper ion and reactive oxygen species (ROS) assays to evaluate cuproptosis, functional enrichment and phenotypic analyses to assess cell proliferation and migration, and luciferase reporter assays to validate molecular interactions. Rescue experiments were further conducted to delineate functional dependencies.

Results: We demonstrated that the WT1-AS/miR-206/BCL11A axis promotes BC malignancy. Suppressing BCL11A significantly increased intracellular copper levels and ROS, thereby enhancing cuproptosis. This axis was essential for driving BC cell proliferation and migration. Mechanistically, luciferase assays confirmed that the long non-coding RNA WT1-AS acts as a molecular sponge for miR-206, which in turn targets and upregulates BCL11A expression. Rescue experiments indicated that the oncogenic effects of WT1-AS are partially mediated through BCL11A.

Conclusions: Our study elucidates a novel ceRNA network, the WT1-AS/miR-206/BCL11A axis, which regulates BC progression and modulates cuproptosis. These findings provide fresh insights into BC biology and highlight potential diagnostic and therapeutic targets centered on cuproptosis regulation.

Background: Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer (NSCLC), exhibits significant clinical heterogeneity and commonly observed therapeutic resistance. Although hypoxia-driven tumor adaptation and centrosome-mediated genomic instability are established microenvironmental drivers, their synergistic molecular contributions to LUAD progression remain poorly characterized. Therefore, this study aims to develop an integrative machine learning (ML) model based on hypoxia and centrosome-related genes to enable prognostic stratification and provide therapeutic insights for LUAD.

Methods: We developed an integrative multi-omics framework that combines weighted gene co-expression network analysis (WGCNA) to identify key regulatory modules and single-sample gene set enrichment analysis (ssGSEA) for assessing the hypoxia and-centrosome pathway. Differential expression analysis of The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohorts identified hypoxia-centrosome-associated genes, which were refined via univariate Cox regression and ML to construct a prognostic signature. Clinical relevance was validated through nomogram development, tumor microenvironment (TME) profiling, mutational burden assessment, and therapeutic response prediction.

Results: A 16-gene prognostic signature was established using 306 differentially expressed genes linked to hypoxia and centrosome dysregulation. Stratification of LUAD patients into high- and low-risk groups demonstrated longer overall survival (OS) in the low-risk cohort. High-risk patients demonstrated elevated tumor mutational burden (TMB) and immunosuppressive microenvironment features, including reduced infiltration of eosinophils, immature dendritic cells, and mast cells. Risk scores were correlated with sensitivity to targeted therapy and chemotherapy.

Conclusions: Our integrative ML model uncovers hypoxia-centrosome crosstalk as a critical driver of LUAD progression. The hypoxia and centrosome score-related genes (HCSRGs) signature enables robust risk stratification and identifies actionable targets for precision oncology, providing a framework for personalized therapeutic strategies in LUAD.

Background: As two major colorectal cancer (CRC) pathways, serrated polyps (SP) and traditional adenomas show distinct cellular and molecular features, yet the key cell types and causal genes driving their malignant progression remain unknown. This study aimed to investigate the pivotal cellular groups and genes in the cancerous transformation of SP and traditional adenomas using multi-omics approach.

Methods: scPagwas (pathway-based polygenic regression method) was used to integrate CRC genome-wide association study (GWAS) data with single-cell sequencing in intestinal polyps, identifying cell groups and genes associated with phenotypic traits. Transcriptome-wide association studies (TWAS) analysis and fine-mapping, based on summary-level expression quantitative trait loci (eQTLs), were utilized to further screen for CRC-associated risk genes. Cell communication and gene set enrichment analysis (GSEA) determined receptor differences and pathway expression variations between SP and traditional adenomas. Mendelian randomization (MR) and phenome-wide association study analyses were used to investigate the connections between crucial genes and specific phenotypes.

Results: Serrated-specific cells (SSC) were identified as the epithelial population most strongly associated with CRC genetic risk, whereas adenoma-specific cells (ASC) showed no significant enrichment. Integrating TWAS, fine-mapping, and SMR analyses, we identified six robust risk genes-MIR4435-2HG, SMAD9, PITPNC1, LIMCH1, POU2AF2, and HES6. SSC and ASC displayed distinct transcriptional programs, with pathway analysis highlighting differences in TGF-β signaling and oxidative phosphorylation. Notably, MIR4435-2HG and SMAD9 emerged as particularly important genes, as they were consistently identified across scPagwas, TWAS and fine-mapping analyses, exhibited strong and contrasting specificity for SSC cells and ASC cells respectively, and demonstrated clear pathway relevance to serrated and conventional adenoma biology.

Conclusions: This multi-omics analysis reveals that the development of sessile serrated adenomas and conventional adenomas (CA) is associated with distinct epithelial origins, with serrated lesions linked to SSC cells and CA linked to ASC cells. These lesion-specific molecular features provide a mechanistic basis for improving preoperative detection and for developing adjunct molecular tools for high-risk polyp assessment.

Background and objective: Anaplastic thyroid cancer (ATC) is among the most aggressive human malignancies, with a median survival of 3-6 months. The tumor microenvironment (TME) drives progression and therapeutic resistance. We provide a narrative literature review integrating preclinical and clinical advances in TME-guided targeted therapy and immunotherapy.

Methods: We systematically searched PubMed and Web of Science Core Collection for English-language studies on ATC TME, targeted therapy, and immunotherapy (January 2020-August 2025). Search strategies combined Medical Subject Headings (MeSH) terms and free-text keywords. We included preclinical and clinical original research while excluding reviews, editorials, and conference abstracts.

Key content and findings: We synthesized 129 studies: 69 preclinical targeted-therapy, 19 clinical targeted-therapy, 13 preclinical immunotherapy, 6 clinical immunotherapy, and 22 clinical combination-therapy studies. ATC features a paradoxical TME with concurrent immune activation and suppression. Tertiary lymphoid structures and C-X-C motif chemokine ligand 13 (CXCL13)⁺ T cells emerge as immunotherapy biomarkers. In BRAF-mutant disease, BRAF/mitogen-activated protein kinase (MEK) inhibitors plus immune checkpoint inhibitors extended median survival from 9 to 17 months, with neoadjuvant reporting reaching 63 months. For non-targetable mutations, anti-angiogenic tyrosine kinase inhibitors (TKIs) plus immunotherapy achieved 66% complete response rates. TME-guided neoadjuvant combinations converted 38.9% of unresectable cases to resectable disease.

Conclusions: This review provides clinicians with decision-making frameworks for TME-based treatment selection and identifies future research directions. Future directions include TME-stratified trials, biomarker standardization, and development of streamlined treatment algorithms to translate these advances into routine practice.

Background: Breast cancer (BRCA) is one of the most prevalent malignant tumors in women worldwide, characterized by significant heterogeneity. Fatty acid metabolism (FAM) plays a crucial biological role in the initiation and progression of cancer. This study aims to identify novel, effective biomarkers related to FAM for improved risk stratification and treatment selection in BRCA patients.

Methods: Gene expression data from 1,217 BRCA patients were obtained from The Cancer Genome Atlas (TCGA) database. A comprehensive machine learning approach, incorporating ten different methods, was used to develop a FAM-related gene prognostic model (FAMGM). The Kaplan-Meier method and correlation analysis were employed to assess differences in overall survival (OS) and immune characteristics between high- and low-risk groups. External validation was performed using independent datasets. Single-cell RNA sequencing (scRNA-seq) data from 26 BRCA patients were analyzed, and the potential functions and mechanisms of the model genes were investigated using single-sample gene set enrichment analysis (ssGSEA), CellChat, and other algorithms. Finally, spatial transcriptomics (ST) analysis was conducted to examine the expression of model genes in the malignant regions of tumors.

Results: The FAMGM, developed using CoxBoost and random survival forest (RSF) methods, was identified as the optimal prognostic model. FAMGM demonstrated stable and robust performance in predicting clinical outcomes for BRCA. The high-risk group showed poor survival prognosis, typically associated with advanced clinical stages, reduced immune cell infiltration, and increased tumor mutational burden (TMB). Model genes were predominantly enriched in macrophages and appeared to influence tumor progression through the upregulation of multiple signaling pathways. Additionally, these model genes exhibited higher expression in malignant tumor regions.

Conclusions: FAMGM holds significant potential as a prognostic marker and could be used in the subsequent diagnosis, treatment, prognostic prediction, and mechanistic research of BRCA.

University Town, Nanjing 210023, China; Faculty of Chinese Medicine and State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau, China. Email: njwych@126.com; Min Chen, PhD. Faculty of Chinese Medicine and State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China. Email: mchen@must.edu.mo.

Background: Accumulating evidence indicates that fermitin family member 1 (FERMT1) is closely related to various disease processes. However, its association with cancer prognosis, tumor microenvironment (TME), and metastatic progression remains unclear, particularly in lung adenocarcinoma (LUAD). We conducted a comprehensive pan-cancer analysis to evaluate the clinical relevance of FERMT1 expression in LUAD and its functional role in metastasis.

Methods: We conducted a multi-omics and functional analysis to evaluate FERMT1 expression across multiple cancer types using 11,069 patient datasets from 33 cancers via The Cancer Genome Atlas (TCGA) database and the University of California, Santa Cruz (UCSC) Xena platform. We assessed FERMT1 expression heterogeneity, prognostic significance, genomic alterations, immune infiltration, and drug sensitivity in pan-cancer and LUAD-specific contexts. Additionally, functional experiments were performed to investigate its role in LUAD cell lines (NCI-H441 and Calu-3).

Results: FERMT1 was significantly overexpressed in 13 tumors and downregulated in 3 compared to normal tissues. Its high expression correlated with poor prognosis in multiple cancers and influenced immune cell infiltration. Genomic alterations in FERMT1 were prevalent across cancers. Pan-cancer analysis revealed significant correlations between FERMT1 expression, TME, and stemness scores. In LUAD, FERMT1 expression was significantly associated with tumor T classification (P=0.001) and higher levels in tumor tissues than in normal tissues. Functional assays demonstrated that FERMT1 deletion reduced LUAD cell migration and invasion.

Conclusions: FERMT1 serves as a potential biomarker for LUAD prognosis and cancer immunotherapy, highlighting its role in tumor progression and therapeutic response.

Background: Growing evidence suggests that the imbalance of liquid-liquid phase separation (LLPS) can alter the spatiotemporal coordination ability of biomolecular condensates, thereby playing an important role in carcinogenesis and cachexia. Gastric cancer (GC), ranking as the fifth most prevalent malignancy globally, remains lacking in systematic analysis at the GC-LLPS level within current research. This study aims to identify differentially expressed LLPS-related genes (LLPSGs) in GC and elucidate the role of LLPS in the initiation and progression of GC. Identifying the role of LLPS in carcinogenesis facilitates the development of personalized treatment strategies.

Methods: The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) dataset was employed as the training cohort, encompassing RNA sequencing data from 375 GC samples and 32 normal samples, along with comprehensive clinical information from 443 GC patients. Differentially expressed genes associated with GC were identified, and LLPS genes correlated with overall survival (OS) in GC patients were determined using the LLPS database. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression were applied to construct LLPS-based prognostic models, validated using the GEO15459 dataset containing clinical and gene expression data from 192 GC patients. Model accuracy was assessed via area under the curve (AUC) values. Multiple algorithms were employed to calculate immune cell infiltration scores for high- and low-risk groups. Finally, gene set enrichment analysis (GSEA) enrichment analysis was performed on the selected genes to explore biological processes and pathways.

Results: Through univariate Cox analysis and the LASSO Cox penalized regression analysis, six genes (VCAN, APOD, MYB, SNCG, F5, BRI3BP) associated with the OS of GC patients were found and an LLPSG prognostic model was constructed. In our LLPS-related prognostic model, GC patients in the high-risk group had a poorer OS rate than those in the low-risk group. For 1-, 3-, and 5-year survival rates, the AUC predictive values of the LLPSG nomogram were 0.63, 0.63, and 0.70, respectively. The GSE15459 cohort confirmed the favorable prognostic effect of our model. The predicted survival rates at 1-, 3-, and 5-year are 0.61, 0.64, and 0.66, respectively. There were also significant differences in immune cell infiltration between the high- and low-risk groups of the model. GSEA analysis showed that the six genes were differentially enriched in various cancer-related pathways.

Conclusions: Our research establishes and validates an LLPS-associated risk model centered on the genes VCAN, APOD, MYB, SNCG, F5, and BRI3BP. These genes are poised to be considered as potential therapeutic targets in the treatment of GC.

Background: Selenium (Se) compounds display selective cytotoxicity toward many tumors, yet their activity against cervical cancer is not well-established. This study evaluates the anti-cervical cancer effects of sodium selenite (SS) and clarifies the underlying mechanisms.

Methods: HeLa cells were treated with graded SS concentrations. Cell viability was measured using the Cell Counting Kit-8, apoptosis was analyzed by Annexin V/PI flow cytometry, and cell migration and invasion were evaluated by scratch assay and Matrigel-Transwell assay, respectively. Autophagic activity and Hippo signaling were analyzed by Western blotting and immunofluorescence. For in vivo validation, 5-week-old female BALB/c nude mice bearing subcutaneous HeLa xenografts received SS (6 mg/kg intraperitoneally, every other day) or saline. Tumor volume was recorded, and excised tumor tissues underwent histopathology.

Results: SS suppressed HeLa cell proliferation in a concentration- and time-dependent manner [24-h half-maximal inhibitory concentrations (IC₅₀) ≈4.9 µM], heightened apoptosis, and markedly reduced migration and invasion. Molecular assays showed increased LC3-II accumulation with concomitant p62 degradation, indicating enhanced autophagic flux. These changes coincided with elevated phosphorylation of LATS1 and YAP and a reduction in total YAP, signifying Hippo signaling pathway activation, which was further confirmed by YAP knockdown-mediated inhibition of SS-induced autophagy. In xenograft models, SS slowed tumor growth and lowered proliferative and YAP immunostaining without overt toxicity.

Conclusions: SS restrains cervical cancer progression by inducing apoptosis and accelerating autophagosome turnover through activation of the YAP-Hippo axis. These findings highlight SS and YAP-directed modulation in general, as promising avenues for future cervical cancer therapy development.