Translational cancer research最新文献

Background: Flavonoids are primary bioactive components of Penthorum chinense Pursh (PCP), which have anti-inflammatory and antioxidant effects. Previous studies have found that the pharmacological effect of PCP on liver cancer may be related to the inhibition of oxidative stress and inflammatory response in vivo. Based on the hepatoprotective effect of total flavonoids extracted from PCP (PCPTF), this study aimed to investigate the underlying mechanism by which PCPTF ameliorates liver cancer.

Methods: A nude mouse model of subcutaneous tumor formation of hepatocellular carcinoma was established. Following PCPTF treatment, the pathological changes, tumor cell proliferation and apoptosis, serum inflammatory factors and oxidative stress levels, and the levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) proteins in tumor tissues were detected. Lipopolysaccharides (LPS) was applied to construct liver cancer cell inflammation models in vitro. After treatment of PCPTF and JAK2 agonist coumermycin A1 (CA1) in the cells, protein levels, cell proliferation, inflammation, and oxidative stress were evaluated to explore the mechanism of PCPTF in improving liver cancer.

Results: In mice with liver cancer, PCPTF treatment inhibited tumor growth, improved the pathological changes, down-regulated interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), reactive oxygen species (ROS), up-regulated superoxide dismutase (SOD), and suppressed JAK2 and STAT3 phosphorylation. In liver cancer cells, PCPTF blocked the JAK2/STAT3 pathway, proliferation, and the release of inflammatory factors, regulated oxidative stress, and promoted apoptosis. However, CA1 reversed the effect of PCPTF on liver cancer cells.

Conclusions: PCPTF suppresses the progression of liver cancer by ameliorating oxidative stress and inflammatory response, primarily through the regulation of the JAK2/STAT3 signaling pathway.

Background: Alectinib is a second-generation tyrosine kinase inhibitor (TKI) that selectively targets anaplastic lymphoma kinase (ALK) rearrangements and is recommended as first-line therapy for patients with advanced ALK-positive non-small cell lung cancer (NSCLC). Pivotal clinical trials have demonstrated its superior efficacy and favorable safety profile compared with earlier ALK inhibitors and chemotherapy. However, long-term real-world outcomes remain insufficiently characterized, particularly in patients harboring concurrent ALK alterations and additional rare genetic variants, whose clinical relevance is often unclear.

Case description: We report a case of a 41-year-old female diagnosed with stage IV lung adenocarcinoma (LUAD) following routine imaging. Comprehensive diagnostic evaluation, including positron emission tomography/computed tomography (PET-CT), cervical lymph node biopsy, and targeted next-generation sequencing, revealed an EML4-ALK fusion (variant 1) together with a concurrent RET p.R820H mutation. The patient initiated first-line treatment with alectinib at a daily dose of 1,200 mg. A partial response was achieved within two months of therapy, and disease control was sustained throughout long-term follow-up. Remarkably, after more than 62 months of continuous alectinib treatment, the patient remained progression-free, with no evidence of disease relapse, distant metastasis, or treatment-related adverse events. The identified RET p.R820H alteration is currently classified as a variant of uncertain significance, and its functional or clinical impact has not been established.

Conclusions: This case demonstrates an exceptionally durable response to first-line alectinib in an ALK-positive LUAD patient with a concurrent rare RET variant. It underscores the long-term efficacy and tolerability of alectinib and highlights the importance of comprehensive genomic profiling in guiding personalized targeted therapy for genetically complex NSCLC.

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.