American journal of cancer research最新文献

Polyubiquitination plays a critical role in tumor biology, yet its significance in prostate cancer remains incompletely understood. Here, we investigated the expression and function of SOCS-box E3 ligases in prostate cancer. Analysis of TCGA data revealed WSB1 overexpression, which correlated with advanced pathological stage, high Gleason score, and poor prognosis. Functional assays demonstrated that WSB1 knockdown suppressed prostate cancer cell proliferation, colony formation, and migration in vitro, and inhibited tumor growth and Ki67 expression in vivo. Mechanistically, mass spectrometry and co-immunoprecipitation identified ISOC2 as a key WSB1 interactor. WSB1 stabilized ISOC2 by promoting its interaction with the deubiquitinase OTUD4, thereby preventing ISOC2 degradation via the ubiquitin-proteasome pathway. Silencing either ISOC2 or OTUD4 phenocopied the tumor-suppressive effects of WSB1 ablation. Importantly, disruption of the WSB1/OTUD4/ISOC2 axis upregulated P16INK4a expression, and co-silencing of P16INK4a partially restored tumorigenic properties. Our findings unveil a novel WSB1/OTUD4/ISOC2 signaling network that drives prostate cancer progression by modulating ubiquitin signaling and repressing P16INK4a, positioning WSB1 as a promising therapeutic target.

The incidence of upper tract urothelial carcinoma (UTUC) continues to rise in Southwestern Taiwan, despite a reduction in known environmental carcinogens. This study aimed to characterize the mutational and molecular profiles of UTUC in this high-incidence region and evaluate potential therapeutic targets. We performed next-generation sequencing using the TruSight Oncology 500 panel on 19 formalin-fixed, paraffin-embedded UTUC samples. We analyzed single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number variants (CNVs), microsatellite instability (MSI), and tumor mutational burden (TMB). MSI was stable in all cases, and 42.1% of samples exhibited high TMB (>20 mutations/Mb), often co-occurring with inactivation of TP53, BRCA1, or BRCA2. CNVs were significantly more frequent in advanced-stage UTUC (46.2%) than in early-stage disease (0%). FGFR3 mutations were enriched in early-stage tumors (83.3%), while TP53 mutations predominated in advanced-stage tumors (46.2%). Notably, actionable mutations in PIK3CA, ERBB2, BRCA1, and BRCA2 occurred at higher frequencies than in previously reported Japanese UTUC cohorts. Our findings reveal a distinct molecular signature of UTUC in Southwestern Taiwan, with early- and late-stage tumors showing divergent mutational landscapes. These insights emphasize the importance of molecular stratification in UTUC management and suggest that a broader repertoire of targeted therapies could benefit patients in this high-incidence region.

Objective: To evaluate the utility of real-time three-dimensional echocardiography (RT-3DE) and two-dimensional speckle tracking imaging (2D-STI) for early detection of chemotherapy-induced cardiotoxicity in lymphoma patients, and to identify independent predictors of cardiotoxicity using these imaging parameters.

Methods: We conducted a single-center retrospective cohort study at The First People's Hospital of Changde City, enrolling 110 lymphoma patients who received anthracycline-based chemotherapy between January 2020 and January 2024. Echocardiographic assessments, including RT-3DE and 2D-STI, were performed before chemotherapy and within 72 hours after the 3rd and 6th cycles. Cardiotoxicity was defined as a ≥ 10% reduction in left ventricular ejection fraction (LVEF) or an LVEF < 50%.

Results: Baseline clinical characteristics showed significant differences in gender and hypertension between the cardiotoxic and non-cardiotoxic groups (both P < 0.05). RT-3DE revealed time-dependent changes, with LAEFa higher and LAEFa/LAEFt lower in the cardiotoxic group at 3 and 6 weeks post-chemotherapy, respectively (all P < 0.05). 2D-STI showed significant differences in LASct and LASr at 3 and 6 weeks (all P > 0.05). GEE analysis indicated that changes in LAEFa, LAEFp, LAEFt, LASr, LASct, and LVEF were driven by the time × group interaction effect (all P < 0.05).

Conclusion: RT-3DE and 2D-STI are sensitive for early detection of anthracycline-induced cardiotoxicity in lymphoma patients. LA functional indices (LAEFa, LAEFp, LAEFt) and LA strain indices (LASr, LASct) may detect cardiotoxicity earlier than LVEF, suggesting their potential role in optimizing cardio-oncology monitoring strategies.

We examined the relationships of sex and age specific groups with cause-specific survival for early-onset colorectal cancer (EOCRC) diagnosis. A retrospective cohort analysis utilizing data from the 2000-2020 Georgia Cancer Registry were performed. Sex and age at diagnosis were exposures of interest. CRC survival at 1-, 3, and 5-year intervals were our primary outcomes of interest. Traditional Cox proportional hazards regression and Piecewise Cox regression models were performed to examine the mentioned association. Among 11,935 EOCRC patients, males had lower 1- (89.4% vs. 91.9%), 3- (75.7% vs. 79.2%), and 5-year (69.7% vs. 74.3%) survival rates than female patients (all p-value <0.001). In adjusted analysis, regardless of survival intervals, male patients aged 30-39 years were more likely to die from CRC at 1-year (HR, 1.40; 95% CI, 1.08-1.82), 3-year (HR, 1.26; 95% CI, 1.06-1.49), 5-year (HR, 1.27; 95% CI, 1.09-1.48) than female aged 30-39 years, respectively. Our piecewise models also confirmed male patients aged 30-39 years were 33% more likely to die from CRC within 1 year interval. Similarly, male patients aged 40-49 years were more likely to die from CRC at 1-year (HR, 1.33; 95% CI, 1.16-1.53), 3-year (HR, 1.20; 95% CI, 1.10-1.32), and 5-year (HR, 1.22; 95% CI, 1.13-1.33) intervals than female patients aged 40-49 years, respectively. In summary, the highest estimate of EOCRC mortality within 1-year interval was observed among male patients aged 30-39 years. Prioritizing prevention and treatment strategies may reduce the risk of 1-year EOCRC mortality for males and 30-39 age group.

Hepatocellular carcinoma (HCC) frequently recurs after hepatectomy. Transarterial chemoembolization (TACE) is a common adjuvant therapy; however, reliable indicators of its efficacy remain limited. This study aimed to evaluate the clinical significance of matrix metallopeptidase 12 (MMP12) in HCC patients undergoing postoperative adjuvant TACE (PA-TACE) and to explore potential strategies to enhance the efficacy of PA-TACE. A retrospective analysis was conducted on 225 HCC patients who received TACE and were categorized into prophylactic and recurrence TACE groups. Clinical data including liver function, tumor characteristics, and imaging findings were collected. Tissue samples were subjected to MMP12 immunohistochemical staining, and patients were further stratified according to MMP12 expression levels. Univariate and multivariate Cox regression analyses were performed to identify risk factors, and a nomogram was constructed for prognostic evaluation. The role of MMP12 in TACE for HCC was examined using Western blotting, RT-qPCR, mass spectrometry, Transwell, wound-healing, and colony formation assays. Kaplan-Meier curves demonstrated significantly better survival in the low-MMP12-expression group. Microvascular infiltration, alpha-fetoprotein (AFP) levels, and MMP12 expression were identified as independent risk predictors for survival. The nomogram derived from these factors exhibited high predictive accuracy (area under the curve: 0.750-0.959) across multiple time points. In vitro experiments revealed that targeting MMP12 inhibited HCC cell invasion, migration, and colony formation by blocking the MEK/ERK signaling pathway. The MMP12 inhibitor GM6001 enhanced the therapeutic effects of TACE. In conclusion, MMP12 was identified as a key and independent prognostic biomarker for PA-TACE in HCC patients. The prognostic model integrating MMP12, AFP, and microvascular infiltration may help identify patients most likely to benefit from PA-TACE. Targeting MMP12 to block the MEK/ERK pathway and suppress HCC cell malignancy highlights its potential as a therapeutic target to improve PA-TACE efficacy.

Background: Prostate cancer (PCa) ranks among the most prevalent malignant tumors affecting the male genitourinary system, presenting a considerable danger to health and human life. Increasing evidence indicates that the ubiquitin-proteasome pathway is essential in both the development and management of PCa.

Methods: Differential expressed genes were screened by integrating the TCGA and GEO databases, and their expression was validated in the HPA dataset. An RCBTB2 overexpression cell line was constructed, and its effects on cellular behavior were analyzed using CCK-8, scratch assay, Transwell, and immunofluorescence staining. A nude mouse model was established to evaluate the tumor-suppressive effects. Furthermore, the interaction between RCBTB2 and GPAA1 was confirmed through multi-omics analysis, co-immunoprecipitation, and immunofluorescence co-localization experiments. GPAA1 knockdown cell lines were then constructed to observe changes in cellular phenotypes.

Results: The expression of RCBTB2 was significantly negatively correlated with the malignancy of PCa. Overexpression of RCBTB2 notably inhibited DU145 cell proliferation, migration, invasion, and EMT, as well as reduced the growth of xenograft tumors in nude mice. Multi-omics analysis revealed that RCBTB2 promoted the ubiquitin-mediated degradation of GPAA1 (protein downregulation without changes in mRNA levels), and experiments confirmed their direct interaction. Furthermore, GPAA1 knockdown suppressed the malignant biological behaviors of PCa cells and reduced the expression of aggrephagy-related factors such as p62.

Conclusion: This study for the first time unveils the molecular mechanism by which RCBTB2 inhibits PCa progression through ubiquitination-mediated degradation of GPAA1. It provides a novel target for protein homeostasis-based therapy, with promising clinical value.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show efficacy against non-small cell lung cancer (NSCLC) in patients with EGFR mutations. However, the impact of antihypertensive medications, particularly beta-blockers (BBs) and renin-angiotensin system blockers (RASBs), on survival outcomes in this population remains controversial. We evaluated the effects of BBs and RASBs on progression-free survival (PFS) and overall survival (OS) in patients with NSCLC receiving EGFR-TKIs. This retrospective study included patients diagnosed with NSCLC who received EGFR-TKIs at a regional teaching hospital in Taiwan between 2009 and 2023. Overall, 308 patients were categorized into groups: EGFR-TKIs only (n=175), BBs(+)/EGFR-TKIs(+) (n=70), and RASBs(+)/EGFR-TKIs(+) (n=63). Primary and secondary outcomes were PFS and OS, respectively. Multivariate Cox proportional-hazards models were used for analysis. Median PFS was 7.79, 11.74, and 10.42 months in the EGFR-TKIs only, BBs(+)/EGFR-TKIs(+), and RASBs(+)/EGFR-TKIs(+) groups, respectively (P=0.056). However, OS was higher in BBs(+)/EGFR-TKIs(+) (17.79 months) and RASBs(+)/EGFR-TKIs(+) (16.64 months) groups than in the EGFR-TKIs only group (12.59 months) (P=0.009). Multivariate analysis identified concomitant BBs or RASBs with EGFR-TKIs as independent prognostic factors for improved OS, particularly in patients without skin toxicity and with favorable Eastern Cooperative Oncology Group performance status. BBs and RASBs have a potential adjunctive role in NSCLC therapy.

This study aimed to characterize serum tumor markers - cytokeratin 19 fragment (Cyfra21-1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and squamous cell carcinoma antigen (SCC) - together with arterial blood gas and pulmonary function parameters (partial pressure of oxygen [PO₂], forced vital capacity [FVC], diffusing capacity of the lung for carbon monoxide [DLCO], DLCO adjusted for alveolar volume [DLCO/VA], and lung reserve rate) in patients with pulmonary fibrosis (PF), lung cancer (LC), and PF combined with lung cancer (PF+LC), and to evaluate their prognostic value for 2-year overall survival (OS) and lung cancer-specific mortality. A retrospective analysis was conducted on 485 PF patients, 135 LC patients, 187 PF+LC patients, and 100 healthy controls enrolled between February 2010 and April 2023. Baseline demographics, tumor markers, and pulmonary function data were compared across groups. Serum markers followed the trend: PF+LC ≈ LC > PF > controls, while pulmonary function was markedly impaired in PF+LC patients compared with PF patients. In PF patients, Cyfra21-1, FVC, DLCO, and age ≥65 years were independent predictors of 2-year OS. For PF+LC patients, Cyfra21-1, FVC, DLCO, age ≥65 years, and fibrosis type were significant prognostic factors, while TNM staging did not correlate with OS. Competing risk analysis identified Cyfra21-1, FVC, fibrosis type, and pirfenidone therapy as independent predictors of lung cancer-specific mortality. These findings demonstrate that serum tumor markers and pulmonary function parameters reflect disease heterogeneity between PF and PF+LC, with Cyfra21-1, FVC, DLCO, age, and fibrosis type serving as important survival determinants. Additionally, pirfenidone therapy may reduce lung cancer-related mortality, underscoring its potential therapeutic benefit in managing PF+LC.

Non-small cell lung cancer (NSCLC) is an aggressive malignancy characterized by poor therapeutic outcomes, and its progression is closely linked to dysregulated PI3K-AKT signaling and resistance to ferroptosis. This study aimed to investigate the anti-tumor effects of Asaraldehyde (Asa) on NSCLC, elucidate its underlying mechanisms, and explore its therapeutic potential by targeting both ferroptosis and the PI3K-AKT pathway. It was revealed that Asa treatment significantly suppressed NSCLC cell proliferation, migration, and epithelial-mesenchymal transition (EMT) while inducing ferroptosis, as evidenced by increased lipid peroxidation, reactive oxygen species (ROS) accumulation, and glutathione (GSH) depletion. Additionally, Asa promoted ubiquitin-mediated degradation of AKT, leading to inhibition of the PI3K-AKT signaling pathway, and this effect was partially attenuated by Ferrostatin-1, a ferroptosis inhibitor. In vivo, Asa administration significantly reduced tumor growth in a xenograft mouse model, accompanied by decreased expression of Ki67, AKT, and ferroptosis-related proteins. These findings demonstrate that Asa exerts potent anti-NSCLC activity through ferroptosis induction and PI3K-AKT pathway suppression, and suggest that targeting these pathways with Asa could provide a novel therapeutic strategy for NSCLC treatment.

Background: Immunotherapy-based regimens are standard first-line treatment for advanced gastroesophageal junction or gastric cancer (GEJ/GC), but their efficacy in alpha-fetoprotein-producing gastric cancer (AFPGC) remains unclear. We investigated the positivity of AFP influenced immunotherapy outcomes in advanced GEJ/GC, and examined whether this role is influenced by the patient's HER2 status. Secondly, we aim to assess the efficacy of anti-angiogenic agents within advanced AFP-positive GEJ/GC (AFP-GEJ/GC).

Methods: This retrospective study analyzed patients with advanced GEJ/GC receiving first-line immunotherapy, stratified by HER2 status. AFP-positive GEJ/GC was defined as a pretreatment serum AFP level ≥ 20 ng/mL or positive immunohistochemistry.

Results: In the overall population, the AFP-GEJ/GC group (n = 79) showed similar median progression-free survival (mPFS; 7.30 vs. 8.53 months; P = 0.42) and median overall survival (mOS; 21.80 vs. 19.70 months; P = 0.38) compared with the AFP-negative group (n = 478). In the HER2-negative cohort, 246 patients receiving standard two-drug chemotherapy combined with PD-1 inhibitors, the AFP-GEJ/GC group (n = 16) exhibited shorter mPFS (5.40 vs. 7.0 months; P = 0.02) and numerically worse mOS (11.40 vs. 16.80 months; P = 0.24) compared with the AFP-negative group (n = 230), despite similar objective response rates (ORRs 50.0% vs. 45.2%; P = 0.80) and disease control rates (DCRs 93.8% vs. 90.4%; P > 0.99). In the HER2-positive cohort, 107 patients receiving standard chemotherapy-based regimens, AFP-GEJ/GC (n = 14) showed numerically shorter mPFS (7.67 vs. 12.20 months; P = 0.60) but similar mOS (32.40 vs. 28.30 months; P = 0.38) versus AFP-negative group (n = 93). Notably, anti-angiogenic combination therapy did not statistically improve mPFS and mOS in AFP-GEJ/GC (n = 79). However, in the HER2-negative AFP-GEJ/GC group (n = 47), anti-angiogenic combination therapy (n = 31) was associated with a modestly longer mPFS (6.33 vs. 5.40 months; P = 0.02) and a numerical improved mOS (15.70 vs. 11.40 months; P = 0.15) compared with chemo-immunotherapy (n = 16).

Conclusion: AFP positivity may indicate inferior efficacy of first-line chemo-immunotherapy in HER2-negative advanced GEJ/GC, and anti-angiogenic therapy warrants further evaluation as a potential strategy to improve outcomes.