Journal of Cancer最新文献

Background: Colorectal cancer (CRC) has emerged as the third most prevalent malignancy worldwide. The pursuit of dependable molecular signatures stands as a crucial endeavor for tailoring treatment approaches, refining prognostic assessments, and heightening therapeutic efficacy in CRC management. This investigation was conducted to elucidate essential genes and molecular mechanisms associated with ferroptosis in CRC through implementing machine-learning approaches and AUcell analysis. Methods: The GEO repository and FerrDb served as primary sources for extracting information of gene sets on colorectal cancer and iron-dependent cell death mechanisms. To determine potential therapeutic targets with biomarker significance, we implemented LASSO and SVM-RFE methodology. The immune infiltrates were characterized followed by a competing endogenous RNA network analysis. The AUCell R package was utilized to examine the targeted gene activity patterns within individual cell lines using single-cell transcriptome data. The qRT-PCR and Human Protein Atlas (THPA) database were used to validate the expression of target genes. Potential therapeutic were explored through the DGIdb database. Results: Through the application of machine learning methodologies, five genes were identified as pivotal biomarker candidates: AQP8, NOX4, NR5A2, SCD, and TIMP1. The result of AUcell algorithm showed that the distribution of AUC values exhibited a bimodal pattern, with 2733 cells demonstrating elevated AUC values above the threshold of 0.091. The result of qRT-PCR showed that NOX4, SCD, and TIMP1 were significantly upregulated, while the expression of AQP8 and NR5A2 did not exhibit the expected differences. Both mRNA and IHC analyses from HPA database confirmed the abnormal expression of these pivotal candidate biomarkers. Algorithmic assessment via CIBERSORT methodology revealed notable shifts in immune cell composition within the tumor microenvironment of individuals diagnosed with CRC. Furthermore, A competing endogenous RNA network and 51 potential drug candidates were identified. Conclusion: A systematic framework implementing machine-learning approaches and AUcell analysis was established for identifying core ferroptosis genes and validating their functional link to ferroptosis. Meanwhile, a reliable ferroptosis-associated signature was established, which shed new light on the ferroptosis-mediated molecular mechanisms and therapeutic potential underlying CRC.

Objectives: irAEs were associated with immunotherapy response in cancer treatment, but severe irAEs discontinued immunotherapy and affected the quality of life. This study aimed to identify ion concentrations as potential biomarkers for irAEs and prognosis in lung cancer patients receiving ICI therapy. Methods: A retrospective analysis was conducted on 459 lung cancer patients who received ICI treatment at Xiangya Hospital from April 2019 to May 2023. Patient characteristics, ion concentrations (K⁺, Na⁺, Cl^-, Ca²⁺, PO₄ ^3- and Mg²⁺), irAEs, and prognosis were systematically collected. Univariable and multivariable regression analyses, including binary logistic regression and Cox regression models, were employed to identify factors associated with irAEs and PFS. Results: Among 459 lung cancer patients receiving ICI treatment, 378 (82.4%) of the patients suffered irAEs. PD-L1 expression, ICI cycles, ORR and DCR were linked to irAEs occurrence. Cardiotoxicity, hypothyroidism, and dermatoxicity were the predominant irAEs types, but mostly mild to moderate. Notably, elevated potassium (K⁺) level was significantly correlated with both a higher risk of irAEs and longer PFS. Conclusions: The findings suggest that K⁺ concentration prior to initiating treatment with ICIs may be a biomarker of irAEs and PFS in lung cancer patients.

Obstructive sleep apnea (OSA) is characterized by recurrent intermittent hypoxia (IH) and has been increasingly associated with lung cancer incidence and mortality. However, how IH-related biological programs relate to immune remodeling, stemness-associated phenotypes, and therapeutic resistance in lung cancer remains incompletely understood. We integrated single-cell RNA sequencing data from IH-exposed murine lung tissues (GSE301350) with bulk transcriptomic datasets from TCGA-LUAD and GSE31210 to examine hypoxia-associated cellular and transcriptional patterns. Stemness was quantified using CytoTRACE and transcriptome-based stemness scoring, and its associations with immune infiltration, immune checkpoint expression, TIDE scores, predicted drug sensitivity, and immunotherapy response were evaluated. A stemness-based prognostic model was constructed using LASSO Cox regression and validated in independent cohorts. Single-cell analysis revealed marked immune remodeling under intermittent hypoxia (IH), including expansion of effector T cells, and monocytes/macrophages, populations alongside reduced B cells and dendritic cells. In human LUAD cohorts, stemness-high tumors were associated with mitochondrial and metabolic stress-related transcriptional programs, and increased expression of immune checkpoint genes (PD-1, PD-L1, CTLA4, LAG3). Elevated stemness scores correlated with higher TIDE scores, poorer overall survival, and reduced predicted responsiveness to immunotherapy. LASSO modeling identified a six-gene stemness signature (EIF5A, MELTF, SEMA3C, CPS1, TCN1, SELENOK), that consistently stratified patients into high- and low-risk groups across TCGA and GSE31210 cohorts. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Drug sensitivity analyses further suggested that stemness-high tumors may exhibit increased susceptibility to selected kinase inhibitors (Dasatinib, A-770041) and metabolic modulators (Phenformin, Salubrinal). OSA-associated IH is linked to stemness-associated transcriptional plasticity, immune suppression, and adverse clinical outcomes in lung cancer. The identified stemness-based gene signature provides a robust prognostic biomarker and highlights potential therapeutic vulnerabilities, supporting integrative strategies that combine stemness and immune -targeted approaches with immunotherapy in OSA-associated lung cancer.

6RK73 is a novel drug designed to target UCHL1 deubiquitinase. Preliminary studies have indicated its anti-cancer activity in breast cancer and renal cell carcinoma. However, its potential anti-cancer effects in other malignancies, including ovarian cancer, remain unclear. In this study, we first determined the IC50 values of 6RK73 in ovarian cancer cell lines OVCAR3 and SKOV3, which were 10.62 μM and 12.90 μM, respectively. Subsequently, we found that 6RK73 effectively inhibited cell proliferation and arrested cell cycle progression in ovarian cancer cells in vitro. Furthermore, 6RK73 suppressed the formation of subcutaneous ovarian cancer tumors in nude mice. Mechanistically, 6RK73 significantly inhibited the AKT1/Sp1/c-Myc signaling pathway, which not only disrupted the interaction between Sp1 and c-Myc but also reduced Sp1 deubiquitination, thereby downregulating c-Myc protein expression. Interestingly, the anti-tumor effects of 6RK73 in ovarian cancer were independent of UCHL1 inhibition. Finally, AKT1 overexpression reversed the 6RK73-mediated suppression of cell proliferation by reactivating the AKT1/Sp1/c-Myc signaling pathway. These findings suggest that 6RK73 is a promising anti-cancer agent that exerts its effects by inactivating AKT1/Sp1/c-Myc signaling in ovarian cancer.

Isoginkgetin (IGG), a naturally occurring biflavonoid found in the leaves of many medicinal plants, is known to inhibit pre-mRNA splicing and display anti-cancer characteristics. However, knowledge regarding the use of IGG on oral squamous cell carcinoma (OSCC) lags behind that on the other common malignancies. The aim of this study is to explore whether IGG hinders OSCC proliferation and further investigated its oncostatic actions. We demonstrated that exposure of OSCC cell lines (HSC-3 and SCC-9) to IGG significantly diminished cell viability and induced apoptotic cell death. Furthermore, levels of several tentative apoptosis suppressors (cIAP-1 and XIAP) were decreased in IGG-treated HSC-3 and SCC-9 cells, accompanied with increased cleavage of caspases. Of note, such activation of caspase cascades by IGG was reduced by pharmaceutical inhibition of c-Jun N-terminal kinase (JNK) via a specific kinase antagonist, suggesting a functional connection of JNK activity with caspase activation during IGG-induced oral cancer cell apoptosis. In conclusion, we exhibited that IGG hampered cell viability and stimulated apoptotic events in OSCC, driven by a JNK-dependent pathway of caspase activations. Our findings present new insights into applications of a natural biflavonoid compound in fighting oral carcinogenesis.

Introduction: The mechanistic role of COL6A2, an extracellular matrix protein, in clear cell renal cell carcinoma (ccRCC) is largely unexplored. This study aimed to investigate COL6A2 expression, its prognostic value, biological functions, and underlying molecular mechanisms in ccRCC. Methods: COL6A2 expression was analyzed in ccRCC tissues and cell lines using public datasets and Western blotting on clinical samples and cell lines. Prognostic associations were evaluated using TCGA-KIRC data via clinicopathological correlations, Kaplan-Meier survival, and Cox regression analyses. Functional effects of COL6A2 knockdown in ccRCC cells were assessed by CCK-8, wound healing, Transwell, and Western blot analysis of EMT-associated proteins. Mechanistic investigations involved bioinformatic analysis, co-immunoprecipitation, Western blotting for Wnt/β-catenin pathway proteins, integrin blockade, and rescue experiments with the Wnt/β-catenin activator. Results: COL6A2 mRNA and protein were significantly upregulated in ccRCC tissues and cell lines. High COL6A2 expression correlated with aggressive clinicopathological features and independently predicted poorer prognosis. COL6A2 knockdown significantly inhibited ccRCC cell proliferation, migration, invasion, and reversed epithelial-mesenchymal transition (EMT). Mechanistically, COL6A2 was found to physically interact with integrin β1, thereby activating the Wnt/β-catenin signaling pathway to induce EMT. Rescue experiments confirmed the role of this signaling axis in mediating the malignant phenotypes. Conclusion: COL6A2 promotes ccRCC aggressiveness and modulates Wnt/β-catenin signaling in an integrin-dependent manner. These findings nominate the COL6A2-integrin interface as a potential therapeutic and biomarker axis in ccRCC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of below 8%. Standard chemotherapy regimens, including gemcitabine and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), offer limited clinical benefits. Although immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, PDAC remains largely unresponsive to ICI monotherapy. In this study, we demonstrate that dasatinib, a multi-targeted tyrosine kinase inhibitor, reduces programmed death ligand 1 (PD-L1) expression in PDAC cells via a proteasome-dependent degradation pathway. Moreover, PD-L1 levels were correlated with dasatinib sensitivity, suggesting its utility as a predictive biomarker. These findings not only elucidate a novel mechanism of dasatinib's action but also provide a strong rationale for combining dasatinib with ICIs to overcome immune resistance and enhance therapeutic efficacy against PDAC.

Objective: To assess the prognostic performance of the 2023 FIGO staging system for endometrial cancer, which incorporates molecular classification (FIGO 2023m), we analyzed survival outcomes and compared them with the 2009 FIGO system (FIGO 2009). Methods: We retrospectively reviewed 720 patients with endometrial cancer treated between 2013 and 2021. Staging was performed according to FIGO 2009 and FIGO 2023m. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Factors associated with survival were identified through univariate and multivariate Cox proportional hazards analyses. Results: Of the 720 patients, 27.4% (197/720) were reclassified under FIGO 2023m, and 182 were upstaged from stage I to stage II, primarily due to p53 abnormalities (54.9%). Patients with stage I disease according to FIGO 2023m had comparable survival rates (PFS: 95.3% vs. 92.8%; OS: 99.2% vs. 95.9% under FIGO 2009). Within stage II, OS in patients classified as FIGO 2023m IIC was slightly lower than in stage IIC but did not differ statistically (92.3% vs. 86.9%). Aggressive histology, positive peritoneal cytology, and deep myometrial invasion were associated with poorer outcomes. Patients harboring POLE mutations showed excellent prognosis (5-year OS, 100.0%), even at advanced stages. Conclusion: Compared with FIGO 2009, the FIGO 2023m staging system offers improved prognostic value and better discriminative ability. Incorporating molecular subtyping is crucial even in advanced disease. However, omitting peritoneal cytology from prognostic assessment may risk undertreatment. Continued refinement in quantifying lympho-vascular space invasion (LVSI) and differentiating complex endometrial-myometrial junctions from genuine myometrial invasion remains a challenge.

To investigate the contribution of individual arginines, we employed site-directed mutagenesis to generate arginine-to-alanine (R→A) substitution mutations in the N-terminal domain of Forkhead box M1 (FoxM1). The R15A mutation impaired FoxM1 transcriptional activity, hindered FoxM1 nuclear translocation and failed to promote the migratory and invasive behavior of glioma cells than other single arginine mutations. Furthermore, we demonstrated that FoxM1 expression was associated with Mitochondrial transcription factor A (TFAM) expression. Overexpressing FoxM1 increased TFAM protein levels, which was reversed by FoxM1 knockdown in glioblastoma multiforme (GBM) cells. The siRNA-mediated reduction of TFAM expression was rescued by FoxM1 overexpression. Also, FoxM1 overexpression promoted TFAM promoter luciferase activity. Importantly, the R15A mutation failed to promote TFAM expression. Additionally, FoxM1 increased the expression of mitochondrial fusion markers, Optic atrophy protein 1 (OPA1) and Mitofusin 1 (MFN1) and led to interconnected mitochondria, while FoxM1 knockdown reversed this effect. Moreover, FoxM1 promoted mitochondrial fission markers, Dynamin-related protein 1 (DRP1), Mitochondrial fission factor (MFF) and Mitochondrial fission protein 1 (FIS1). Notably, the R15A mutation resulted in loss of FoxM1 regulation of fusion and fission-related protein expression. Taken together, our findings reveal that that the N-terminal arginine 15 is a key site for the transcriptional activation and function of FoxM1 in GBM cells, suggesting its potential as a therapeutic target in GBM.

Background: Gastric cancer remains one of the most common causes of cancer death, with a notably high incidence in East Asian countries. Regulatory T cells (Tregs) suppress antitumor immunity in the tumor microenvironment, and recent studies have identified C-C motif chemokine receptor 8 (CCR8) as a selective marker for tumor-infiltrating activated Tregs. However, the role of CCR8⁺ Tregs in gastric cancer remains unclear. Methods: This study retrospectively analyzed 80 gastric cancer patients who underwent curative resection. Immunohistochemistry dual staining for CCR8/Foxp3 and granzyme B/CD8 was performed, followed by automated image analysis and spatial profiling. The correlation between CCR8⁺ Tregs and CD8⁺ T cells, as well as their prognostic significance, was evaluated. Results: CCR8⁺ Treg density positively correlated with CD8⁺ T cell infiltration. However, a low CD8⁺ T cell/CCR8⁺ Treg ratio was significantly associated with worse recurrence-free survival (P = 0.023). Reduced granzyme B expression was observed in CCR8⁺ Treg-dense hotspots, suggesting the presence of a localized immunosuppressive environment. Spatial analysis revealed that CCR8⁺ Tregs were preferentially localized at the tumor invasion front. Furthermore, distance analysis showed that fewer CD8⁺ T cells were present around CCR8⁺ Tregs than around CCR8⁻ Tregs, suggesting a localized immunosuppressive effect that may restrict CD8⁺ T cell proliferation. Conclusions: Our findings suggest that CCR8⁺ Tregs suppress antitumor immunity in gastric cancer by affecting surrounding CD8⁺ T cells through spatial segregation. Targeting CCR8⁺ Tregs may offer a promising strategy to improve the efficacy of immunotherapy in gastric cancer.