Journal of Cancer最新文献

Background: The use of immune checkpoint inhibitors (ICI) and other targeted molecular agents for non-small cell lung cancer (NSCLC) has led to unprecedented rates of major pathologic response and improvements in overall survival. The aim of this study was to evaluate the prognostic significance of lymph node downstaging following neoadjuvant chemoimmunotherapy for resectable NSCLC. Methods: This study used retrospective data from the National Cancer Database (NCDB), which was queried for all patients diagnosed with NSCLC between 2017-2021 who underwent lung cancer surgery after receiving neoadjuvant chemoimmunotherapy. Only those staged as cN1 or cN2 were included. Patients were stratified according to post-therapy pathologic lymph node status, whether positive (ypN+) or negative (ypN-). Five-year overall survival (OS) was examined using Kaplan-Meier analyses with log-rank tests. Univariate and multivariate Cox regression analyses were conducted to identify significant predictors of survival. Results: Of the total 621 patients, 229 (37%) were diagnosed with cN1 disease and 392 (63%) with cN2. With neoadjuvant chemoimmunotherapy, 59% of cN1 and 40% of cN2 patients were down-staged to ypN0. While 5-year OS was not significantly different according to clinical N stage (76% for cN1 vs. 63% for cN2, p=0.08), higher post-therapy nodal staging correlated with poorer long-term survival (5-year OS of 84% for ypN0, 64% for ypN1, and 51% for ypN2, p <0.001). On multivariate analysis, cN1 to ypN+ (HR 2.56, p=0.009) and cN2 to ypN+ (HR 3.09, p=0.001) were predictors of worse OS compared to cN1 to ypN-, while the difference was not statistically significant for cN2 to ypN- (HR 1.01, p=0.051). Among ypN- patients, similar 5-year OS was seen among those who received adjuvant chemoimmunotherapy and those who did not (82.2% vs. 86.2%, p = 0.26). Conclusion: Patients receiving neoadjuvant chemoimmunotherapy for resectable NSCLC experience high rates of nodal down-staging. Achieving ypN0 status post-therapy strongly predicts favorable long-term survival in this population, while pretreatment cN stage becomes less prognostically relevant.

Background: Renal cell carcinoma (RCC) is a leading malignancy of the urinary system, with clear cell RCC (ccRCC) being the most prevalent subtype. Despite advances in treatment, the prognosis of advanced RCC remains poor, and the molecular mechanisms underlying its pathogenesis are not fully understood. Methods: This study utilized multiple renal cancer cohorts from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). By integrating Mendelian randomization (MR) analyses of expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL), we investigated causal associations between candidate genes and RCC. Immune infiltration, drug sensitivity, and survival analyses were performed to further explore functional significance. In vitro experiments validated the biological role ofISOC1 in RCC progression. Results: We focused on ISOC1, a gene previously implicated in other malignancies but not well studied in RCC. Through integrative MR analysis, we identified ISOC1 as a novel RCC-associated gene, with potential tumor-suppressive functions in this specific context. ISOC1 expression was significantly linked to tumor immune infiltration, drug sensitivity, and patient prognosis. Functional assays demonstrated that ISOC1 knockdown promoted RCC cell proliferation, migration, and invasion. Conclusions: ISOC1 plays a critical role in RCC progression and may act as a tumor suppressor. These findings highlight ISOC1 as a potential biomarker for prognosis and a promising target for therapeutic intervention in RCC. Moreover, this study underscores the utility of MR-based integrative analyses in uncovering novel molecular mechanisms and therapeutic targets for cancer.

Background: While a link between coronavirus disease 2019 (COVID-19) and prostate cancer (PrCa) has been observed in clinical settings, the shared underlying genetic influences remain unclear. Methods: Leveraging summary statistics from the hitherto largest genome-wide association studies (GWASs) of European-ancestry populations, we performed the first comprehensive genome-wide cross-trait analysis to investigate the shared genetic architecture, pleiotropy, and potential causal relationships between three COVID-19 phenotypes and PrCa. Results: We found no evidence of significant genome-wide genetic correlations between COVID-19 phenotypes and PrCa (P > 0.05). However, after partitioning the whole genome into 2353 independent regions, we observed significant local genetic correlations at chromosome 1 (chr1), chr7, and chr14 for PrCa with at least one COVID-19 phenotype (P < 0.05/2353). Cross-trait meta-analysis identified 22 independent single nucleotide polymorphisms (SNPs) shared between PrCa and at least one COVID-19 phenotype, totalling 25 associations, including 2 with infection, 14 with hospitalization, and 9 with critical illness. Transcriptome-wide association study (TWAS) revealed eight distinct shared genes (CCHCR1, TCF19, ADAM15, HLA-C, CYP21A1P, HCP5, ATF6B, and HLA-DQB2), predominantly enriched in tissues of the respiratory, neurological, and reproductive systems. Bidirectional Mendelian randomization (MR) demonstrated no causal association between COVID-19 phenotypes and PrCa. Conclusions: Using a multi-layered analytical framework, our study provides novel insights into the shared genetic bases between COVID-19 phenotypes and PrCa, supported by significant local genetic correlations, pleiotropic SNPs, and shared genes. These findings highlight common biological mechanisms rather than direct causal relationships, suggesting the limited benefits of additional PrCa screening in COVID-19 survivors. Furthermore, the identified genes represent promising targets for future mechanistic research and clinical interventions, warranting further validation.

Background: Patients with "driver gene-negative" LUAD lack effective targeted therapies. This study aimed to elucidate the role of the glycolysis pathway in driver gene-negative LUAD to identify key genes and potential therapeutic targets. Methods: Bulk RNA sequencing data from 49 patients with driver gene-negative LUAD were analyzed. The driver gene-negative status of patients was confirmed by immunoblotting. Gene set enrichment analysis (GSEA) was conducted on six hallmark pathways related to glycolysis. Additionally, key genes were identified and a risk score model was constructed. Finally, single-cell RNA sequencing data were processed using the Seurat package for data cleaning, dimensionality reduction clustering, and cell type identification. Results: GSEA analysis revealed significant enrichment of the glycolysis pathway in driver gene-negative LUAD. Differential expression analysis identified 144 genes associated with the glycolysis pathway. Six glycolysis-related genes (ANKZF1, GPR87, KIF2A, LCT, MIF, SDHC) were identified associated with poor prognosis. Single-cell sequencing analysis validated the key role of MIF in the glycolysis process and revealed a positive feedback regulatory axis between MIF and HIF-1α, which may promoting glycolysis and malignant transformation. Conclusion: This study elucidated glucose metabolic reprogramming mechanisms and highlighted the MIF-HIF-1α axis as a promising therapeutic target in "driver gene-negative" LUAD, which may offer new avenues for improving outcomes, particularly those lacking conventional targeted therapy options.

Background: Exposure to lead, a harmful heavy metal, is one of the risk factors for the development of Colorectal cancer (CRC). However, limited information is available on the impact of serum lead on the incidence of CRC. Therefore, this study utilized data from the National Health and Nutrition Examination Survey (NHANES) to explore the relationship between serum lead and CRC. Methods: A total of 32,894 American adults from the 1999-2020 NHANES cycles were included in this study, among whom 225 reported having CRC. Additionally, we also collected data on 3,024 other cancer patients from the same period. Weighted logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for the risk of CRC associated with serum lead, with adjustments for potential confounding factors. Restricted cubic spline (RCS) analysis was conducted to examine the dose-response relationship between serum lead and the risk of CRC. Concurrently, we performed propensity score matching (PSM) analysis and validated our conclusions through ICP-MS quantification in clinical tissue specimens. Results: This study revealed that patients diagnosed with CRC exhibited significantly elevated serum lead levels in comparison to both the general population and other cancer cohorts. Weighted logistic regression analysis showed a significant positive correlation between serum lead and the risk of CRC with or without adjusting for sociodemographic variables, BMI, diabetes, hypertension, and other covariates. The RCS model detected a dose-response relationship. Subgroup analysis indicated that the association between serum lead and CRC was similar across different sociodemographic characteristics, health behaviors, and comorbidities. However, the risk of CRC increased with higher serum lead levels among individuals aged ≥45, males, whites, BMI ≥24, alcohol users, smokers, and patients with diabetes. Despite the lack of statistically significant differences in lead levels after PSM analysis-potentially attributable to cohort size variations-our ultimate ICP-MS quantification of clinical tissues revealed markedly elevated lead concentrations in CRC specimens (p <0.0001). Conclusion: This cross-sectional study indicates a significant positive correlation between serum lead and the risk of CRC. Further prospective studies are needed to confirm these findings and elucidate the underlying mechanisms.

Colorectal cancer (CRC) ranks among the leading causes of cancer-related morbidity and mortality worldwide, with colitis-associated colorectal cancer (CAC) driven by inflammatory cancer transformation. Arachidonic acid (AA), a key ω-6 polyunsaturated fatty acid, and its metabolites, including prostaglandins (PGs) and leukotrienes (LTs), play pivotal roles in this process by modulating inflammation, immune responses, and the intestinal microenvironment. Notably, a multi-enzyme co-expression nanoplatform integrating lipoxygenase (LOX) and phospholipase A₂ (PLA₂) has been developed, synergistically inducing immunogenic ferroptosis and upregulating AA expression to enhance CD8⁺ T cell-mediated anti-tumor immunity. Additionally, dual COX-2/soluble epoxide hydrolase (sEH) inhibitors, such as PTUPB, demonstrate enhanced anti-tumor activity and reduced toxicity when combined with cisplatin, offering a promising approach to mitigate gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, natural products like ginsenoside Rk3 and berberine have been identified to regulate AA metabolism and gut microbiota, alleviating CAC by modulating lipid peroxidation and inflammatory pathways. This review synthesizes these innovative findings, highlighting the role of AA metabolism in maintaining intestinal homeostasis, promoting inflammatory cancer transformation, and serving as a therapeutic target to inhibit CAC progression, thus providing new insights into its prevention and treatment.

The roles of cancer stem cells and Octamer-binding transcription factor 4 (OCT4) have been implicated in human tumorigenesis and metastasis. However, the role of OCT4 in the metastasis of non-small-cell lung cancer (NSCLC) remains undetermined, especially regarding stem cell-related pathways. Previous research has reported that dual-specificity phosphatase 6 (DUSP6), a mitogen-activated protein kinase (MAPK) phosphatase, is associated with cancer cells that display anti-apoptotic, migratory, and drug-resistance phenotypes. However, the regulation of DUSP6 in NSCLC is unclear. This study focused on the role of OCT4 in NSCLC, particularly its interaction with DUSP6. Here, we show a positive correlation between OCT4 and DUSP6 expression in NSCLC cells. Overexpression of OCT4 increased, whereas knockdown of OCT4 reduced DUSP6 expression. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays revealed that OCT4 transactivated DUSP6 expression by directly binding to the DUSP6 promoter, indicating that DUSP6 is a downstream target of OCT4. Furthermore, knockdown of DUSP6 in OCT4-overexpressing A549 human NSCLC cells decreased cell migration in vitro and reduced tumor growth and pulmonary metastasis in NOD/SCID mice. In conclusion, our findings highlight the importance of the OCT4-DUSP6 pathway in NSCLC progression. Furthermore, the OCT4-DUSP6 axis is a potential therapeutic target for NSCLC.

Objectives: Implanting a hydrogel spacer in radiation therapy for prostate cancer is effective in reducing rectal dose. Hydrogel spacer can be unevenly distributed. we often encountered in which the hydrogel spacer was not in place at the prostatic apex. This study had two objectives. The first was to analyze whether the rectal dose could be reduced in patients who underwent hydrogel-spacer implantation at our hospital. The second was to analyze whether the rectal dose could be reduced in cases where the hydrogel spacer was unevenly distributed and not in place at the prostatic apex, as compared with cases without hydrogel-spacer implantation. Methods: We retrospectively reviewed the records of patients who underwent intensity-modulated radiation therapy for prostate cancer at our hospital between March 2020 and June 2022. Initially, the rectal dose parameters were compared between patients who underwent hydrogel-spacer implantation and those who did not. Additionally, the same parameters were compared between patients who did not undergo hydrogel-spacer implantation and those who did, but in whom the spacer was not in place at the apex. Results: 45 patients did not undergo hydrogel-spacer implantation and 36 patients did. A comparison of rectal dose parameters between patients with and without hydrogel-spacer implantation showed a reduction in all parameters in those with implantation. The 36 patients with hydrogel-spacer implantation included 16 patients in whom the hydrogel spacer was not in place at the apex. A comparison of rectal dose parameters between the 45 patients without hydrogel-spacer implantation and the 16 patients with the hydrogel spacer not in place at the apex showed a reduction in all parameters in the latter group. Conclusion: Hydrogel-spacer implantation was effective in reducing the rectal dose. The rectal dose could be reduced even in cases with uneven distribution of the spacer, as compared with cases without spacer implantation.

Background: Extrachromosomal circular DNA (EccDNA) is widespread in various heterogeneous tumors and closely associated with tumor resistance and progression. Methods: Circle-seq and mRNA-seq were done on samples from three multiple myeloma (MM) patients, one when they had a complete response and one when they relapsed. Results: A large number of EccDNA molecules were detected with high heterogeneity among the six samples. Circle-seq combined with mRNA-seq analyses revealed that there is no linear relationship between mRNA expression and EccDNA quantity. Chromosome 19 presented the highest density of differentially expressed EccDNA genes, followed by chromosome 17. Only the T3 sample showed del(17p) by fluorescence in situ hybridization at the time of relapse. Approximately 92% of all upregulated EccDNA genes from chromosome 17 (137) were present in the T3 sample. By integrating Circle-seq and mRNA-seq data, we obtained several potentially functional candidate protein-coding genes and miRNAs from chromosome 17. We further assessed the prognostic value of the three protein-coding genes in the MMRF-COMPASS clinical trial and found that all three genes were poor prognostic indicators for MM. Furthermore, WB, CCK8 and Annexin V-FITC/PI assays revealed that the overexpression of 2',3'-cyclic nucleotide 3' phosphodiesterase (CNP) downregulated the apoptotic pathway and increased bortezomib tolerance in MM cells. Conclusion: We performed a Circle-seq analysis of MM and investigated the heterogeneity of EccDNA. Analysis of data from clinical studies and basic experiments revealed that the gene carried on EccDNA most likely contributed to the increased tolerance of bortezomib in MM with del(17p).

Lung cancer has one of the highest mortality rates. Although epidermoid lung cancer is one of the most prevalent subtypes of lung cancer, no targeted therapy is currently available for this type of cancer. CX3CL1 is a chemokine that has emerged as a potential molecular target for several malignancies. Chemokines direct the migration of various cell types to the tumor and influence tumor cell behavior. To date, little information is available on the role of this chemokine in squamous cell lung cancer. Using immunofluorescence, we evaluated the expression of CX3CL1 in histological specimens of neoplastic lung tissue from squamous cell lung cancer patients. CX3CL1 was expressed in squamous neoplastic lung tissues at all grades of tumor differentiation. We found this chemokine in the cytoplasm and nucleus of non-transformed cells in the adjacent tissue, but it was infrequent in the nucleus of neoplastic cells, which could have biological relevance.