Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer最新文献

Background: Lung adenocarcinoma (LUAD) is one of the most malignant tumors with significant implications for population health and life. Nicotinamide metabolism may play a pivotal part in influencing the prognosis of LUAD. This study aimed to figure out the potential value of nicotinamide metabolism-related genes (NMRGs) in LUAD prognosis.

Methods: Forty-two NMRGs were obtained from the Molecular Signatures Database and intersected with differentially expressed genes (DEGs) in LUAD from The Cancer Genome Atlas. Unsupervised consensus clustering was conducted based on the intersecting genes, followed by identification of DEGs between clusters. Enrichment analyses and LASSO-Cox regression analyses were conducted. Immune cell infiltration was calculated using the ssGSEA algorithm. Wilcoxon test was conducted on the TIDE scores of different risk groups. Targeted small molecule drug prediction was performed on the DEGs in groups.

Results: A total of 10 nicotinamide metabolism-related differentially expressed genes (NMRDEGs) were identified for LUAD clustering. LUAD patients were divided into two clusters. Cluster 1 had considerably higher overall survival rates compared to cluster 2. Differential genes between clusters were mainly enriched in hormone metabolic processes and the neuroactive ligand-receptor interaction pathway. An 11-gene prognostic model was established to predict the overall survival of LUAD patients. The validation set showed that the model had a good prognostic effect. Analysis of immune cell infiltration demonstrated that in the high-risk (HR) group, infiltration levels of mast cells and neutrophils were considerably lower than low-risk (LR) group, while infiltration levels of NK cells and Th2 cells were considerably higher than LR group. TIDE scores indicated a lower likelihood of immune evasion and a potentially better response to immunotherapy in LR patients. Drug prediction showed that FGIN-1-43, deferiprone, and griseofulvin were potential drugs.

Conclusion: We successfully developed a predictive model for the survival and immunotherapy response of LUAD patients.

Cholangiocarcinoma (CCA) is a life-threatening malignancy, and there is an urgent need for new biomarkers to improve the prognosis of patients. The expression of ELF3 in CCA tumor and non-tumor tissues was examined in two cohorts. ELF3 expression and the methylation level of its promoter in CCA patients with various clinicopathological features were analyzed using the UALCAN website. Co-expressed genes significantly associated with ELF3 were screened using the LinkedOmics website. A protein-protein interaction (PPI) network for these co-expressed genes was constructed using the STRING website. Core co-expressed genes correlated with ELF3 were identified through random walk with restart (RWR) analysis. GeneMANIA was utilized to analyze the major biological functions within networks of kinases and TFs mediated by ELF3. Potential targeted drugs for CCA treatment were screened using the Connectivity Map (CMAP) database. ELF3 expression in CCA tissue was significantly increased compared with that in normal tissue. Among CCA patients with distinct clinicopathological features, ELF3 expression was notably elevated in tumor tissues compared to normal tissue, while ELF3 promoter's methylation levels in tumor tissue were significantly decreased. In total, 307 co-expressed genes, evidently relevant to ELF3, were identified through LinkedOmics analysis. RWR analysis revealed 61 co-expressed genes closely associated with ELF3. Enrichment analysis indicated that these genes control cell junctions and epithelial cell differentiation. GeneMANIA analysis uncovered that ELF3-involved regulatory networks of kinases and TFs were primarily linked to the regulation of immune cells and cell adhesion. CMAP analysis identified 10 potential small molecules for CCA treatment including 4 existing drugs used for other diseases. ELF3 shows promise as a diagnostic marker for CCA, and the drugs we have identified hold great potential for the treatment of this fatal disease.

Invasive ductal carcinoma (IDC) is a major type of breast cancer. The utilization of inhibitors targeting histone methyltransferases introduces novel therapeutic avenues for the treatment of cancer. Immunohistochemistry, Western blot, and reverse transcription quantitative polymerase chain reaction experiments were applied to assess the levels of EHMT2 in IDC and adjacent tissues. HCC70 cells were treated with EHMT2 inhibitors (UNC0646 and BIX-01294), and assessed using Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and transwell assays to evaluate cell viability, apoptosis, and migratory capacity, respectively. The reactive oxygen species (ROS) levels were assessed using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe. The expressions of Hippo pathway were analyzed via Western blot assay. Immunofluorescence staining was employed to detect the subcellular localization changes in YAP expression. A xenograft tumor model of HCC70 cells was applied to validate the tumor-suppressive influences of EHMT2 inhibitors in vivo. We observed significant upregulation of EHMT2 in both IDC clinical samples and IDC cell lines, with high EHMT2 expression correlating with poor prognosis. After treatment with EHMT2 inhibitors UNC0646 or BIX-01294, HCC70 cells exhibited inhibition of proliferation and migratory capacity, alongside an increase in apoptosis rate and ROS production levels. UNC064 or BIX-01294 promoted the phosphorylation levels of MST1, LATS1, MOB1A, and YAP, indicating the activation of the Hippo pathway by EHMT2 inhibitors. Moreover, UNC0646 and BIX-01294 enhanced the cytoplasmic expression of YAP while inhibiting its nuclear localization, preventing its nuclear activation. EHMT2 was upregulated in IDC, and EHMT2 inhibitors suppressed IDC progression by modulating the Hippo signaling pathway.

Breast cancer (BC) is one of the main causes of cancer-related death in women. The purpose of this study was to evaluate the expression of miR-605-5p in BC and its diagnostic and prognostic value. BC patients and healthy individuals who met the study criteria were included. Real-time fluorescence quantitative PCR (RT-qPCR) was used for the detection of miR-605-5p expression in BC patients and BC cell lines. The ROC curve was used for the assessment of the diagnostic value of miR-605-5p. The Kaplan-Meier survival curve was used to assess the prognostic value of miR-605-5p. CCK-8 and Transwell assays were performed to detect the effect of miR-605-5p on BC cell activity. The results of this study showed that miR-605-5p was markedly downregulated in BC and correlated with the clinicopathological features of the patients. The expression level of miR-605-5p has high diagnostic accuracy for distinguishing BC patients from healthy individuals. Low expression predicts an unfavorable prognosis for BC patients, while up-regulation of miR-605-5p inhibited the activity of BC cells. In summary, miR-605-5p has the potential to serve as an important molecular marker for prognostic analysis and prediction of BC patients.