Discover. Oncology最新文献

Background: N-Nitrosodimethylamine (NDMA), classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC), is ubiquitous in drinking water, processed foods, and certain pharmaceuticals. Emerging epidemiological evidence links NDMA exposure to an increased risk of Bladder Urothelial Carcinoma (BLCA), yet the specific molecular mechanisms driving its role in BLCA initiation and progression remain unclear.

Objective: This study aimed to elucidate the mechanisms of NDMA-induced BLCA by identifying core targets, validating their expression and immune correlation, and constructing a hypothetical Adverse Outcome Pathway (AOP) framework for NDMA-associated BLCA.

Methods: We integrated network toxicology and machine learning (LASSO, SVM-RFE, Random Forest) to screen core targets from the intersection of NDMA-related and BLCA-related genes obtained from public databases. Their expression levels and diagnostic value were validated using GEO (GSE13507) and TCGA data. Immune infiltration analysis, molecular docking, and 100-ns molecular dynamics simulations were performed to assess tumor microenvironment associations and NDMA-target binding stability, followed by the establishment of an AOP framework.

Results: A total of 575 intersecting targets were identified, with five core targets (IL7R, BCL2, CDC20, GADD45A, NRAS) screened via machine learning. These targets exhibited significant dysregulation in BLCA samples (p < 0.01) and demonstrated strong diagnostic performance (AUC: 0.766-0.869). Furthermore, core targets showed distinct correlations with immune cell infiltration. Molecular docking confirmed stable binding of NDMA to all targets, with the highest affinity observed for BCL2, which was further validated by dynamics simulations. Based on these findings, a novel AOP framework was proposed: NDMA exposure → dysregulation of core targets → pathway disruption → immune microenvironment imbalance and epithelial cell dysfunction → BLCA progression.

Conclusion: NDMA likely promotes BLCA through multi-target and multi-pathway mechanisms. The identified core genes serve as potential diagnostic biomarkers, and the proposed AOP provides a theoretical basis for environmental risk assessment and targeted intervention strategies.

Background: AHNAK2 is acknowledged to function as an oncoprotein that enhances the invasive and metastatic potential of tumor cells in multiple types of malignancy. Nevertheless, its specific role in gastric cancer (GC) remains unclear.

Methods: Immunohistochemistry (IHC) was used to examine AHNAK2 expression in matched GC tissues and paracancerous tissues, Clinical and pathological data was gathered for the purpose of investigate the association of AHNAK2 expression and prognosis in patients with GC. AHNAK2 protein expression and location was examined using Western blotting (WB) and immunofluorescence (IF). The effects of AHNAK2 knockdown on the malignant biological behavior of GC cells were evaluated. Transcriptome sequencing and WB analyses were conducted to explore the potential molecular mechanisms underlying AHNAK2-mediated regulation of GC progression.

Results: WB, IF, and IHC analyses demonstrate that AHNAK2 expression is upregulated in GC, and patients with high AHNAK2 protein expression exhibit poorer overall survival rates. Knockdown of AHNAK2 results in reduced invasive, proliferative, and migratory capacities of GC cells, along with increased apoptosis. RNA sequencing and WB analysis further confirmed that AHNAK2 exacerbates the malignant phenotypic characteristics of GC through activation of the Wnt/β-catenin pathway.

Conclusion: AHNAK2 may serve as a new prognostic biomarker and a prospective therapeutic target in GC.

Permanent hair dyes have been linked to an increased risk of breast cancer (BC), though the underlying mechanisms remain unclear. To address this knowledge gap, our investigation employed an integrated approach combining network toxicology, molecular docking, molecular dynamics simulations, and machine learning to decipher the molecular mechanisms by which permanent hair dyes might promote BC pathogenesis. Five permanent hair dye ingredients classified by IARC as carcinogenic were included in this study: p-phenylenediamine, resorcinol, pyridine, Disperse Yellow 3, and HC Blue No. 2. These chemicals can regulate BC progression through various signaling pathways, with key core targets identified as HSP90AA1, HSP90AB1, ESR1, CDK1, STAT3, MAPK8, HDAC1, and SRC. A machine learning model comprising 128 algorithms confirmed that these eight targets possess strong prognostic predictive capabilities for BC. Subsequent SHAP analysis revealed SRC, HSP90AB1, HSP90AA1 and CDK1 as the key contributors to prognostic prediction, with each being highly expressed in BC and linked to poor clinical prognosis. Notably, among all chemicals screened, Disperse Yellow 3 exhibited the strongest binding affinity to these four key targets, demonstrating the strongest association with BC risk.

Purpose: The heterogeneous nuclear ribonucleoprotein (HNRNP) family plays pivotal roles in multiple aspects of RNA metabolism. Recent studies suggest that HNRNP dysregulation can promote tumor development. Therefore, this study aims to systematically characterize the expression profiles, immunological associations, and prognostic significance of HNRNP family members in LUAD.

Methods: Comprehensive transcriptomic and proteomic analyses were conducted using TCGA, GTEx, GEO, and CPTAC LUAD cohorts. Differential expression, immune infiltration, and survival analyses were performed using bioinformatics approaches including ssGSEA, TIDE, and Cox regression modeling. Functional enrichment and alternative splicing profiling were further applied to explore potential mechanisms, with a focus on HNRNPC.

Results: Multiple HNRNP genes were significantly overexpressed in LUAD tissues across datasets. Their expression levels positively correlated with tumor stage, metastasis, recurrence, and TP53 mutation status. High expression of several HNRNPs was associated with poor overall survival, with HNRNPC identified as an independent prognostic indicator in both TCGA and GEO cohorts. Elevated HNRNP expression was linked to reduced immune cell infiltration and lower stromal, immune, and ESTIMATE scores, alongside increased TIDE and Exclusion scores, suggesting immunosuppressive roles in the tumor microenvironment. Functionally, HNRNPC was associated with the activation of cell cycle progression and DNA damage repair. Alternative splicing analysis revealed that HNRNPC predominantly regulates exon skipping events, with enriched downstream pathways involved in chromatin remodeling and transcriptional regulation.

Conclusion: This study highlights the critical roles of HNRNP family members in LUAD, identifying HNRNPC as a key prognostic biomarker and potential intervention candidate to improve patient outcomes.