BMC Cancer. 2026 May 29. doi: 10.1186/s12885-026-16068-1. Online ahead of print.
ABSTRACT
BACKGROUND: Nanomaterials (NMs) with tunable physicochemical and redox properties offer powerful tools for probing cellular regulatory pathways. Accumulating evidence suggests that nanoparticles (NPs) exposure can engage autophagy, a conserved lysosome‑dependent stress‑adaptation process. In this context, iron oxide-gold core-shell nanoparticles (Fe₂O₃/Au NPs) provide a rational platform to investigate nanoparticle‑mediated modulation of autophagy‑related gene (ATG) expression in cancer cells.
METHODS: MCF-7 breast cancer cells and human umbilical vein endothelial cells (HUVECs) were cultured under standard conditions and treated with Fe₂O₃/Au core-shell NPs (20 µg/mL). Nanoparticle uptake was quantified by inductively coupled plasma mass spectrometry (ICP-MS). Gene expression of Beclin1 (BECN1), autophagy-related gene 5 (ATG5), autophagy-related protein light chain 3 (LC3-II), Sequestosome 1 (SQSTM1 or p62), and NBR1 was measured using quantitative polymerase chain reaction (RT-qPCR), normalized to Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and analyzed via the 2-ΔΔCt method. Statistical analyses were conducted with GraphPad Prism 6, with significance set at p < 0.05. Bioinformatics validation was performed using Gene Expression Omnibus (GEO) dataset GSE116436, focusing on five ATGs.
RESULTS: ICP-MS confirmed efficient nanoparticle internalization, with higher uptake in MCF-7 cells than in HUVECs. In MCF-7 cells, Fe₂O₃/Au NPs significantly upregulated BECN1, ATG5, and LC3-II, while p62 and NBR1 were downregulated (p < 0.05), indicating considerable autophagy activation and enhanced without direct flux validation. In contrast, HUVECs showed only mild, non-significant changes, consistent with partial or protective autophagy (p > 0.05). Bioinformatic analysis of the GEO dataset GSE116436 confirmed significant dysregulation of five core ATGs (BECN1, ATG5, SQSTM1/p62, NBR1, and MAP1LC3B) in chemotherapy‑resistant MCF‑7 cells, with BECN1 and ATG5 showing the strongest statistical significance. Gene ontology/ Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment indicated involvement of autophagy, mechanistic target of rapamycin (mTOR), p53, and stress‑response pathways. Kaplan-Meier (KM) survival analysis in the Cancer Genome Atlas-breast cancer (TCGA‑BRCA) cohort revealed gene‑specific, heterogeneous prognostic associations higher BECN1 and NBR1 linked to improved survival, while elevated ATG5 and SQSTM1 correlated with poorer outcomes. STRING‑based protein-protein interaction (PPI) analysis highlighted enrichment of growth factor signaling, extracellular matrix (ECM) organization, and focal adhesion networks, supporting functional coordination among dysregulated genes and associated stromal‑adaptive signaling modules.
CONCLUSION: Fe₂O₃/Au core-shell NPs selectively altered the transcription of key ATGs in MCF‑7 breast cancer cells, with minimal effects in non‑malignant HUVECs. Bioinformatic analyses in chemotherapy‑resistant MCF‑7 models confirmed persistent dysregulation of the same ATGs and enrichment of stress‑adaptive pathways. Collectively, these findings indicate a cancer‑selective, autophagy‑associated transcriptional response and support a hypothesis‑generating link to adaptive features of resistant breast cancer cells.
PMID:42216165 | DOI:10.1186/s12885-026-16068-1
