Integrative meta-analysis reveals coordinated H19/miR-675/circRNA network remodeling and metabolic reprogramming in tamoxifen-treated MCF-7 cells

Abstract

Objectives: This study aimed to identify transcriptomic signatures associated with established tamoxifen resistance in ER-positive MCF-7 cells through integrative meta-analysis of public datasets and to evaluate whether H19-centered non-coding RNA networks constitute early adaptive transcriptional responses following acute tamoxifen exposure.

Materials and methods: We interrogated three publicly available transcriptomic datasets (GSE67916, GSE26459, GSE5840) comprising 32 biological samples from tamoxifen-resistant and parental MCF-7 cells using the ImaGEO analytical framework. Pathway-level characterization was achieved via Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome enrichment pipelines. To corroborate computational predictions, we quantified transcript abundance of lncRNA H19, miR-675-5p, circRNA sponge for miR-7 (ciRS-7), and circRNA homeodomain-interacting protein kinase 3 (circHIPK3) using quantitative polymerase chain reaction following a 48-h tamoxifen challenge at the experimentally derived IC₅₀ (5 µM).

Results: Computational screening unveiled 2,096 transcripts exhibiting consistent expression alterations (false discovery rate (FDR) <0.05), comprising 1,180 induced and 916 repressed genes. Pathway mapping revealed pronounced activation of the cholesterol synthesis machinery and sterol regulatory element-binding protein-driven transcriptional circuits, along with enhanced immunological signatures, in resistant cells. Conversely, genes governing mitochondrial protein synthesis and forkhead-box class O/Hippo tumor-suppressive cascades showed marked attenuation. Laboratory validation demonstrated coordinate elevation of H19, miR-675-5p, and ciRS-7 transcripts, while circHIPK3 levels declined substantially upon tamoxifen challenge (all p<0.001).

Conclusion: This investigation uncovers synchronized alterations in lipid metabolic programming and the H19/miR-675/circRNA regulatory axis triggered by tamoxifen exposure. Our observations illuminate molecular perturbations that may foreshadow the emergence of treatment-refractory disease and highlight candidate nodes warranting therapeutic exploration in hormone-dependent breast malignancies.

Cite this article as: Yorgun E, Acar Ö. Integrative meta-analysis reveals coordinated H19/ miR-675/circRNA network remodeling and metabolic reprogramming in tamoxifen-treated MCF-7 cells. D J Med Sci 2025;11(3):134-143. doi: 10.5606/ fng.btd.2025.208.