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Objective: The study aimed to recognize potential molecular targets and signal pathways whereby phenolic environmental estrogen promotes the proliferation of uterine leiomyoma cells. Methods: Primary cultured cell lines of uterine leiomyoma were treated with 0.1% DMSO, 10.0μmol/L Bisphenol A (BPA), and 32.0μmol/L Nonylphenol (NP) for 48 h before RNA-seq was performed. Those genes affected by BPA and NP were identified. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Protein-protein Interaction (PPI) analysis were performed. Quantitative real-time polymerase chain reaction (q-PCR) and western blot were used to verify the differentially expressed gene and protein. Results: Compared to with the control group, 739 differentially expressed genes were identified in both the BPA group and the NP group. GO enrichment analysis showed that the most enriched GO terms were connective tissue development and G1/S transition of mitotic cell cycle, and extracellular matrix. The results of KEGG enrichment analysis showed that differentially expressed mRNA were enriched mainly in three primary pathways, including environmental information processing, human diseases, and cellular processes. The cell cycle, PI3K-Akt signaling pathway are significantly enriched. The q-PCR and western blot verified the cell cycle associated genes and proteins were upregulated in both BPA group and NP group. Both BPA and NP activated the PI3K-AKT signaling pathway. Conclusion: Phenolic environmental estrogens may promote the proliferation and cell cycle progression of uterine leiomyoma cells through rapid non-genomic ER signaling, which leads to disordered cell cycle regulation and accelerates the transition of the cell cycle from G0/G1 phase to S phase. In addition, as an external stimulant, phenolic estrogen promotes the upregulation of inflammatory factors in uterine leiomyomas. |
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