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  • Title: GR silencing impedes the progression of castration-resistant prostate cancer through the JAG1/NOTCH2 pathway via up-regulation of microRNA-143-3p.
    Author: Zhang L, Jiang H, Zhang Y, Wang C, Xia X, Sun Y.
    Journal: Cancer Biomark; 2020; 28(4):483-497. PubMed ID: 32568179.
    Abstract:
    BACKGROUND: Despite notable progression from a therapeutic point of view, castration resistant prostate cancer (CRPC) remains a clinical significant stumbling block. The current study aimed to elucidate the functional role of the gene glucocorticoid receptor (GR) in CRPC, and identify the contributions of the GR gene in CRPC in connection with microRNA-143-3p (miR-143-3p)/Jagged1 (JAG1)/NOTCH2. METHODS: The expression of GR and miR-143-3p in CRPC tissues and cells as well as JAG1/NOTCH2 expression in CRPC tissues was initially determined by quantitative polymerase chain reaction and Western blot analyses. The relationship among GR, JAG1, NOTCH2 and miR-143-3p was subsequently verified using the dual-luciferase reporter gene assay. ChIP assay confirmed the binding of GR to miR-143-3p promoter. Gain- and loss-function approaches were applied to ascertain the role of GR and miR-143-3p in progression of CRPC. Additionally, xenograft tumor models in nude mice were established to further confirm our results. RESULTS: GR was found to be highly expressed while miR-143-3p was lowly expressed in the CRPC tissues and cells. Silencing GR reduced migration, invasion, proliferation and increased apoptosis of CRPC cells. GR was enriched in the miR-143-3p promoter region and could down-regulate miR-143-3p expression. The overexpression of miR-143-3p led to a reduction in the migration, invasion, proliferation and increased apoptosis of CRPC cells. JAG1 and NOTCH2 were the target genes of miR-143-3p, and GR up-regulated the JAG1/NOTCH2 expression by down-regulating miR-143-3p. Silencing JAG1/NOTCH2 inhibited epithelial-mesenchymal transition and CRPC progression in vitro. Furthermore, the in vitro findings were reproduced in the in vivo experiments. CONCLUSION: The key findings of the current study demonstrated that silencing GR suppressed the progression of CRPC through the JAG1/NOTCH2 pathway via up-regulation of miR-143-3p.
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