GR silencing impedes the progression of castration-resistant prostate cancer through the JAG1/NOTCH2 pathway via up-regulation of microRNA-143-3p

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.

Circulating MicroRNAs Indicative of Sex and Stress in the European Seabass (Dicentrarchus labrax): Toward the Identification of New Biomarkers

“…For instance, we identified the glucocorticoid receptor (gr or nr3c1) as potential target of miR-143-3p in silico. Such a link would make sense since 1) miR-143-3p is highly expressed at T0 compared to other time-points, supporting a possible production of GR post-stress and 2) gain-and loss-function approaches in GR and miR-143-3p confirmed that the glucocorticoid receptor was indeed a target of miR-143-3p in humans (L. Zhang et al, 2020). This support a specific role of miR-143-3p in the primary stress response.…”

Kaempferol Inhibits Hepatic Stellate Cell Activation by Regulating miR-26b-5p/Jag1 Axis and Notch Pathway

“…Recently, miRNA-mediated Jag1 expression has been found in various human diseases ( Zhang et al, 2020a ; Zhang et al, 2020b ). Herein, bioinformatics analysis (miRDB) was performed to identify the potential miRNAs targeting Jag1, and 10 miRNAs with the highest target score were shown in Figure 5A .…”

SOX8 Knockdown Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting the Notch Signaling Pathway

“…Notch1 was found to be overactivated in PCa, while its inhibition by a γ -secretase inhibitor restored enzalutamide function [ 24 , 26 , 27 , 51 ]. Also, inhibition of Notch2 activation by GSI-1, another γ -secretase inhibitor, decreased the cell survival of prostate cells and promoted their apoptosis [ 24 , 52 ]. A recent study reported that Notch3 is responsible for PCa-induced bone lesion by activating MMP-3 signaling [ 53 ].…”