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A trio of tumor suppressor miRNA downregulates CREB5 dependent transcription to modulate neoadjuvant hormonal therapy sensitivity

Neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy (RP) is an approach that can potentially maximize survival outcomes in prostate cancer (PCa) patients with high-risk disease. Unfortunately, subsets of patients do not respond well to such hormonal therapy. We previously identified several pathological parameters in predicting differences in response to NHT of PCa. However, little is known about the potential role and mechanism of miRNAs mediated NHT resistance (NHT-R) in PCa. Here we demonstrate that miR-l42-3p, miR-150-5p and miR-342-3p are the top downregulated miRNAs in PCa tissues with NHT-R. Functional analysis reveals that the three miRNAs inhibit cell proliferation in vitro. Transfection of miRNAs mimics strengthens the inhibitory effects of bicalutamide and enzalutamide to PCa cells. Luciferase reporter assay reveals that CREB5 is the common target of these three miRNAs. Clinically, high expression level of CREB5 correlates with high Gleason score, advanced tumor stage and NHT-R in PCa tissues. CREB5 expression promotes antiandrogen therapy resistance in LNCaP cells and IL6 signaling pathway may be involved in this process. In all, our findings highlight an important role of miR-142-3p, miR-150-5p, and miR-342-3p in contributing NHT-R by targeting CREB5 in PCa.

 

Comments：

MiRNAs play a role in neoadjuvant hormonal therapy resistance in prostate cancer by targeting CREB5, with miR-142-3p, miR-150-5p, and miR-342-3p being the top downregulated miRNAs in prostate cancer tissues with NHT resistance, inhibiting cell proliferation, and promoting the inhibitory effects of bicalutamide and enzalutamide to prostate cancer cells.

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S1190 Bicalutamide Bicalutamide is an androgen receptor (AR) antagonist with IC50 of 0.16 μM in LNCaP/AR(cs)cell line. Bicalutamide promotes autophagy.

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Androgen Receptor Autophagy