LAUSR

Introduction Chromosome 8q24 prostate cancer (PCa) susceptibility region encodes miR-1207–3 p which directly targets fibronectin type III domain containing 1 (FNDC1) to regulate fibronectin (FN1) and subsequently the androgen receptor (AR), and FNDC1/FN1/AR is overexpressed in metastatic PCa (Das et al, Exp Cell Res, 2016). Material and methods Expression of miR-1207–3 p and c-MYC in histologically confirmed normal prostate, benign prostatic hyperplasia (BPH) and PCa from prostatectomy or transrectal ultrasound-guided biopsies was analysed. Molecular mechanisms were elucidated using mCRPC cell lines. Effects of NB1207 and NB5, two novel synthetic analogues of miR-1207–3 p, on AR-V7 (implicated in PCa therapeutic resistance), mCRPC tumour growth in mice were studied. Results and discussions miR-1207–3 p is underexpressed in PCa (0.10±0.02, 95% CI [0.1, 0.2], p=0.000) in comparison to normal prostate (1.02±0.17, 95% CI [0.7, 1.4], p=0.000) and BPH (0.74±0.15, 95% CI [0.4, 1.1] p=0.004). c-MYC was overexpressed in PCa (34.76±8.11, 95% CI [18.1, 51.4], p=0.000; normal: 1.99±0.34, 95% CI [1.3, 2.7]; BPH: 1.01±0.21, 95% CI [0.6, 1.4], p=0.000). miR-1207–3 p was underexpressed by nearly 3-fold in PCa with Gleason score ≥8 versus those with Gleason score <8, while c-MYC was overexpressed by nearly 5-fold in PCa with Gleason score ≥8 versus those with Gleason score <8. NB1207 significantly inhibited c-MYC expression in mCRPC cell lines: PC-3, E006AA-hT and C4-2B. miR-1207–3 p regulates c-MYC expression via the miR-1207–3 p/FNDC1/FN1/AR pathway: c-MYC protein expression is inhibited in mCRPC cell lines by overexpression of miR-1207–3 p, and by inhibition of expression of FNDC1, FN1, and AR. In AR-V7-expressing mCRPC cell lines, NB1207 and NB5 significantly reduced AR-V7 expression, and NB1207 and NB5 more effectively inhibited AR-V7 compared to abiraterone, enzalutamide and apalutamide. In mCRPC cell lines, abiraterone, enzalutamide, and apalutamide failed to significantly inhibit cell proliferation or induce apoptosis. However, NB1207 and NB5 significantly inhibited proliferation and induced apoptosis. In mCRPC 22RV1 tumor-bearing mice, NB5 and NB1207 significantly inhibited tumour growth and metastatic spread. While enzalutamide minimally inhibited growth of 22RV1 tumours in mice, apalutamide and abiraterone had no inhibitory effects on tumour growth. Conclusion This study shows potential diagnostic and prognostic value of miR-1207–3 p in mCRPC, and that NB5 and NB1207, novel analogues of miR-1207–3 p, may be candidate therapeutics for mCRPC.