Date of Degree

2-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor(s)

Olorunseun O. Ogunwobi

Committee Members

Frida E. Kleiman

Nancy L. Greenbaum

Brian D. Robinson

Joseph R. Osborne

Subject Categories

Biological Factors | Genetic Processes | Male Urogenital Diseases | Medical Cell Biology | Medical Genetics | Medical Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Translational Medical Research | Urology

Keywords

prostate cancer, microRNA-1207-3p, androgen receptor, CRPC, c-MYC

Abstract

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines compared to normal prostate epithelial cells. Moreover, the increased expression of miR-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of Fibronectin type III domain containing 1 (FNDC1) and consequent loss of expression of fibronectin (FN1), and consequent loss of expression of the androgen receptor (AR). PCa cell lines and patient-derived tissues revealed significant overexpression of FNDC1, FN1 and AR which are factors that positively correlate with aggressive PCa. Also, metastatic PCa displayed concurrent overexpression of FNDC1, FN1 and AR. Taken together, this is the first description of a novel miR-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa. For the unbiased discovery of the molecular targets of miR-1207-3p, we designed and synthesized a novel synthetic biotinylated miR-1207-3p duplex (NB1207), and a novel synthetic biotinylated scramble duplex (NB1). We observed that NB1207, but not the scrambled duplex NB1, directly targets the 3’UTR of FNDC1 and more effectively inhibits proliferation, inhibits migration and increases apoptosis of PCa cells including those aggressively tumorigenic. Interestingly, the location of miR-1207-3p on the 8q24 human chromosomal region is downstream of the proto-oncogene, c-MYC. c-MYC has been linked to castration resistant prostate cancer (CRPC). However, the mechanisms regulating c-MYC remain unclear in CRPC. In this study, we discovered that c-MYC is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in CRPC. miR-1207-3p negatively correlates with c-MYC in prostate tumors with Gleason score ≥8. Additionally, we discovered that overexpression of miR-1207-3p significantly inhibited proliferation and increased apoptosis in CRPC cells. We also compared the efficacy of NB1207 and NB5, two novel synthetic analogs of miR-1207-3p, with the currently used therapies against CPRC: abiraterone, enzalutamide, and apalutamide (phase 3 clinical trial). Treatment with NB1207 and NB5 resulted in increased inhibition of AR-V7 protein expression, and more significant inhibition of proliferation and increases in apoptosis of CRPC cells compared to abiraterone, enzalutamide and apalutamide. These results demonstrate that synthetic analogs of miR-1207-3p, such as NB5 and NB1207, may be a novel strategy for successful therapeutic targeting of c-MYC via the miR-1207-3p/FNDC1/FN1/AR pathway in CRPC. In summary, the present study indicates that miR-1207-3p may have potential diagnostic, prognostic, and therapeutic applications in PCa.

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