Abstract
Prostate cancer is a major hormone-dependent tumor affecting men, and is often treated by hormone therapy at the primary stages. Despite its initial efficiency, the disease eventually acquires resistance, resulting in the recurrence of castration-resistant prostate cancer. Recent studies suggest that dysregulation of microRNA (miRNA) function is one of the mechanisms underlying hormone therapy resistance. Identification of critical miRNAs involved in endocrine resistance will therefore be important for developing therapeutic targets for prostate cancer. In the present study, we performed an miRNA library screening to identify anti-androgen bicalutamide resistance-related miRNAs in prostate cancer LNCaP cells. Cells were infected with a lentiviral miRNA library and subsequently maintained in media containing either bicalutamide or vehicle for a month. Microarray analysis determined the amounts of individual miRNA precursors and identified 2 retained miRNAs after one-month bicalutamide treatment. Of these, we further characterized miR-216a, because its function in prostate cancer remains unknown. miR-216a could be induced by dihydrotestosterone in LNCaP cells and ectopic expression of miR-216a inhibited bicalutamide-mediated growth suppression of LNCaP cells. Furthermore, a microarray dataset revealed that the expression levels of miR-216a were significantly higher in clinical prostate cancer than in benign samples. These results suggest that functional screening using an miRNA expression library could be useful for identifying novel miRNAs that contribute to bicalutamide resistance in prostate cancer.
Highlights
Prostate cancer is the second most common cancer among men worldwide and the incidence of prostate cancer has been increasing in Japan
Because the growth of prostate cancer is primarily regulated by androgen signaling, androgen deprivation therapy is often performed as prostate cancer treatment
To identify miRNAs involved in the bicalutamide responses in LNCaP cells, we performed functional screening with a lentiviral library comprising 445 miRNA precursors
Summary
Prostate cancer is the second most common cancer among men worldwide and the incidence of prostate cancer has been increasing in Japan. Because the growth of prostate cancer is primarily regulated by androgen signaling, androgen deprivation therapy is often performed as prostate cancer treatment. The hormone therapy is initially effective for inhibiting the growth of prostate cancer by suppressing androgen receptor (AR) activity. Patients eventually acquire resistance to hormonal therapy during long-term treatment, and develop an advanced form of the disease, termed castration-resistant prostate cancer (CRPC) [1–3]. Patients with CRPC have a poor prognosis and account for the majority of deaths due to the disease. Recent studies have shown that AR signaling regulates prostate cancer growth even under the condition of androgen deprivation in CRPC.
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