Abstract
Prostate cancer is one of the most common cancers among men. Currently available therapies improve patient survival against local prostate cancer but have shown severe side effects. Advanced prostate cancer is still incurable. Studies have suggested the involvement of non-coding RNAs, especially micro-RNAs (miRNAs), in the regulation of multiple cellular events in cancer and thus several clinical trials are ongoing using miRNAs mimics or inhibitors. We previously demonstrated that miRNA-29b-3p (miR-29b) was downregulated in prostate cancer and that the overexpression of miR-29b limited prostate cancer metastasis. However, the therapeutic potential of the miR-29b against prostate cancer remains unknown. Here, we evaluated the therapeutic role of miR-29b in in vivo prostate tumors in a mouse model. Intratumoral injection of mimic miR-29b significantly inhibited prostate cancer xenograft tumor growth in nude mice. Subsequent study demonstrated that the overexpression of miR-29b reduced prostate cancer cell PC3 proliferation in a time dependent manner and induced cell death. Mechanistic study using a cancer pathway specific transcriptomic array revealed a significant overexpression of the pro-apoptotic gene BCL2L11 (Bim) in the miR-29b overexpressed PC3 cells, which was further verified in PC3 cells overexpressing miR-29b. We also observed a significant induction of Bim protein in miR-29b treated xenograft tumors. The induction of cytosolic accumulation of cytochrome C and PARP cleavage in miR-29b overexpressed PC3 cells was observed. Thus, our results suggest that miR-29b can be used as a potential molecule for prostate cancer therapy.
Highlights
IntroductionProstate cancer is one of the most common cancers in men and the estimated incidence rate is
Prostate cancer is one of the most common cancers in men and the estimated incidence rate is174,650 with 31,620 deaths in United States in 2019 [1]
We examined whether mimic miR-29b treatment inhibits tumor growth in a PC3 xenograft mouse mouse model
Summary
Prostate cancer is one of the most common cancers in men and the estimated incidence rate is. Locked nucleic acid (LNA)-modified antisense oligonucleotide of oncogenic miRNAs and mimic of tumor suppressor miRNAs showed potential roles in Phase 1 and 2 clinical trials [6]. We first demonstrated that miRNA-29b (miR-29b) expression is significantly lower in prostate cancer and inhibits prostate cancer metastasis [10,11]. Other studies showed downregulation of miR-29b in different cancers, and miR-29b targets several genes of cell survival, angiogenesis, metastasis, fibrosis, and epigenetic modification pathways [15,16]. The therapeutic potential of miR-29b against prostate cancer is not being examined. We evaluated the therapeutic potential of miR-29b in a pre-clinical model. We developed prostate xenograft tumor in nude mice implanting PC3 cells and miR-29b was delivered intratumorally. We observed regression of tumor growth and induction of apoptotic cell death
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