The Functional Role of Prostate Cancer Metastasis-related Micro-RNAs

Abstract

The mortality of patients with hormone-resistant prostate cancer can be ascribed to a large degree to metastasis to distant organs, predominantly to the bones. In this review, we discuss the contribution of micro-RNAs (miRs) to the metastatic process of prostate cancer. The criteria for selection of miRs for this review were the availability of preclinical in vivo metastasis-related data in conjunction with prognostic clinical data. Depending on their function in the metastatic process, the corresponding miRs are up-or downregulated in prostate cancer tissues when compared to matching normal tissues. Up-regulated miRs preferentially target suppressors of cytokine signaling or tumor suppressorrelated genes and metastasis-inhibitory transcription factors. Down-regulated miRs promote epithelial-mesenchymal transition or mesenchymal-epithelial transition and diverse pro-metastatic signaling pathways. Some of the discussed miRs exert their function by simultaneously targeting epigenetic pathways as well as cell-cycle-related, antiapoptotic and signaling-promoting targets. Finally, we discuss potential therapeutic options for the treatment of prostate cancer-related metastases by substitution or inhibition of miRs. In 2017, 160,000 new cases of prostate cancer (PC) were diagnosed in the US and an equal number in the EU with 27,000 patients dying due to metastatic PC in the US and the EU (1). Localized disease can be potentially cured by therapies such as surgery and radiation, but in some patients, the disease progresses despite these therapies (2). Androgendeprivation therapy leads to long-lasting responses between 2 and 3 years, however the disease inevitably progresses to castration-resistant prostate cancer (CRPC) that is associated with metastatic disease and poor prognosis. Over the past 5 years, five drugs have been approved for treatment of CRPC (2). These are cabazitaxel, a taxane-based cytostatic; radium 223, an α-emitter; enzalutamide, a small-molecule androgen receptor (AR) antagonist; abiraterone, a blocker of de novo synthesis of androgens; and Sipuleucel, a dendritic cell-based immunotherapy (3). The recent genetic classification of PC has revealed seven subtypes and new molecular targets for molecular intervention such as vets erythroblastosis virus E26 homolog (ETS) family transcription factor-based fusion proteins as well as mutations in speckle-type POZ protein (SPOP), forkhead protein A1 (FOXA1) and isocitrate dehydrogenase 1 (IDH1) (4). The serine protease inhibitor Kazal-type 1 (SPINK), which is up-regulated in ETSrearrangement-negative tumors, is also being pursued as a new target for treatment of CRPC (5). Nucleic acid-based therapy is another approach for treatment of CRPC. Custirsen, a second-generation phosphorothioate antisense oligonucleotide targeting clusterin mRNA is presently undergoing phase III clinical studies in combination with chemotherapy in patients with CRPC (6, 7). Clusterin is upregulated in patients with CRPC and functions as an ATPindependent molecular chaperone with anti-a...

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