Abstract
Prostate cancer (PCa) is one of the most prevalent cancer types in males and the consequences of its distant metastatic deposits are the leading cause of PCa mortality. Therefore, identifying the causes and molecular mechanisms of hematogenous metastasis formation is of considerable clinical importance for the future development of improved therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs. Numerous studies have identified miRNAs as promotors or inhibitors of metastasis and revealed, in part, their targeting pathways in PCa. Because miRNAs are remarkably stable and can be detected in both tissue and body fluid, its potential as specific biomarkers for metastasis and therapeutic response is also currently under preclinical evaluation. In the present review, we focus on miRNAs that are supposed to initiate or suppress metastasis by targeting several key mRNAs in PCa. Metastasis-suppressing miRNAs include miR-33a-5p, miR-34, miR-132 and miR-212, miR-145, the miR-200 family (incl. miR-141-3p), miR-204-5p, miR-532-3p, miR-335, miR-543, miR-505-3p, miR 19a 3p, miR-802, miR-940, and miR-3622a. Metastasis-promoting RNAs, such as miR-9, miR-181a, miR-210-3, miR-454, miR-671-5p, have been shown to increase the metastatic potential of PCa cells. Other metastasis-related miRNAs with conflicting reports in the literature are also discussed (miR-21 and miR-186). Finally, we summarize the recent developments of miRNA-based therapeutic approaches, as well as current limitations in PCa. Taken together, the metastasis-controlling miRNAs provide the potential to be integrated in the strategy of diagnosis, prognosis, and treatment of metastatic PCa. Nevertheless, there is still a lack of consistency between certain miRNA signatures and reproducibility, which impedes clinical implementation.
Highlights
Dai et al recently reported a negative correlation of ZEB1 expression and TGF-β signaling activity with miR-33a-5p expression in Prostate cancer (PCa) [50]: downregulated miR-33a-5p expression in PCa tissues with bone metastases and bone-derived cells was positively correlated with advanced clinicopathological characteristics, shorter overall survival, and bone metastasisfree survival of the patients
The authors assumed that the frequent loss of miR-3622a at the chr8p21 region leads to the induction of epithelialmesenchymal transition (EMT) states and is responsible for PCa progression and metastasis
The significance of miRNAs for the metastatic progression of PCa and their potential as biomarkers is of growing clinical importance
Summary
Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer-related death in males [1]. Zhu et al have used public databases and miRNA sequencing data in order to identify and explore the relationships between differentially expressed miRNAs and genes [25] They performed a pathway and process enrichment analysis and built a protein-protein interaction network and miRNA-mRNA regulatory network, enabling them to systematically define molecular signatures of bone metastasis in PCa. For instance, Zhu et al identified miR-636 to be up-regulated in bone metastatic PCa tissue and found that this miRNA could promote migration and invasion by targeting MBNL2, TNS1 and STAB1. Twist family consists of a basic helix–loop–helix (bHLH) domain and a c-terminal Twist box for its transcriptional activity [39] These EMT-TFs regulate the expression of various EMTand tumor-related genes and are associated with cancer progression and metastasis formation [40]
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