Expression Profiles and Mechanisms of microRNAs in Prostate Cancer

MicroRNAs are small non-coding RNA molecules with a length of 20 to 25 nucleotides. As gene expression regulators, microRNAs can completely or not completely complementarily bind with mRNA to inhibit translation or degradate mRNA. Aberrant expression of microRNAs is closely related to the occurrence, development, metastasis and prognosis of prostate cancer. Some microRNAs may promote cancerization, while others are tumor suppressors. In this review, we summarized the expression profiles of microRNAs in recent years, in particular, the data obtained by large-scale high-throughput technologies. We also summed up microRNAs which had the potential to be biomarkers of prostate cancer, and the mechanisms of microRNAs in the developmental progression of prostate cancer. The review provided medical and scientific researchers with an overview of the status and role of microRNAs in prostate cancer. In short, we summarized the expression profiles of microRNAs discovered in recent years and their roles and mechanisms in the occurrence and development of prostate cancer.


Introduction
Prostate cancer (PCa) is a high incidence of male reproductive system malignancy all over the world. In 2017; 161,360 new cases were reported, and 26,730 patients died from PCa in America [1]. In China, the incidence of PCa and the threat to men's health are also increasing. At present, PSA (prostate specific antigen) test was most widely used to screen PCa patients in clinical practice, combined with imageological examination and fine needle puncture to diagnose PCa. For low-risk PCa, the treatment strategies were closely monitor and active surveillance. For patients with high-risk PCa, options were radical prostatectomy (RP), radiation therapy, and androgen deprivation therapy (ADT). However, in the advanced cases of castration resistance and metastases, patients would receive chemotherapy. Nowadays, nanoparticle delivery system has attracted great attention from the scientific community. Nanoparticles display infinite potential to increase anti-tumor efficacy of highly hydrophobic chemotherapeutic drugs, which makes them more attractive to provide the opportunities in targeted drug delivery [2,3]. microRNAs (miRNAs) are small conserved endogenous noncoding RNAs with the length of 20-25 nt, which regulate target genes by complementarily binding to the 3'-untranslated regions (UTR) of target mRNAs. It was estimated that each miRNA could regulate hundreds of target genes, and each mRNA could be bound by hundreds of different miRNAs. So, about 60% of coding genes were regulated by miRNAs encoded by 1% of human genome [4]. Nowadays, more than 4800 human mature miRNAs were reported in miRBase v22 (http://www.mirbase.org/). miRNAs may effect a wide variety of cellular processes, such as cell proliferation, differentiation, and apoptosis, etc. miRNAs may also participate in multiple cellular pathways in a variety of solid tumors by dual roles: Oncogenic miRNAs or tumor suppressor miRNAs.
The goals of this review are to summarize the expression 2 This article is available in: http://biomarkers.imedpub.com/archive.php differentially expressed data were collected from different studies screening various prostate samples, such as prostate cancer (PCa), benign prostate controls, castration resistance prostate cancer (CRPC) and hormone sensitive PCa, and metastatic PCa, etc.
Following the rapid development of new high-throughput technologies, such as whole-genome analysis, deep sequencing and microarray, in particular, single-cell genome/transcriptome sequencing, researchers may get the miRNAs expression data in specific time and space from these large-scale analyses.

microRNAs as biomarkers for prostate cancer
At present, a lot of studies have focused on the correlation between specific miRNA expression level and various clinical features of PCa, such as tumor stage, Gleason score, metastasis, biochemical recurrence and disease specific death, etc. We also conducted a meta-analysis to evaluate the application value of miRNAs as PCa biomarkers. Our results supported that miRNAs might distinguish the different states of PCa and predict the prognosis of PCa [8]. About 180 miRNAs related to the prognosis, recurrence and metastasis of PCa have been found and summarized in Table 2.
miRNAs were good biomarkers because they not only could noninvasively identify PCa, but also were stable in a variety of samples and could be detected in a variety of methods. In Table   profiles of microRNAs in PCa, and to identify the predictive biomarkers which may isolate the lethal or drug-resistant patients to reduce overtreatment and to improve personalized treatment effect.

The Expression Profiles Of Micrornas In Prostate Cancer
Previously, we scanned the miRNAs expression profiles in highrisk and low-risk PCa tissue samples using the second-generation sequencing and quantitative real-time PCR (qRT-PCR) technology [5]. The obtained results were summarized in Table 1 together with other literatures' data [6,7]. Some of these miRNAs expression were controversial in different studies, while others were consistent in tissue and body fluid specimens, which were all marked in Table 1. Obviously, miRNAs with consistent results reported in all literatures could provide more valuable information. For example, miR-26a, miR-106a and miR-141 were up-regulated in PCa tissues and serum samples. In addition, the gene encoded a sort of miRNA may produce multiple mature miRNA products due to different splicing processes, and they often have the same target genes and synergistic effects. Currently, there were more than 300 miRNAs differentially expressed in PCa tissues, and 49 miRNAs detected in serum, 4 in urine samples (    2, we found that the miRNA biomarkers in serum, especially urine samples, were still insufficient, which would be the direction of scientific researchers' efforts. In addition, a large number of studies have begun to focus on multiple miRNAs combined with other indicators to jointly predict PCa and its prognosis, such as PSA (prostate specific antigen), PCA3 (prostate cancer antigen 3) and fusion gene TMPRSS2-ERG, etc. In Table 2, the miQ index was invented by Larne et al. [9]. It could differentiate PCa accurately and had the potential to predict prognosis [9]. This was also an effective strategy to avoid high heterogeneity of PCa.

THE Mechanism Of Micrornas In Prostate Cancer Progression
Most miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and transported out of the nucleus by Exportin-5 during this period. Finally, the mature miRNAs become the 18-25 nt duplexes, assembled into the RNA-induced silencing complex (RISC). Moreover, most mature miRNAs combine with the 3'-UTR of the target messenger RNA, a few mature miRNAs bind to 5'-UTR. Some studies have shown that miRNAs can also combined to the coding regions or the specific sequence promoter of target genes [10][11][12].

The Mechanism Of Abnormal Expression Of Mirnas In Prostate Cancer
miRNAs have dual functions: oncogenic miRNAs can activate carcinogenesis, tumor suppressor miRNAs can inhibit tumor progression. Among them, carcinogenic miRNAs are usually highly expressed in PCa, while tumor suppressor miRNAs are down-regulated. In high-risk PCa and CRPC (Castration Resistant Prostate Cancer), the expression of Dicer and Drosha/DGCR8 was significantly increased, which contributed to the processing and up-regulated the expression of oncogenic miRNAs [13,14]. On the contrary, Drosha or Dicer expression decreased would attenuate mature miRNA biogenesis [15,16]. Myc could inhibit the binding of miR-26a/b to RNA polymerase II, thus affecting its transcription [17].
On the other hand, the genes that encoded tumor suppressor miRNAs were deleted in 60% of PCa samples [18,19]. Mutations or polymorphisms of tumor suppressor miRNAs might also lead to down-regulation of their expression, and increase the susceptibility to PCa [20,21]. In addition, methylation of the promoters of tumor suppressor miRNAs also reduced their expression, increasing the risk of PCa [22][23][24].
In addition to the above mentioned mechanisms leading to abnormal miRNAs expression, it was worth mentioning that the absence or variation of target genes was also one of the important reasons for the development of PCa. Feng et al. found that the C/T polymorphism of BMPRlB located in the 3'-UTR of this gene where was the binding site of miR-125b, could cause miR-125b not to bind to this region and lose its regulatory role, increasing the risk of cancer [25,26].

Micrornas Associated With Androgen Receptor Signaling Pathways
Early clinical PCa was mostly androgen-sensitive, but some of these cases would progress to incurable CRPC or metastatic PCa after initial treatment or ADT. These suggested that androgen receptor (AR) played an important role in the evolution of PCa. AR is a nuclear hormone receptor as a transcription factor to regulate the expression of a large number of downstream target genes. Previously, we had reviewed miRNAs related to AR signaling pathways [27]. In the review, we had not only summarized many miRNAs regulated by AR, but also gathered the miRNAs that directly and indirectly regulated AR [27].

MicroRNAs associated with metastatic prostate cancer and CRPC
Metastasis and castration resistance were two characteristics of advanced PCa. EMT (epithelial to mesenchymal transition) was the important performance of metastasis, while MET (mesenchymal to epithelial transition) was the phenotype of benign reversion of PCa. The researchers commonly used interdermal markers: fibronectin, ZEBl, ZEB2, vimentin, ZO1, snail and epithelial marker: E-cadherin, to monitor the occurrence and development of metastasis.

Conclusion
As a group of small non-coding RNA molecules, microRNAs, combined with long non-coding RNAs, jointly regulate complex signal networks with different mechanisms. Are they subordinate or dominant in the occurrence and development of PCa? What are the mechanisms by which they contribute to PCa? These questions are far from being answered by researchers. We still need a lot of further researches to reveal the rules, and to provide the powerful theoretical basis for early diagnosis, prognosis prediction and targeted treatment for PCa.