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MicroRNAs in Prostate Cancer: Small RNAs with Big Roles
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
Open Access

ISSN: 2155-9899

+44 1223 790975

Review Article - (2015) Volume 0, Issue 0

MicroRNAs in Prostate Cancer: Small RNAs with Big Roles

Ping Mu1*, Su Deng2,3 and Xiaozhou Fan4
1Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, 1275 York Avenue, New York, NY, 10065, USA
2Memorial Sloan Kettering Cancer Center, Developmental Biology Program, 1275 York Avenue, New York, NY, 10065, USA
3Weill Cornell Graduate School of Medical Sciences of Cornell University, Physiology, Biophysics and System Biology Program, 1300 York Avenue, New York, NY, 10065, USA
4Department of Immunology, Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
*Corresponding Author: Ping Mu, Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, 1275 York Avenue, New York, NY, 10065, USA, Tel: 646-888-2139 Email:

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression either by mediating translational repression or reducing the stability of a target mRNA. Deregulated expression of miRNAs is a common feature of human cancers and a growing body of evidence demonstrates the role of miRNAs as either oncogenes or tumor suppressors. Many miRNAs have been reported to be associated with the pathogenesis of primary prostate cancer (PCa) and the development of castration resistant prostate cancer (CRPC). PCa is the most common cancer and second leading cause of cancer death in American men. Although patients with primary PCa can be treated with chemotherapy and hormone therapy, many of them will develop resistance to conventional therapies and progress to a more sever condition called CRPC, which remains one of the most difficult cancers to treat. Since emerging evidence suggests miRNAs’ significant roles in the tumorigenesis of primary PCa and CRPC, the potential of using miRNAs as drug targets and biomarkers for primary PCa and CRPC has been gaining more attention. The aim of this review is to summarize recent studies on the involvements and mechanisms of the actions of several miRNAs in the development and progression of primary PCa and CRPC. Additionally, the potentail applications of using miRNAs as biomarkers and drug targets are briefly discussed.

Keywords: Micro RNA, Prostate cancer, Castration resistance, Oncogene, Tumor suppressor, Biomarker

Introduction

MicroRNA and mechanism of action

MicroRNAs (miRNAs) are small non-coding RNAs which are approximately 19-23 nucleotides in length and regulate gene expression at the post-transcriptional level [1]. More than two thousand miRNAs have been identified in human genomes since their initial identification in the nematode Caenorhabditis elegans [2,3]. miRNAs have been shown to be important regulators of gene expression [4], impacting cell proliferation, apoptosis, differentiation and many other physiological functions. The biogenesis of miRNA starts from its transcription, by RNA Polymerase II, of a longer precursor called pri-miRNA [5]. This pri-miRNA is then cleaved by the Drosha and DGCR8 complex in the nucleus to generate a 70-nucleotide stem-and-loop precursor called pre-miRNA [6-8]. After being exported to the cytoplasm by Exportin-5 [9], pre-miRNA is then cleaved by the RNAse Dicer to yield a 20 base pair miRNA/miRNA* duplex. This duplex is further loaded onto Argonaute (Ago) proteins to form a RNA-induced silencing complex (RISC) [10].

miRNAs suppress their target genes either by mediating translational repression or reducing the stability of a target mRNA via induction of its deadenylation and degradation [11-16]. miRNAs bind to the 3’-untranslated region (3’ UTR) of target mRNAs through partial sequence complementarity [2,3,17] and the critical determinants of binding specificity are the nucleotides from position 2 to position 7, comprising the miRNA “seed sequence” [4,14,18,19]. Thus, miRNAs that have the same “seed sequence” are predicted to have highly overlapping sets of mRNA targets and thus similar biological functions [20].

MicroRNA and carcinogenesis

Deregulated expression of miRNAs is a common feature of human cancers and a growing body of evidence demonstrated the role of miRNAs as either oncogenes or tumor suppressors. miRNAs modulate tumorigenesis through multiple mechanisms. For example, miRNAs have been shown to function as oncogenes by inhibiting key molecules in anti-oncogenic pathways. Deletion of a miRNA that targets and represses oncogenes can lead to the activation of oncogenic pathways [21]. Furthermore, recent reports show that chromosomal translocations can sometimes cause truncation of the 3’ UTRs of oncogenes, leading to loss of miRNA-mediated repression and promotion of oncogenic transformation [22]. Several miRNAs have been frequently reported to act as oncogenic miRNAs in various human cancers, especially in human prostate cancer (PCa), including miR-21, the miR-125 family and the miR-221~222 cluster. Their functions in the carcinogenesis of various human cancers, especially prostate cancer will be discussed in more detail in the next sections.

On the other hand, several miRNAs have been implicated as tumor suppressors based on their frequent deletion or reduced expression in multiple human cancers [23]. Several tumor suppressor miRNAs suppress oncogenic pathways by repressing the expression of critical oncogenes. For example, members of the let-7 family are reported to repress the RAS oncogene in lung cancer [24], decrease the mRNA of MYC, and lead to reduced proliferation in Burkitt lymphoma cells [25]. Several miRNAs have been indicated to act as tumor suppressors in PCa, such as the miR-15a~miR-16-1 cluster, the miR-34 family and miR-200 family. Their roles in modulating carcinogenesis of prostate cancer and other human cancers will be discussed more thoroughly later.

Prostate cancer and castration resistance

Prostate cancer is the most common cancer among American men, with 220,800 estimated new cases in 2015. Typically, patients with localized prostate cancer are treated with radical prostatectomy or primary radiation therapy and around 70% of those patients are cured. However, approximately 30% of patients will relapse and require hormone therapy in the form of androgen deprivation, also called “chemical castration”. Patients receiving this conventional hormone therapy will typically be treated with agents such as leuprolide, which lowers serum testosterone and is often combined with antiandrogens such as bicalutamide. Although these conventional agents are initially effective, most patients will eventually develop resistance to hormone therapy. This relapsed disease is called castration-resistant prostate cancer (CRPC) and is responsible for almost all prostate cancer deaths in the US (~30,000 annually). This makes prostate cancer the second leading cause of cancer death amongst American men. Although CRPC can be treated with taxane-based chemotherapy, this kind of treatment provides only a moderate survival benefit of 1-2 months [26,27]. Since none of the conventional therapies can provide significant clinical benefit, CRPC remains one of the most difficult cancers to treat.

A notable characteristic of CRPC is its tremendous amount of genetic heterogeneity [28], which dramatically increases the difficulty in developing effective therapies. One of the primary mechanisms of resistance to antiandrogen therapy is elevated androgen receptor (AR) expression, which is not only required but is also sufficient to restore AR activity and CRPC growth [29]. Based on this finding, several second-generation antiandrogens have been developed, such as enzalutamide and ARN-509 [30,31]. Compared to first-generation antiandrogens, these second-generation antiandrogens have much higher binding affinities to AR and also have significant clinical activities in patients with chemotherapy-refractory CRPC [32,33]. However, despite the exciting clinical success of second-generation antiandrogens, many patients showed only a modest response and some of the initial responders quickly developed resistance again [32,33]. The vast genetic heterogeneity of CRPC and highly variable responses to antiandrogens limit the clinical benefit of hormone therapy, underscoring the importance of developing novel biomarkers and drug targets. Because of the critical roles of miRNAs in regulating PCa carcinogenesis and conferring castration resistance, miRNAs may serve as good candidates for both drug targets and biomarkers in primary PCa and CRPC.

Roles of MicroRNAs in Prostate Cancer and Castration Resistance

Deregulation of miRNAs in PCa

The deregulation of miRNAs has been frequently reported in primary PCa and also CRPC samples [34-36]. Porkka and colleagues have profiled the miRNA expression in 6 PCa cell lines, 9 PCa xenografts samples, 4 benign prostatic hyperplasia (BPH), and 9 PCa tumor samples. In this study they demonstrated 51 individual miRNA have been differentially expressed and the miRNAs expression profile can be used to further cluster the tumor samples into hormone naïve versus hormone refractory PCa [35]. This data not only demonstrates the important role of miRNAs in mediating PCa carcinogenesis, but also suggests that miRNAs can be useful as novel therapeutic targets or biomarkers for diagnosis and classification of PCa. Recently, more than 50 miRNAs have been reported to be involved in PCa carcinogenesis and the functions of many have been identified as well, including miR-21, miR-32, miR148a, miR-221~222, miR-616, miR-15a~16-1, miR-200, miR-101, miR-126, miR-330, miR-34 family and miR-125 family. The function of these miRNAs in PCa is summarized in Table 1.

miRNA Expression1 Role in PCa Mediated Function Validated Target Genes Castration Resistance2 Biomarker Application
miR-21 Upregulated Oncogene Viability, invasion, apoptosis, migration MARCKS, TPM1, PDCD4 Yes Diagnostic, prognostic, predictive
miR-221~222 Upregulated Oncogene Proliferation CDKN1B, HECTD2, IRF2, RAB1A, SOCS3 Yes Diagnostic, prognostic
miR-125 Upregulated Oncogene Apoptosis, proliferation BAK1, EIF4EBP1, TP53, PUMA, ARF Yes  
miR-32 Upregulated Oncogene Apoptosis BTG2 Yes  
miR-148a Upregulated Oncogene Proliferation PIK3IP1    
miR-616 Upregulated Oncogene Proliferation TFPI-2 Yes  
miR-34 Downregulated Tumor suppressor Proliferation, apoptosis, metastasis, EMT3 Cyclin-E2, CDK6, E2F5, E2F1, E2F3, BCL2, CD44   Diagnostic
miR-15~16 Downregulated Tumor suppressor Proliferation, invasion, metastasis CDK1, CDK2, BCL2, CCND1, WNT3A   Diagnostic
miR-141/200 Downregulated Tumor suppressor EMT3 ZEB1, ZEB2, SNAIL2   Diagnostic, prognostic
Let-7 Downregulated Tumor suppressor Proliferation, clonogenicity MYC Yes Diagnostic, prognostic
miR-101 Downregulated Tumor suppressor Proliferation, invasion, metastasis EZH2    
miR-126 Downregulated Tumor suppressor Viability, invasion, migration Prostein    
miR-146a Downregulated Tumor suppressor Proliferation, invasion, metastasis ROCK1 Yes  
miR-330 Downregulated Tumor suppressor Proliferation, apoptosis E2F1    

1PCa cohort vs Benign cohort
2Involved in the development of Castration Resistant Prostate Cancer (CRPC)
3EMT: epithelial mesenchymal transition

Table 1: Summary of studies on deregulated miRNAs in PCa.

miRNAs and androgen receptor (AR) signaling

As discussed above, the signaling pathway related to androgen receptor (AR) plays crucial role not only in the carcinogenesis of primary PCa, but also in the development of CRPC. A deregulated level of AR expression is one of the primary mechanisms of resistance to antiandrogen therapy, which restores the AR signaling and promotes the growth of CRPC [29]. Another known mechanism of resistance to hormone therapy is mutations in AR. For example, F876L, an identified mutation in AR, can convert antiandrogen enzalutamide into an AR agonist and lead to resistance to therapy [37]. Because of the importance of AR signaling, the interactions of AR and several miRNAs play crucial roles in the carcinogenesis of PCa and development of CRPC.

A good example is miR-21, whose promoter has an androgen-response element (ARE). Androgen-induced AR can directly bind to the promoter of miR-21 and cause the overexpression of miR-21, consequently leading to castration-resistant growth of the PCa cell line [38]. Another microRNA with an ARE in its promoter is miR-125b-1, which can be directly regulated by AR binding to its promoter region and recruiting chromatin remodelers EZH2 or JMJD3. Repression of miR-125b-1 by androgen actually protects some target genes, such as the prostate cancer growth factor IGF1R, from degradation, which rescues the androgen-induced cell proliferation in LNCaP cells [39]. miR-141, one member of the miR-200 family, is also regulated by AR in both PCa cell lines and xenografts. Up-regulation of AR leads to ectopic overexpression of miR-141 and enhanced LNCaP cell growth [40]. Two other important targets of miR-141 are PTEN and CDKN1B (p27), which are also important mediators of AR-signaling-regulated proliferation and apoptosis [41,42]. The expression level of miR-34a is negatively correlated with AR level and reduced miR-34a expression confers paclitaxel resistance via derepression of its target BCL2 [43]. Rokhlin et al. reported that cooperation between miR-34a and miR-34c plays a crucial role in AR-dependent p53-mediated apoptosis in PCa cell lines [44]. miR-221 and miR-222 are two other miRNAs being down-regulated by AR signaling in PCa. Stable overexpression of miR-221 in LNCaP cells reduces the transcription of a group of androgen-responsive genes and confers androgen independent growth [45]. Down-regulation of miR-15a and miR-16-1 is also very common in advanced PCa. Restoration of miR-15a and miR-16-1 in the 13q14-defective LNCaP androgen-dependent cell line leads to growth arrest and apoptosis, possibly due to targeting BCL2 and CCND1 [46].

Since miR-21, miR-221~222, miR-15a~16-1, miR-200 family (miR-141), miR-34 family and miR-125 family are among the most thoroughly studied miRNAs in PCa and their functions are closely regulated by AR signaling, we will discuss their function in PCa in more detail in next section. Moreover, their relationships with AR signaling and related cellular function are summarized in Figure 1. Limited by the scope of this manuscript, other PCa related miRNAs will only be briefly summarized in Table 1 as well.

clinical-cellular-immunology-miRNA-families

Figure 1: Schematic representation of selected miRNA families and their roles in regulating common signalling pathways in PCa carcinogenesis. AR: Androgen Receptor; ARAs: Androgen Receptor-Associated Coregulators; HSPs: Heat Shock Proteins; LH-RH agonists: Luteinizing Hormone-Releasing Hormone agonists; GnRH agonists: Gonadotropin-Releasing Hormone agonists; ARE: Androgen Response Element; PSA: Prostate-Specific Antigen; Inhibitory regulation is represented as red bars; promoting regulation is represented as green arrow.

Oncogenic miRNAs in PCa

miR-21: Among the oncogenic miRNAs in PCa, miR-21 is one of the most thoroughly studied. The oncogenic role of miR-21 is strongly suggested by the observation that it is overexpressed in many different human cancers, including diffuse large B cell lymphoma, acute myeloid leukaemia, chronic lymphocytic leukaemia and Hodgkin’s lymphoma [47-50]. Overexpression of miR-21 in a transgenic mouse model leads to a pre-B malignant lymphoid-like phenotype and the tumors regress completely when miR-21 is inactivated [51]. In addition, overexpression of miR-21 in another transgenic mouse model (CAG-miR-21; K- rasLA2) leads to enhanced tumorigenesis of non-small-cell lung cancer (NSCLC), by repressing multiple negative regulators (Spry1, Spry2, Btg2, Pdcd4) of the Ras/MEK/ERK pathway. In contrast, genetic deletion of miR-21 results in impaired Ras-driven tumor development [52].

In prostate cancer, overexpression of miR-21 has been demonstrated in androgen-independent, more malignant, and metastatic PCa cell lines, including PC-3 and DU-145. Interestingly, its expression is barely detectable in the androgen-dependent LNCaP cell line. In this study, Li et al. also showed that suppression of miR-21 decreases the motility and invasion of PCa cell lines, driving them to undergo apoptosis through modulating the target genes such as MARCKS, TPM1 and PDCD4 [53]. Ribas et al. reported that AR directly binds to the miR-21 promoter miPPR-21 and leads to miR-21 overexpression, thus elevating the level of miR-21 that is required for androgen- dependent PCa growth. More interestingly, overexpression of miR-21 alone is sufficient to confer castration resistance to androgen-dependent PCa tumors [38]. miR-21’s involvement in mediating androgen-independent growth of PCa was shown in yet another study, in which reduced expression of miR-21 in an androgen-independent PC-3M-MM2 cell line lead to reduced cell viability, migration and invasiveness. The expression and function of miR-21 in this cell line is dependent on Akt signaling [54].

Notably, miR-21’s potential application as both a diagnostic and prognostic biomarker in PCa has also been demonstrated by Yaman Agaoglu et al., who found that the miR-21 level was not only significantly higher in the blood plasma of 26 patients with localized PCa compared to 20 healthy controls, but also higher in the serum of advanced prostate cancer patients compared to localized PCa patients [55]. Furthermore, serum level of miR-21 is highest in patients with CRPC compared to patients with androgen-dependent PCa, which suggests its potential to be utilized as a predictive biomarker as well [56]. More recently, high stromal expression of miR-21 has been proved to be associated with poor biochemical recurrence-free survival after radical prostatectomy in PCa patients with high Gleason score [57].

The miR-221~222 cluster: Another member of the PCa related oncogenic miRNA is the miR-221~222 cluster. The miR-221~222 cluster is frequently overexpressed in a variety of human cancers, including prostate carcinoma, glioblastoma, thyroid papillary carcinoma, non-small cell lung cancer, breast cancer and diffuse large B cell lymphoma [58-63]. Notably, the fact that the ectopic expression of the miR-221~222 cluster is at a much higher level in the androgen-independent PCa cell lines (DU-145 and PC-3) than it is in androgen-dependent lines (LNCaP and VCaP), strongly indicates the possible role of the miR-221~222 cluster in conferring androgen-independent growth [58,64]. Sun and colleagues have confirmed the critical role of miR-221~222 in conferring castration resistance by showing that overexpression of this cluster in the LNCaP cell line greatly attenuated the dihydrotestosterone (DHT) induced up-regulation of prostate- specific antigen (PSA) and promoted androgen-independent growth of this androgen-dependent PCa cell line. Moreover, this androgen-independent growth is largely dependent on an ectopic level of miR-221~222 because knock-down of this cluster restored the response to DHT induction of PSA [65]. One of the known mechanisms underlying miR-221~222 mediated castration resistance is their direct binding to and suppression of the p27Kip1 gene [58-66], consequently rescuing PCa cells from cell cycle arrest at the G1 phase. miR-221~222 has also been reported to suppress HECTD2 and RAB1A genes and the down-regulation of HECTD2 significantly enhances AR mediated transcription and androgen-independent PCa cell growth [45]. Similar results have been reported in vivo. Mercatelli et al showed that anti-miR-221-222 antagomir treatment in the castration resistant PC-3 xenografting model led to reduced tumor growth by removing the inhibition on p27 [66]. Yang et al., also reported that down-regulation of miR-221 and miR-222 leads to decreased cell proliferation, migration and increased apoptosis in androgen-independent PCa cell line [67].

Similar to miR-21, miR-221 has been reported to be upregulated in the blood plasma in patients with localized PCa compared to healthy individuals, suggesting its potential to be used as a diagnostic biomarker for localized PCa. miR-221 is also more highly expressed in advanced PCa patients compared to localized PCa patients, suggesting its potential to be a prognostic biomarker as well [55]. miR-221 is recently reported as an independent predictor for cancer-related death of high-risk PCa patients, by partially regulating JAK/STAT signaling pathway [68].

The miR-125 family: In contrast to miR-21 and miR-221~222, the relationship between the miR-125 family and carcinogenesis is much more complicated because its members have been reported to function as either tumor suppressor miRNAs or oncogenic miRNAs in different types of tumors [69,70]. The miR-125 family is highly conserved and consists of three miRNAs: miR-125a, miR-125b-1 and miR-125-2. Considering the oncogenic properties of this family, miR-125b-1 has been reported primarily to promote carcinogenesis in various types of tumors and cell lines. miR-125b-1 have been previously reported to be overexpressed in pancreatic cancer, oligodendroglia cancer and especially in prostate cancer [70-73]. White et al. has reported that miR-125b-1 is overexpressed in all the five AR-positive (CWR22R, PC-346C, LNCaP, cds1, cds2) and four AR-negative (DU145, PC-3, pRNS-1-1, RWPE-1) prostate cancer cell lines [74]. Moreover, the level of miR-125b-1 in PC-3 cell lines is regulated directly by androgen-AR signaling and transfection of synthetic miR-125b-1 promotes androgen-independent growth of LNCaP cells, partially by targeting one of its target genes, BAK1. Since knockdown of BAK1 alone cannot fully restore the effect of overexpressed miR-125b-1, more targets are expected to be involved in mediating miR-125b-1’s function in PCa [72]. Ozen and colleagues examined the miRNA expression profile as well as their potential targets in PCa tumor samples and found that EIF4EBP1 is another miR-125b-1 target involved in mediating PCa carcinogenesis [75]. The other reported miR-125b-1 targets in PCa are TP53 and PUMA [72-74]. More recently, Amir et al. reported that miR-125b-1 represses p14ARF, which releases the suppression on Mdm2 and inhibits p53. Consequently, this inhibits p21 and Puma, leading to suppression of apoptosis in PCa cell lines. Treatment of PCa cells with a miR-125b-1 inhibitor can reverse its action by increasing p14, decreasing Mdm2 and inducing apoptosis [76]. Knock-down of miR-125b-1 using RNA interference in PC-3 prostate cancer cells leads to reduced proliferation, which can be restored by the reintroduction of synthetic mature miR-125b-1 [77]. Taken together, these results confirm the role of miR-125b-1 in conferring castration resistance in prostate cancer.

However, the relationship between miR-125b-1 and AR illustrates a good example of the complexity of miRNA-mediated regulation in PCa carcinogenesis. Sun et al. demonstrated that AR directly binds to the promoter region of miR-125b-1 and down-regulates its expression to protect multiple AR target genes from degradation, such as IGF1R, which plays an important role in carcinogenesis of metastatic CRPC [39]. These results are controversial to the previously demonstrated role of miR-125b-1 in promoting PCa carcinogenesis and conferring castration resistance growth.

Tumor Suppressor miRNAs in PCa

The miR-34 family: MicroRNAs belonging to the miR-34 family, miR-34a, miR-34b and miR-34c, have also been reported to be tumor suppressors and modulators of p53 function in regulating cell cycle arrest and apoptosis [78]. The genomic loci of miR-34a or miR-34b~c are frequently deleted in various human cancers including pancreatic cancer, neuroblastoma, breast cancer, lung cancer and prostate cancer [79-82]. Ectopic expression of miR-34a in the p53 mutant colon cancer cell line or miR-34a~c in human lung fibroblast cells significantly induces cell cycle arrest [83,84] by repressing targets involved in cell cycle regulation, including Cyclin-E2, CDK6 and E2F5 [78,83]. miR-34a can also negatively regulate cell cycle machinery by repressing E2F1 and E2F3 levels [85]. Moreover, the miR-34 family may modulate p53-mediated apoptosis by repressing the expression of the anti-apoptotic protein Bcl2 [83,86].

In prostate cancer, doxorubicin (DOX) treatment led to 3-fold increase of miR-34a and apoptosis, which can be counterbalanced by knocking down AR. Interestingly, this DOX induced miR-34 up-regulation does not exist in AR-negative PCa cell lines such as DU-145 and PC-3, or AR-positive LNCaP cells being cultured in androgen free medium. Moreover, the AR-dependent inhibition of p53 suppressed the expression level of both miR-34a and miR-34c. On the other hand, simultaneous inhibition or forced overexpression of both miR-34a and miR-34c modulated the apoptosis induced by DOX [44]. It is reported that prostate cancer stem cells (CSCs) are enriched in the CD44+ population and that miR-34a is under-expressed in these CSCs isolated from xenograft and primary tumors. Enforced expression of miR-34a in these prostate CSCs cells inhibited tumor regeneration and metastasis, while the expression of antagomirs against miR-34a promoted carcinogenesis and metastasis. miR-34a’s function in modulating prostate CSCs survival is due to its targeting of CD44 because knockdown of CD44 can recapitulate miR-34a overexpression in prostate CSCs [87]. Members of the miR-34 family have potential to be diagnostic markers since they are significantly overexpressed in the serum of patients with stages 3 and 4 PCa compared to normal control cohorts.

As discussed above, since one miRNA can simultaneously regulate hundreds of target genes and its regulation is frequently modest [11,15], the relationship between miRNAs and their targets can be very complicated. Although many previous in vitro studies have proposed miR-34 family as key downstream effectors of p53 and that they have crucial roles in regulating PCa carcinogenesis, miR-34 is not required for p53-mediated cell cycle arrest or apoptosis in a miR-34-deficient mouse model. Furthermore, in contrast to previous in vitro studies, genetic ablation of miR-34 is not sufficient to accelerate tumorigenesis in different in vivo settings [88]. More recently, Cheng et al. reported that prostate epithelium-specific co-inactivation of both miR-34 and p53 significantly expands the prostate stem cell compartment and develop adenocarcinomas, while inactivation of either one has no such effect [89]. These results suggest that the function of certain miRNA in carcinogenesis is highly contextual and condition dependent.

The miR-15a~miR-16-1 cluster: Another notable member of the family of tumor suppressor miRNAs is the miR-15a~miR-16-1 cluster. The genomic region of the miR-15a~miR-16-1 cluster (13q14) is deleted in more than half of B cell chronic lymphocytic leukemias (B- CLL) [90]. Deletion of miR-15a~miR-16-1 promotes the development of clonal lymphocytosis in the peripheral blood and leads to B-CLL in mice [91]. Furthermore, altered expression of miR-16-1 is associated with the development of autoimmune and B lymphoproliferative disease (B-LPD) in New Zealand black (NZB) mice, a mouse model for human chronic lymphocytic leukemia (CLL) [92]. In prostate cancer, miR-15a and miR-16-1 levels are significantly down-regulated compared to normal prostate. Bonci et al. knocked-down miR-15a and miR-16-1 by antagomirs and reported an increase in proliferation and invasiveness of untransformed prostate cells. Furthermore, restoration of miR-15a and miR-16-1 in the 13q14-defective LNCaP androgen-dependent cell line leads to growth arrest, apoptosis and marked regression of prostate tumor xenografts [46]. Transfection of synthetic miR-16-1 alone is sufficient to reduce cell proliferation of various PCa cell lines, such as 22Rv1, DU-145, PC-3M-luc and PPC-1. Injection of synthetic miR-16-1 in the therapeutic bone metastasis mouse model (PC-3M-luc xenograft model) significantly inhibits the progression of prostate tumors in bone. This antitumorigenic effect of miR-16-1 is likely due to its targeting of CDK1 and CDK2 associated with cell cycle control and cellular proliferation [93]. Although the miR-15a~miR-16-1 cluster is also reported to target multiple oncogenes including BCL2, CCND1 (encoding cyclin D1) and WNT3A in prostate cancer [46,94], the identities of the critical targets of these miRNAs remains unclear [21]. Moreover, serum level of miR-16 has been reported to be up-regulated in patients with stages 3 and 4 PCa compared to normal donors, suggesting its potential to be used as a diagnostic marker of PCa [95].

The miR-200 family: The miR-200 family consists five miRNAs belonging to two clusters: the miR-200a/b/429 cluster (miR-200a, miR-200b, miR-429) and the miR-200c/141 cluster (miR-200c and miR-141), which are located on chromosomes 1p36 and 12p13 in humans. The seed sequences of these two clusters only differ by one nucleotide and their target genes largely overlap [96]. The critical role of the miR-200 family in carcinogenesis was first demonstrated by the feedback loop between its family members and transcription factors of the ZEB family (ZEB1 and ZEB2) in controlling the epithelial–mesenchymal transitions (EMT) program. Overexpression of miR-200b and miR-200c repress ZEB2 (also termed ZFHX1B) and ZEB1 (also termed TCF8) and increase E-CADHERIN expression [97,98]. The transcription of miR-200c and miR-141 are regulated by DNA methylation of a CpG island near their transcription start sites. Interestingly, this CpG island is aberrantly methylated in PC-3 prostate cancer cells, which leads to a loss of expression of miR-200c and miR-141, while this island and correlated miR-200c/miR-141 expression in LNCaP and DU-145 prostate cancer cells are not changed [99]. Kong et al. also reported that the miR-200 family is significantly down-regulated in PC-3 cells with platelet-derived growth factor-D (PDGF-D) overexpression and an EMT phenotype, which can be reversed by re- expression of miR-200b. Furthermore, transfection of PC-3 PDGF-D cell (which has an EMT phenotype) with miR-200b leads to inhibition of cell migration and invasion, due to the suppression of ZEB1, ZEB2 and SNAIL2 [100]. Small molecules have also been used to target the miR-200 family. Li et al. treated gemcitabine-resistant pancreatic cancer cells with 3,3’-diindolylmethane (DIM) and isoflavone, resulting in increased expression of miR-200 and a reversed EMT process [101]. Williams et al. also reported overexpression of miR-200b inhibits the EMT, growth and metastasis potential of PC-3 cells [102]. Similar results were also confirmed in another EMT model of DU145-LN4 that decreased expression of miR-200 family induced and EMT phenotype [103].

Since the level of miR-141 was found to be correlated with serum PSA level, the miR-200 family also has promising potential to be used as a diagnostic biomarker for PCa [104]. Serum levels of miR-141 and miR-200b have been found to be significantly higher in advanced PCa patients compared to localized PCa patients, and their levels are elevated with increasing tumor stage as well [105,106]. These results strongly suggest the potential application of using the miR-200 family as prognostic biomarkers.

Conclusion and Future Challenges

Although the study of miRNAs’ function in prostate cancer carcinogenesis only began less than a decade ago, huge progress has been made in demonstrating the critical role of miRNA in primary PCa carcinogenesis, as well as in the development of castration resistant prostate cancer. More than 50 miRNAs have been reported to be involved in PCa carcinogenesis and the functions of many have been identified as well, including miR-21, miR-32, miR148a, miR-221~222, miR616, miR-15a~16-1, miR-200, miR-101, miR-126, miR-330, miR-34 family and miR-125 family. Limited by the scope of this review, we only discussed those most thoroughly studied in PCa (others were also summarized in Table-1). As discussed above, these miRNAs play important roles in modulating the progression of PCa tumors and are also involved in the development of castration resistance in CRPC. Because of the high genetic heterogeneity, CRPC is still one of the most difficult cancers to treat with conventional chemotherapy and hormone therapy, underscoring the importance of developing novel biomarkers and drug targets. Therefore, miRNAs’ potential for use as treatment targets and biomarkers in PCa has attracted continued attention in recent years. However, there are still many challenges and more work need to be done to address these challenges.

One of the future challenges is effectively identifying the key targets of miRNAs in PCa carcinogenesis, because one miRNA can simultaneously regulate hundreds of target genes and its regulation is frequently modest [11,15]. Many new approaches have been developed in recent years for this purpose, such as HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) and SILAC (stable isotope labeling with amino acids in cell culture) [11,107,108]. Combined with RNA-Seq and functional library screening, the identification of function relevant miRNA targets in PCa is much more effective. Another challenge in utilizing miRNAs as novel drug targets for PCa is developing antagonist and delivery system with high efficiency and specificity. Various types of chemically modified anti-miRs have been utilized to repress miRNAs, such as locked nucleic acid oligonucleotides (LNAs), polylysine- conjugated peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) [109-112]. However, because the cellular internalization of these hydrophobic, large anti-miRs is often ineffective, a more efficient delivery system needs to be developed. Some attempts have been made to enhance the cellular uptake of anti-miRs by conjugating the antisense oligonucleotides with cell-penetrating peptides (CPPs), such as Tat, Ant, MPG and more recently, Polymer nanoparticles (NPs) [109,113,114].

Overall, because of the complicated relationship between miRNAs and their targets in different cell contexts, there is still a lot of work to be done to determine the key mechanisms by which miRNAs regulate PCa carcinogenesis and confer castration resistance, and design novel agents and effective delivery approaches for miRNA targeting therapy.

Acknowledgement

We thank Elizabeth Hoover for editing the manuscript and members of the Sawyers laboratory for helpful discussions. The authors greatly acknowledge Dr. Charles L. Sawyers’ support on this project.

References

  1. Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5: 396-400.
  2. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegansheterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843-854.
  3. Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75: 855-862.
  4. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115: 787-798.
  5. Lee Y, Kim M, Han J, Yeom KH, Lee S, et al. (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23: 4051-4060.
  6. Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432: 231-235.
  7. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, et al. (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432: 235-240.
  8. Lee Y, Ahn C, Han J, Choi H, Kim J, et al. (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415-419.
  9. Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303: 95-98.
  10. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentateribonuclease in the initiation step of RNA interference. Nature 409: 363-366.
  11. Baek D, Villén J, Shin C, Camargo FD, Gygi SP, et al. (2008) The impact of microRNAs on protein output. Nature 455: 64-71.
  12. Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, et al. (2005) Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122: 553-563.
  13. Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S, et al. (2006) Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312: 75-79.
  14. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, et al. (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769-773.
  15. Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58-63.
  16. Wu L, Fan J, Belasco JG (2006) MicroRNAs direct rapid deadenylation of mRNA. ProcNatlAcadSci U S A 103: 4034-4039.
  17. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9: 102-114.
  18. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, et al. (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27: 91-105.
  19. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15-20.
  20. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215-233.
  21. Ventura A, Jacks T (2009) MicroRNAs and cancer: short RNAs go a long way. Cell 136: 586-591.
  22. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315: 1576-1579.
  23. Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10: 704-714.
  24. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, et al. (2005) RAS is regulated by the let-7 microRNA family. Cell 120: 635-647.
  25. Sampson VB, Rong NH, Han J, Yang Q, Aris V, et al. (2007) MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67: 9762-9770.
  26. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, et al. (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351: 1513-1520.
  27. TannockIF, de Wit R, Berry WR, Horti J, Pluzanska A, et al. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351: 1502-1512.
  28. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, et al. (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18: 11-22.
  29. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, et al. (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33-39.
  30. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, et al. (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72: 1494-1503.
  31. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, et al. (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324: 787-790.
  32. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, et al. (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375: 1437-1446.
  33. Scher H, Fizazi K, Saad F, Taplin ME, Sternberg CN, et al. (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367: 1187-1197.
  34. Mattie MD, Benz CC, Bowers J, Sensinger K, Wong (2006) Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5:24.
  35. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, et al. (2007) MicroRNA expression profiling in prostate cancer. Cancer Res 67: 6130-6135.
  36. Prueitt RL, Yi M, Hudson RS, Wallace TA, Howe TM, et al. (2008) Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate 68: 1152-1164.
  37. Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, et al. (2013) Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife 2: e00499.
  38. Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, et al. (2009) miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 69: 7165-7169.
  39. Sun D, Layer R, Mueller AC, Cichewicz MA, Negishi M, et al. (2014) Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells. Oncogene 33: 1448-1457.
  40. Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, et al. (2011) Androgen regulation of micro-RNAs in prostate cancer. Prostate 71: 604-614.
  41. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, et al. (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19: 575-586.
  42. Chen P, Guo X, Zhou H, Zhang W, Zeng Z, et al. (2013) SPLUNC1 regulates cell progression and apoptosis through the miR-141-PTEN/p27 pathway, but is hindered by LMP1. PLoS One 8: e56929.
  43. Kojima K, Fujita Y, Nozawa Y, Deguchi T, Ito M (2010) MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate 70: 1501-1512.
  44. Rokhlin OW, Scheinker VS, Taghiyev AF, Bumcrot D, Glover RA, et al. (2008) MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer BiolTher 7: 1288-1296.
  45. Sun T, Wang X, He HH, Sweeney CJ, Liu SX, et al. (2014) MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene 33: 2790-2800.
  46. Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, et al. (2008) The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14: 1271-1277.
  47. Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, et al. (2007) Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 109: 4944-4951.
  48. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Löwenberg B (2008) MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111: 5078-5085.
  49. Lawrie CH, Soneji S, Marafioti T, Cooper CD, Palazzo S, et al. (2007) MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer 121: 1156-1161.
  50. Navarro A, Gaya A, Martinez A, Urbano-Ispizua A, Pons A, et al. (2008) MicroRNA expression profiling in classic Hodgkin lymphoma. Blood 111: 2825-2832.
  51. Medina PP, Nolde M, Slack FJ (2010) OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467: 86-90.
  52. Hatley ME, Patrick DM, Garcia MR, Richardson JA, Bassel-Duby R, et al. (2010) Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18: 282-293.
  53. Li T, Li D, Sha J, Sun P, Huang Y (2009) MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. BiochemBiophys Res Commun 383: 280-285.
  54. Sheth S, Jajoo S, Kaur T, Mukherjea D, Sheehan K, et al. (2012) Resveratrol reduces prostate cancer growth and metastasis by inhibiting the Akt/MicroRNA-21 pathway. PLoS One 7: e51655.
  55. YamanAgaoglu F, Kovancilar M, Dizdar Y, Darendeliler E, Holdenrieder S, et al. (2011) Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol 32: 583-588.
  56. Zhang HL, Yang LF, Zhu Y, Yao XD, Zhang SL, et al. (2011) Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate 71: 326-331.
  57. Melbø-Jørgensen C, Ness N, Andersen S, Valkov, Dønnem T, et al. (2014) Stromal expression of MiR-21 predicts biochemical failure in prostate cancer patients with Gleason score 6. PLoS One 9: e113039.
  58. Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, et al. (2007) miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J BiolChem 282: 23716-23724.
  59. Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, et al. (2008) MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene 27: 3845-3855.
  60. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, et al. (2005) The role of microRNA genes in papillary thyroid carcinoma. ProcNatlAcadSci U S A 102: 19075-19080.
  61. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, et al. (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26: 3699-3708.
  62. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, et al. (2008) MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J BiolChem 283: 29897-29903.
  63. Visone R, Russo L, Pallante P, De Martino I, Ferraro A, et al (2007) MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. EndocrRelat Cancer 14: 791-798.
  64. Siva AC, Nelson LJ, Fleischer CL, Majlessi M, Becker MM, et al. (2009) Molecular assays for the detection of microRNAs in prostate cancer. Mol Cancer 8: 17.
  65. Sun T, Wang Q, Balk S, Brown M, Lee GS, et al. (2009) The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res 69: 3356-3363.
  66. Mercatelli N, Coppola V, Bonci D, Miele F, Costantini A, et al. (2008) The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS One 3: e4029.
  67. Yang X, Yang Y, Gan, Zhao, Li W, et al. (2014) Down-regulation of mir-221 and mir-222 restrain prostate cancer cell proliferation and migration that is partly mediated by activation of SIRT1. PLoS One 9: e98833.
  68. Kneitz B, Krebs M, Kalogirou C, Schubert M, Joniau S, et al (2014) Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3. Cancer Res 74: 2591-2603.
  69. Banzhaf-Strathmann J, Edbauer D (2014) Good guy or bad guy: the opposing roles of microRNA 125b in cancer. Cell Commun Signal 12: 30.
  70. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297: 1901-1908.
  71. Nelson NT, Mahomed AJ, Pitcher JM, Tsai BM, Wang M, et al. (2006) Does endogenous testosterone mediate the lower preconditioning threshold in males? J Surg Res 131: 86-90.
  72. Shi XB, Xue L, Yang J, Ma AH, Zhao J, et al. (2007) An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. ProcNatlAcadSci U S A 104: 19983-19988.
  73. Shi XB1, Xue L, Ma AH, Tepper CG, Kung HJ, et al. (2011) miR-125b promotes growth of prostate cancer xenografttumor through targeting pro-apoptotic genes. Prostate 71: 538-549.
  74. DeVere White RW, Vinall RL, Tepper CG, Shi XB (2009) MicroRNAs and their potential for translation in prostate cancer. UrolOncol 27: 307-311.
  75. Ozen M, Creighton CJ, Ozdemir M, Ittmann M (2008) Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27: 1788-1793.
  76. Amir S, Ma AH, Shi XB, Xue L, Kung HJ, et al. (2013) Oncomir miR-125b suppresses p14(ARF) to modulate p53-dependent and p53-independent apoptosis in prostate cancer. PLoS One 8: e61064.
  77. Lee YS, Kim HK, Chung S, Kim KS, Dutta A (2005) Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J BiolChem 280: 16635-16641
  78. He L, He X, Lowe SW, Hannon GJ (2007) microRNAs join the p53 network--another piece in the tumour-suppression puzzle. Nat Rev Cancer 7: 819-822.
  79. Calin GA, Sevignani C, Dumitru CD, Hyslop T, NochE,et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. ProcNatlAcadSci U S A 101: 2999-3004.
  80. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, et al. (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26: 745-752.
  81. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, et al. (2005) MicroRNA expression profiles classify human cancers. Nature 435: 834-838.
  82. Welch C, Chen Y, Stallings RL (2007) MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 26: 5017-5022.
  83. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, et al. (2007) p53-mediated activation of miRNA34 candidate tumor-suppressor genes. CurrBiol 17: 1298-1307.
  84. He L, He X, Lim LP, de Stanchina E, Xuan Z, et al. (2007) A microRNA component of the p53 tumour suppressor network. Nature 447: 1130-1134.
  85. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H (2007) Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. ProcNatlAcadSci U S A 104: 15472-15477.
  86. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, et al. (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26: 731-743.
  87. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, et al. (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17: 211-215.
  88. Concepcion CP, Han YC, Mu P, Bonetti C, Yao E, et al. (2012) Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet 8: e1002797.
  89. Cheng CY, Hwang CI, Corney DC1, Flesken-Nikitin A1, Jiang L2, et al. (2014) miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment. Cell Rep 6: 1000-1007.
  90. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, et al. (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. ProcNatlAcadSci U S A 99: 15524-15529.
  91. Klein U, Lia M, Crespo M, Siegel R, Shen Q, et al. (2010) The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17: 28-40.
  92. Raveche ES, Salerno E, Scaglione BJ, Manohar V, Abbasi F, et al. (2007) Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109: 5079-5086.
  93. Takeshita F, Patrawala L, Osaki M, Takahashi RU, Yamamoto Y, et al. (2010) Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. MolTher 18: 181-187.
  94. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, et al. (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. ProcNatlAcadSci U S A 102: 13944-13949.
  95. Lodes MJ, Caraballo M, Suciu D, Munro S, Kumar A, et al. (2009) Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One 4: e6229.
  96. Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22: 894-907.
  97. Christoffersen NR, Silahtaroglu A, Orom UA, Kauppinen S, Lund AH (2007) miR-200b mediates post-transcriptional repression of ZFHX1B. RNA 13: 1172-1178.
  98. Hurteau GJ, Carlson JA, Spivack SD, Brock GJ (2007) Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67: 7972-7976.
  99. Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, et al. (2010) Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One 5: e8697.
  100. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, et al. (2009) miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells 27: 1712-1721.
  101. Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, et al. (2009) Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 69: 6704–6712.
  102. Williams LV, Veliceasa D, Vinokour E, Volpert OV (2013) miR-200b inhibits prostate cancer EMT, growth and metastasis. PLoS One 8: e83991.
  103. Banyard J, Chung I, Wilson AM, Vetter G, Le Béchec A, et al. (2013) Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci Rep 3: 3151.
  104. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, et al. (2008) Circulating microRNAs as stable blood-based markers for cancer detection. ProcNatlAcadSci U S A 105: 10513-10518.
  105. Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, et al. (2011) Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer 128: 608-616.
  106. Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, et al. (2012) Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer 106: 768-774.
  107. Chi SW, Zang JB, Mele A, Darnell RB (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460: 479-486.
  108. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, et al. (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456: 464-469.
  109. Cheng CJ, Saltzman WM (2012) Polymer nanoparticle-mediated delivery of microRNA inhibition and alternative splicing. Mol Pharm 9: 1481-1488.
  110. Fabani MM, Abreu-Goodger C, Williams D, Lyons PA, Torres AG, et al. (2010) Efficient inhibition of miR-155 function in vivo by peptide nucleic acids. Nucleic Acids Res 38: 4466-4475.
  111. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, et al. (2005) Silencing of microRNAs in vivo with 'antagomirs'. Nature 438: 685-689.
  112. Lennox KA, Behlke MA (2011) Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther 18: 1111-1120.
  113. Astriab-Fisher A, Sergueev D, Fisher M, Shaw BR, Juliano RL (2002) Conjugates of antisense oligonucleotides with the Tat and antennapedia cell-penetrating peptides: effects on cellular uptake, binding to target sequences, and biologic actions. Pharm Res 19: 744-754.
  114. Crombez L, Divita G (2011) A non-covalent peptide-based strategy for siRNA delivery. Methods MolBiol 683: 349-360.
  115. Bullock MD, Pickard KM, Nielsen BS, Sayan AE, Jenei V, et al. (2013). Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression. Cell Death Dis 4: e684.
  116. Yan X, Liang H, Deng T, Zhu K, Zhang S, et al. (2013) The identification of novel targets of miR-16 andcharacterization of their biological functions incancer cells. Molecular Cancer 12: 1.
  117. Mahn R, Heukamp LC, Rogenhofer S, von Ruecker A, Müller SC, et al. (2011) Circulating microRNAs (miRNA) in serum of patients with prostate cancer. Urology 77: 1265.
  118. Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB, et al. (2012) MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS One 7: e32832.
  119. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, et al. (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322: 1695-1699.
  120. Musiyenko, A., Bitko, V., and Barik, S. (2008). Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J. Mol. Med. 86, 313–322.
  121. Lin SL, Chiang A, Chang D, Ying SY (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14: 417-424.
  122. Lee KH, Chen YL, Yeh SD, Hsiao M, Lin JT, et al. (2009) MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. Oncogene 28: 3360-3370.
  123. Ma S, Chan YP, Kwan PS, Lee TK, Yan M, et al. (2011) MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2. Cancer Res 71: 583-592.
Citation: Mu P, Deng S, Fan X (2015) MicroRNAs in Prostate Cancer: Small RNAs with Big Roles. J Clin Cell Immunol 6:315.

Copyright: © 2015 Mu P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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