Clinical and Translational Oncology

, Volume 14, Issue 11, pp 803–811

miRNAs as biomarkers in prostate cancer

Authors

  • Irene Casanova-Salas
    • Laboratory of Molecular BiologyFundacion Instituto Valenciano de Oncologia
  • José Rubio-Briones
    • Department of UrologyFundacion Instituto Valenciano de Oncologia
  • Antonio Fernández-Serra
    • Laboratory of Molecular BiologyFundacion Instituto Valenciano de Oncologia
    • Laboratory of Molecular BiologyFundacion Instituto Valenciano de Oncologia
Educational Series - Blue Series Advances in Translational Oncology

DOI: 10.1007/s12094-012-0877-0

Cite this article as:
Casanova-Salas, I., Rubio-Briones, J., Fernández-Serra, A. et al. Clin Transl Oncol (2012) 14: 803. doi:10.1007/s12094-012-0877-0

Abstract

Current prostate cancer (PCa) diagnosis is based in the serum prostate-specific antigen biomarker and digital rectal examination. However, these methods are limited by a low predictive value (24–37 %) and a high risk of mistaken results. During last years, new promising biomarkers such as Prostate Cancer Antigen 3 (PCA-3) and TMPRSS2-ETS fusion genes have been evaluated for their clinical use. However, the search of new biomarkers that could be used for PCa diagnosis and prognosis is still needed. Recent studies have demonstrated that the aberrant expression of microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, is related with the development of several cancers, including PCa. Since miRNAs serve as phenotypic signatures of different cancers, they appear as potential diagnostic, prognostic and therapeutic tools. Here, we review the current knowledge of miRNA expression patterns in PCa and their role in PCa prognosis and therapeutics.

Keywords

Prostate cancerBiomarkerMicroRNA

Introduction

Prostate cancer (PCa) is the first most common cancer in men and leads to a 10 % of cancer deaths in Europe [1]. Approximately, one in three men over the age of 50 years shows histologic evidence of PCa. However, only 10 % will be diagnosed with clinically significant PCa, implying that most PCa never progress to become life threatening. Thus far, little is known about what makes some PCas biologically aggressive and more likely to progress to metastatic and potentially lethal disease. Clinical phenotypes of PCa vary from an indolent disease requiring no treatment to one in which tumors metastasize and escape local therapy even when with early detection. Identification of candidate biomarkers for aggressive PCa is a clear need for urologists.

The current standard for the diagnosis of PCa consists of a serum test for prostate-specific antigen (PSA) and digital rectal examination (DRE) [2]. Serum PSA levels above 2.5–4 ng/ml and/or abnormalities felt during DRE may indicate the presence of PCa after a diagnostic biopsy, although the positive predictive value of these methods is only 24–37 %, respectively [2, 3]. Serum PSA levels have other limitations. Non-cancerous conditions such as prostatitis and benign prostatic hyperplasia (BPH) can cause an increase in serum PSA, resulting in a high false-positive rate relative to prostate biopsy [4]. In addition, the widespread use of the serum PSA test has led to an increase in the number of biopsies performed each year, of which many are negative for cancer [5]. Conversely, there is also a significant number of diagnosed PCa with a PSA below 4 ng/ml (estimated at 20–30 %) resulting in undiagnosed disease [6]. Although PSA is a very good marker for monitoring patients after a radical prostatectomy, its utility as a diagnostic marker is far from being optimal. Other promising biomarkers, such as Prostate Cancer Antigen 3 (PCA3) [7] or TMPRSS2-ETS fusion genes [8], are being evaluated for their use in the clinical management of the PCa patients, although we are still waiting for studies with a high grade of evidence. Therefore, there is an urgent need for new and more specific biomarkers to improve diagnosis accuracy and to predict PCa progression. Furthermore, the lack of therapies to deal with those PCa that become resistant to castration and turn into a metastatic cancer underlines the need for developing novel therapeutic targets.

An emerging field of research in recent years has been the microRNAs (miRNAs). miRNAs are small (17–27 nt) non-coding single-stranded RNA molecules that negatively regulate gene expression by binding to imperfect complementary sites within the 3′ untranslated region (UTR) of their mRNA target at the post-transcriptional level. miRNA binding is based in the perfect complementary binding of miRNA’s first nucleotides (2–7  nt) to their corresponding mRNA and a needless equal binding of miRNA’s flanking regions [9]. This process allows a complex regulatory network in which the individual miRNA may target more than 200 different mRNAs and, vice versa, a particular target could be regulated by different miRNAs [10].

Regulatory pathways controlled by miRNAs have been investigated during last years and an association between altered miRNA expression and tumorogenesis has been established [11]. They have been shown to be involved in the regulation of growth, development, invasion, metastasis and prognosis of various cancers, including PCa [12]. Moreover, recent studies demonstrate that miRNA expression patterns serve as phenotypic signatures of different cancers and could be used as diagnostic, prognostic and therapeutic tools [13].

The purpose of this review is to highlight the biological implication of the miRNAs in the pathogenesis of PCa and to discuss their role as potential biomarkers in the clinical management of PCa patients.

miRNA biogenesis

Many miRNAs loci are located within cancer-associated genomic regions. These genes are transcribed by RNA Polymerase II to generate a long double-stranded RNA called pri-miRNA. The RNase enzyme III, Drosha, and the RNA-binding protein Pasha (DGCR8) binds to the pri-miRNA processing it into a shorter (~70 nucleotides) strand known as pre-miRNA. This pre-miRNA, which works as the precursor for mature miRNA synthesis, is transported to the cytoplasm by the RAN-GTP-dependent transporter exportin 5. Once in the cytoplasm, the ribonuclease Dicer processes the pre-miRNA into a miRNA:miRNA* duplex of ~22 nucleotides [14]. Mature miRNA binds to the RNA-induced silencing complex (RISC) and triggers its inhibitory function through silencing its mRNA targets (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs12094-012-0877-0/MediaObjects/12094_2012_877_Fig1_HTML.gif
Fig. 1

miRNA biogenesis. miRNA biogenesis starts with gene translation into immature pri-miRNA, pre-processed by Drosha and Pasha into the Pre-miRNA, which is finally processed by Dicer to obtain the mature miRNA with capacity of binding to the target mRNA at 3′UTR

Some of the mechanisms that lead to an aberrant expression of miRNAs could be caused by epigenetic modification of miRNA gene, mutations in the precursor gene or failure in miRNA processing. For example, expression of Dicer was found to be up-regulated in aggressive PCa, which may be one of the mechanisms of inducing up-regulation of the miRNAs related to prostate tumors [10]. DGCR8, which encodes an essential cofactor for Drosha, was also up-regulated in prostate tumors. Other studies showed that reduced expression of Dicer correlates with shortened postoperative survival in lung cancer [15]. The Argonaute proteins which are crucial components of RISC complex have also been associated with tumor development. AGO1, AGO3 and AGO4 are frequently deleted in Wilms tumors where AGO1 is notably increased in renal tumors that lack Wilms-tumor suppressor gene (WT1). Another Argonaute gene, HIWI, was found to be up-regulated in most testicular seminomas [14].

miRNAs in cancer

The first association of miRNA and tumor biology was described by down-regulation or deletion of miR-15a and miR-16-1 in B cell chronic lymphocytic leukemias [11]. Altered miRNA expression was found to be closely associated with the control of cell growth, differentiation and apoptosis. In fact, miR-15a and miR-16-1 induce apoptosis by targeting the anti-apoptotic gene BCL2 [16].

Later, other studies reported changes of miRNA expression in several cancers. Volinia et al. [17] performed a large-scale miRNome analysis and identified a large portion of overexpressed miRNAs in solid tumors. They found that miR-21, miR-191 and miR-17-5p were significantly overexpressed in all the considered tumor types. However, they also validated particular miRNA signatures for each tumor: miR-125b, miR-145 and miR-21 in breast samples; and miR-103, miR-155 and miR-204 in endocrine pancreatic cancers [17]. Lu et al. [18] analyzed the expression of 217 miRNAs from 334 different human cancer samples and found that miRNA expression was different between tumors of different developmental origin, and there was also a differential expression between tumors and normal tissue. Some of the altered miRNAs found were miR-20, miR-181a, miR-15a, miR-16, miR-17-5p, miR-221, let-7a and miR-2. Most of these differentially expressed miRNAs had lower expression levels in tumors compared with normal tissues [18]. miRNA signatures have also been described in lung cancer [19], colon cancer [20], glioblastoma multiforme [21, 22], lymphomas [23], hepatocellular carcinoma [24], and other tumor types.

Functional studies suggest that those miRNA whose expression is increased in tumors may be considered as oncogenes. These oncogenic miRNAs usually promote tumor development by negatively inhibiting tumor suppressor genes or genes that control cell cycle, differentiation or apoptosis. On the other hand, some miRNAs’ expression is decreased in cancerous cells. These types of miRNAs are considered tumor suppressor genes, which prevent tumor development by negatively inhibiting oncogenes or genes that control cell differentiation or apoptosis [25].

During last years, numerous miRNA expression-profiling studies have been performed to identify cancer-specific signatures, since the miRNA signatures of cancers of different cellular origin seem to be unique.

miRNAs in prostate cancer

The first miRNA expression profile in PCa was carried out by Porkka et al. [12]. They performed an oligonucleotide array hybridization method to study the expression of 319 human miRNAs in PCa and found 51 miRNAs differentially expressed in PCa [12]. Following studies confirmed some of the results achieved by these authors while others showed different expression profiles or newly identified altered miRNAs. Table 1 describes those miRNA involved in the pathogenesis of PCa.
Table 1

miRNAs altered in PCa

miRNA

Expression

Location

Predicted/validated target(s)

Altered function

References

miR-10a

Up-regulated

17q21.32

HOXA1

Gene expression, cell differentiation

[53]

miR-20a

Up-regulated

13q31.3

E2F1-3

Apoptosis

[17]

miR-21

Up-regulated

17q23.1

MARCKS, PDCD4, PTEN, TPM1, SPRY2, TIMP3, RECK

Apoptosis, castrate resistant (CR)

[30]

miR-24

Up-regulated

9q22.32/19p13.13

FAF1

Apoptosis

[39]

miR-25

Up-regulated

7q21.11

PTEN

Cell proliferation, cell cycle

[17, 37, 39, 52]

miR-31

Up-regulated

9p21.3

Bcl-w, E2F6

Apoptosis, cell cycle

[55, 56]

miR-32

Up-regulated

9q31.3

C9orf5, Bim

Apoptosis

[39]

miR-34b

Up-regulated

11q23.1

CDK6, CREB, c-MYC, MET

Cell cycle, cell proliferation

[39, 57]

miR-96

Up-regulated

7q32.2

FOXO1, hZIPs

Apoptosis

[55, 58, 59]

miR-106a

Up-regulated

Xq26.2

RB1

Cell cycle

[17, 37]

miR-125b

Up-regulated

11q24.1/21q21.1

BAK1

Apoptosis, AR, metastasis

[29, 60]

miR-141

Up-regulated

12p13.31

Clock

AR, metastasis

[12, 34, 61]

miR-148a

Up-regulated

7p15.2

CAND1, MSK1

Cell cycle, cell proliferation

[12, 62, 63]

miR-181a-1

Up-regulated

1q31.3

RB1, RBAK

Cell cycle, tumor progression

[39, 64, 65]

miR-182

Up-regulated

7q32.2

FOXO1, FOXO3, BRCA1, hZIP1

Apoptosis

[39, 55, 58, 59, 66]

miR-194

Up-regulated

1q41/11q13.1

DNMT3a, MeCP2

Genomic instability

[40]

miR-200a/b

Up-regulated

1p36.33

β-catenin, SIRT1

EMT, cell growth

[37, 39, 6769]

miR-200c

Up-regulated

12p13.31

SEC23A, JAGGED1

Cell growth, apoptosis, metastasis

[70, 71]

miR-210

Up-regulated

11p15.5

EFNA3, MNT, HOXA1, APC, ELK3

Hypoxia, cell proliferation, migration

[12, 72]

miR-214

Up-regulated

1q24.3

EZH2, N-Ras, PTEN

Cell cycle, cell proliferation

[17, 7375]

miR-218

Up-regulated

4p15.31/5q34

RAS, c-myc, Laminin 5 β3, THAP2, SMARCA5, and BAZ2A

Cell proliferation, apoptosis

[76]

miR-224

Up-regulated

Xq28

KLK1, API-5

Apoptosis, cell proliferation, invasion

[33, 42, 64]

miR-296

Up-regulated

20q13.32

HMGA1

Cell proliferation, invasion

[12, 77]

miR-345

Up-regulated

14q32.2

BAG3

Apoptosis, invasion, metastasis

[12, 78]

miR-375

Up-regulated

2q35

Sec23A

Cell proliferation

[34, 37, 55]

miR-521

Up-regulated

19q13.42

CSA

DNA repair

[79]

miR-26a

Up and down-regulated

3p22.2

PLAG1, EZH2

Apoptosis, cell proliferation, invasion

[12, 17, 64]

miR-30c

Up and down-regulated

1p34.2/6q13

BCL-9, MTA1

Metastasis

[12, 17, 64, 80, 81]

miR-100

Up and down-regulated

11q24.1

RAS, c-myc, Laminin 5 β3, THAP2, SMARCA5, and BAZ2A

Cell proliferation, apoptosis

[12, 64, 76, 82]

miR-125a

Up and down-regulated

19q13.41

ERBB2, ERBB3

Cell proliferation, apoptosis

[12, 39, 83]

miR-195

Up and down-regulated

4p16.1

CDK4, GLUT3, WEE1, CDK6, Bcl-2

Cell cycle, cell proliferation, apoptosis

[12, 39, 64, 8486]

miR-221

Up and down-regulated

Xp11.3

p27kip1

Cell cycle

[12, 40, 55, 87, 88]

miR-222

Up and down-regulated

Xp11.3

p27kip1

Cell cycle

[12, 40, 55, 87]

miR-30b

Up and down regulated

8q24.22

GalNAc, Snail1

Invasion, immunosuppression

[12, 37, 89]

let-7-family

Down-regulated

9q22.32

Ras, Cdc25A, Cyclin D1

Apoptosis, cell proliferation, cell cycle

[82]

miR-1

Down-regulated

20q13.33/18q11.2

Exportin-6, Tyrosine kinase 9, PNP

Cell proliferation, invasion

[39, 90]

miR-7

Down-regulated

9q21.32/15q26.1

ERBB2

Cell proliferation, tumor progression

[91]

miR-16

Down-regulated

13q14.2

Bcl-2, cyclin D1 and D3, CDK1, CDK2

Apoptosis, cell cycle, metastasis

[11, 16, 92]

miR-22

Down-regulated

17p13.3

PTEN

Cell proliferation, cell cycle

[12, 42, 54]

miR-23a/b

Down-regulated

19p13.13/9q22.32

Mitochondrial glutaminase

Advantage in growth

[93, 94, 97]

miR-27b

Down-regulated

9q22.32

CYP1B1, Notch1

Hormone metabolism, cell proliferation

[12, 64]

miR-29a

Down-regulated

7q32.3

Dkk1, Kremen2, sFRP2, B7-H3

Cell differentiation, immune response

[12, 95, 96]

miR-34a

Down-regulated

1p36.22

BCL-2,SIRT1,E2F3, N-MYC, MET, CDK4-6, DLL1

Apoptosis, proliferation, survival

[39, 57, 97, 98]

miR-34c

Down-regulated

11q23.1

CDK4, E2F3, MET, c-MYC

Apoptosis, cell proliferation

[39, 57]

miR-92

Down-regulated

13q31.3/Xq26.2

Bim

Apoptosis

[12, 17, 99]

miR-99a

Down-regulated

21q21.1

SMARCA, SMARCD1, mTOR

Apoptosis, cell cycle

[12, 100]

miR-101

Down-regulated

1p31.3/9p24.1

EZH2

Cell proliferation, invasion

[101]

miR-106b-25

Down-regulated

7q22.1

MCM7

Cell cycle, cell proliferation

[39, 54]

miR-107

Down-regulated

10q23.31

Granulin

Cell proliferation

[17, 102]

miR-126

Down-regulated

9q34.3

CRK, Spred1, PIK3R2/p85-beta

Cell proliferation, invasion, tumor progression

[36, 64, 103, 104]

miR-126*

Down-regulated

9q34.3

Prostein

Metastasis

[36, 105]

miR-128a

Down-regulated

2q21.3

GOLM1, PHB, TROVE2, TMSB10

Tumor progression, invasion

[39, 106, 107]

miR-143

Down-regulated

5q32

MYO6, ERK5, KRAS

Cell proliferation, migration, metastasis

[12, 37, 108, 109]

miR-145

Down-regulated

5q32

MYO6, MYC, BNIP3

Cell migration, metastasis, apoptosis

[12, 40, 64, 110, 111]

miR-146a

Down-regulated

5q34

CXCR4, ROCK1

CR, metastasis

[17, 112]

miR-203

Down-regulated

14q32.33

ZEB2, Bmi, survivin, Runx2

EMT, metastasis

[41]

miR-205

Down-regulated

1q32.2

ErbB3, E2F1, E2F5, ZEB2, Protein Kinase Cε, IL24, IL32

Cell cycle, cell proliferation, apoptosis,EMT

[36, 113, 114]

miR-223

Down-regulated

Xq12

NFI-A

Cell differentiation

[17, 115]

miR-301a

Down-regulated

17q22

FOXF2, BBC3, PTEN, COL2A1

Cell proliferation

[88, 116]

miR-320a

Down-regulated

8p21.3

ETS2

Tumor progression

[37, 117]

miR-330

Down-regulated

19q13.p32

E2F1

Apoptosis

[118]

miR-331-3p

Down-regulated

12q22

ERBB2

Cell cycle

[32]

miR-449a

Down-regulated

5q11.2

HDAC-1

Cell cycle, apoptosis

[39, 119]

A rapidly increasing number of platforms have been developed for miRNA expression profiling. Microarray analysis was the most common method carried out to identify tumor-specific miRNA signatures. However, the arrivals of next generation sequencing (NGS) technologies have offered a new approach in the identification of previously unknown miRNAs [18]. While miRNA array hybridization system is based in the accumulated knowledge of miRNA databases, NGS technologies allow the identification of new miRNA genes. In parallel, qRT-PCR has been established the most suitable technology to validate miRNA expression-profiling results.

Since miRNA expression profiling has been able to classify between health and tumor tissues and even between different prostate tumors, its role as potential clinical biomarkers is being investigated. miRNAs have been found to be remarkably stable in plasma and serum samples, consequently, circulating miRNAs became potential candidates for blood-based biomarkers. Michel et al. [26] showed that serum levels of miR-141 significantly discriminated patients with PCa and healthy controls. Moreover, Taylor and Gercel-Taylor demonstrated the up-regulation of miR-21, miR-141, miR-200, miR-200c, miR-200b, miR-203, miR-205 and miR-214 in circulating cancer exosomes [27]. Some other miRNAs, previously identified in cells and tissues, have also been found in extracellular fluids such as plasma serum, saliva and urine [28]. Urine is an easily available source for molecular markers, therefore, detection of miRNAs in urine of patients with PCa would represent an ideal non-invasive diagnosis approach.

miRNAs and PCa prognosis

Androgen ablation, the mainstay for management of advanced PCa, reduces symptoms in about 70–80 % of patients, but most tumors relapse within 2 years to an incurable castration resistant state, which is ultimately responsible for PCa mortality [13]. On the contrary, for early stage clinically localized disease, radical prostatectomy and radiotherapy are curative; therefore, the choice of the best treatment for a particular PCa is not trivial. For instance, serum PSA level, primary tumor stage and Gleason grade do not reliably predict outcome for individual patients, and an identification of molecular indicators of aggressiveness is still needed.

Androgen signaling has been related with miRNA expression, since some miRNAs have been found to modulate the androgen pathway and further classified prostate carcinomas according to castration resistance [12] (Table 2). For instance, the expression of miR-125b [29] (Fig. 2), miR-21 [30] and miR-141 [31] is regulated by an androgen responsive element (ARE) which controls the up-regulation of these miRNAs and consequently the inhibition of their targets. miR-331-3p is also related with regulation of androgen receptor (AR) pathway since overexpression of its target, ERBB-2, has been related with disease progression and AR signaling [32]. Other miRNAs, such as miR-141, miR-143 (Fig. 3) and miR-145, have been found to be involved in cancer-related cell migration (Table 2). miR-141 is up-regulated in metastatic PCa and its expression was correlated with Gleason score [33, 34]. Loss of expression of miR-143 and miR-145 was related with development and progression of PCa [35] and metastasis [13, 3638] and it was also related with Gleason score [38].
Table 2

miRNAs implicated in PCa prognosis

miRNA

Expression

Prognosis parameter(s)

Target

miR-21

Up-regulated

Castrate resistant PCa (CR)

MARCKS

miR-331-3p

Down-regulated

CR

ERBB-2

miR-141

Up-regulated

CR, Gleason score

Clock

miR-146

Down-regulated

CR, metastasis

CXCR4, ROCK1

miR-125b

Up-regulated

CR, metastasis, tumor stage, perineural invasion (PNI)

BAK1

miR-96

Up-regulated

Biochemical progression, tumor recurrence

FOXO1, hZIPs

miR-1

Down-regulated

Gleason score, pT, recurrence

XPO6, PTK9, PNP

miR-143

Down-regulated

Metastasis

MYO6

miR-145

Down-regulated

Metastasis

MYO6, MYC

miR-16

Down-regulated

Metastasis

Bcl-2

miR-34a

Down-regulated

Metastasis

CD44

miR-126*

Down-regulated

Metastasis

Prostein

miR-301

Down-regulated

Metastasis

FOXF2, BBC3, PTEN, COL2A1

miR-200 family

Down-regulated

Metastasis, Gleason score, tumor stage

ZEB2, Bmi, survivin, Runx2, ErbB3, E2F1, E2F5, PKCɛ

miR-221

Down-regulated

Metastasis, TMPRSS2:ERG presence

p27kip

miR-10

Up-regulated

PNI

HOXA1

miR-100

Up-regulated

PNI

RAS, c-myc, Laminin 5 β3, THAP2, SMARCA5, and BAZ2A

miR-30c

Up-regulated

PNI

BCL-9, MTA1

miR-224

Up-regulated

PNI

KLK1, API-5

https://static-content.springer.com/image/art%3A10.1007%2Fs12094-012-0877-0/MediaObjects/12094_2012_877_Fig2_HTML.gif
Fig. 2

miR-125b function. miR-125b is overexpressed in prostate tumors and seems to play a role in castrate-resistant PCa growth. Androgen stimulation induces an increased miR-125b expression which leads to a suppression of the expression of the pro-apoptotic protein Bak1, which is necessary for the apoptotic cascade. Cyt C, cytochrome c

https://static-content.springer.com/image/art%3A10.1007%2Fs12094-012-0877-0/MediaObjects/12094_2012_877_Fig3_HTML.gif
Fig. 3

miR-143 function. miR-143 is down-regulated in PCa and is inversely correlated with cell proliferation. Down-regulation of miR-143 induces an increased expression of its target ERK5, which is implicated in the regulation of cell proliferation. ERK5 overexpression is associated with metastasis, cell proliferation, motility and invasion. Moreover, miR-143 plays an important role in PCa proliferation by suppressing KRAS and subsequent inactivation of MAPK pathway

PCa metastasis has been also linked with the down-regulation of miR-16, miR-34a, miR-126*, miR-205, miR-146a and the up-regulation of miR-301 and miR-125b (Table 2). miR-126* inhibit the expression of prostein, which is frequently overexpressed in PCa. Interestingly, miR-126, which corresponds to the alternative miR-126* strand, was reported to be up-regulated in metastatic xenograft cell line, suggesting that strand selection mechanism could be involved in the development of metastasis [36]. miR-200 family is regulating the epithelium-mesenchymal transition (EMT) and was found down-regulated in tumor tissues [12, 39, 40]. In fact, miR-203 is progressively lost in advanced metastatic PCa showing a linkage between its expression and an antimetastatic role [41]. miR-146a is down-regulated in metastatic tumors, because it is implicated in the formation of the pre-metastatic niche [42], and in castrate resistant PCa cell lines [43].

Some other miRNAs were also related with Gleason score (miR-1, miR-31 and miR-205), tumor stage (miR-125b, miR-205 and miR-222), pT stage (miR-1), perineural invasion (PNI) status (miR-1, miR-10, miR-30c, miR-100, miR-125b and miR-224) and biochemical progression (miR-96) (Table 2).

Approximately, 50 % of PCa are characterized by the expression of the TMPRSS2-ERG fusion gene [44]. Although the clinicopathological significance of this alteration still remains to be elucidated, there is evidence that the status of the fusion gene defines groups of patients characterized by different prognostic factors [45] that could be taken into consideration in the clinical management of PCa patients. To date, the only association between TMPRSS2-ERG fusion and miRNA expression has been described in a cohort of 170 patients subjected to radical prostatectomy, in which the low expression of miR-221, a miRNA previously linked to metastasis, was significantly associated to the presence of the fusion gene [46].

miRNA therapeutics for PCa treatment

Since miRNAs were described to be involved in tumor initiation, progression and metastasis, their targeting is expected to emerge as an effective therapeutic option for cancer treatment. Different approaches are being developed to modulate the gain or loss of miRNA functions. miRNAs which act as tumor suppressors are usually down-regulated in cancer while miRNAs acting as oncogenes are commonly overexpressed; therefore, restoring its function, in the first case, or inhibiting its expression, in the second one, may become interesting therapeutic options.

To date, there is no PCa model in this field. However, it has been reported that the introduction of miR-26a using adenoassociated virus (AAV) in an animal model of hepatocellular carcinoma inhibited tumor progression [47]. In a similar way to AAV technology, cationic liposomes or polymer-based nanoparticle formulations can be developed to achieve the delivery of miRNA mimics, synthetic miRNAs which are able to restore miRNA function within the tumor cell [48].

Multiple approaches have been designed to achieve miRNAs down-regulation. One of these approaches consist in the introduction of an anti-miRNA oligonucleotide (AMO) which is able to interact between miRNA and its target through competitive inhibition of base-pairing. AMOs against miR-21 have been shown to inhibit the growth of MCM-7 cells [49]. Other study showed that intravenous administration of AMOs against miR-16, miR-122, miR-192 and miR-194 in animals offers efficient and sustained silencing [50]. Introduction of a modified mRNA to carry multiple pairing sites for endogenous miRNAs, known as miRNA sponge, was also tested to inhibit the function of some miRNAs through its real targets [51]. Recent studies down-regulate oncogene miRNAs introducing a synthetic miRNA molecule (anti-miRNA or miRNA inhibitor) which is able to interact by complementarity with the endogenous miRNA and inhibit its function. In another study, several small organic molecules were also screened to find a potential inhibitor of miRNA function. Azobenzene, for example, was found to block miR-21 function acting as a potential inhibitor of miRNA expression [52]. Therefore, miRNA-based therapeutics offer promising results for cancer treatment although they are still far away from clinical application. Nevertheless, there is already a phase I clinical trial for antisense-mediated blocking of liver-specific miR-122 in non-human primates, which resulted in reduced cholesterol synthesis and improved fatty acid metabolism [48].

Hence, we can conclude stating that there is no agreement in which would be the miRNA-profiling signature of PCa. However, it is patent the relevance of some miRNAs (Table 1) that appear strongly up- or down-regulated in prostate tumors and could even classify PCa regarding tumor stage, castration resistance or invasion capacity. These miRNAs represent potential factors for PCa diagnosis and prognosis and promising therapeutic tools. Nevertheless, further studies should be performed to obtain a better knowledge of the particular function and relation with PCa development of these high-potential biomarkers.

Acknowledgments

This study is supported by Grants FIS PI10/01206 and FI11/00505 from the Instituto de Salud Carlos III; and ACOMP12/029 from the Generalitat Valenciana.

Conflict of interest

None.

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2012