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Review

A Brief Review of MicroRNA Profiling in Human Prostate Cancer Tissues and Plasma

by
Georgios Kallinikas
1,
Amin M. Ektesabi
2,
Chirag M. Vaswani
2,
Georgios Haronis
1,
Eirini Kallinika
3,
Diomidis Kozyrakis
1,
Evangelos Rodinos
1,
Athanasios Filios
1,
Panagiotis Filios
1,
Despoina Mityliniou
1,
Konstantinos Safioleas
1,
Dimitrios Bozios
1,
Athanasios Karmogiannis
1,
Vasileios Konstantinopoulos
1,
Anna Maria Konomi
1 and
James N. Tsoporis
2,*
1
Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece
2
Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
3
Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
*
Author to whom correspondence should be addressed.
Biomolecules 2025, 15(8), 1156; https://doi.org/10.3390/biom15081156
Submission received: 6 June 2025 / Revised: 17 July 2025 / Accepted: 4 August 2025 / Published: 12 August 2025
(This article belongs to the Collection Molecular Biology: Feature Papers)
Browse Figures
Versions Notes

Abstract

(1) Background: The gold standard, prostate-specific antigen (PSA) screening lacks the sensitivity and specificity required for confident, early prostate-cancer detection. MicroRNAs (miRNAs) are small, highly stable, non-coding RNAs whose expression changes reproducibly in malignancy and therefore offer promise as minimally invasive biomarkers. Although prostate cancer biopsies are the gold standard for prostate cancer diagnosis, limitations in the field continue to persist. Since circulating fluids can also be a source of miRNA biomarkers, we investigated the overlap between miRNAs enriched in prostate cancer tissue and those isolated from the plasma of patients with prostate cancer. (2) Methods: We synthesized the published literature (PubMed, Google Scholar, ResearchGate, 2005–April 2025) and re-analyzed three Gene Expression Omnibus (GEO) datasets (GSE54516, GSE21032—tissue; GSE206793—plasma) to identify miRNAs consistently dysregulated in prostate cancer tissue and circulation. (3) Results: Of the 318 screened full-text articles, 24 met the inclusion criteria. From the GEO reanalysis (false-discovery-rate < 0.05, |log2FC| ≥ 1), 219 and 326 miRNAs were differentially expressed in tissue, whereas 12 were altered in plasma. Two miRNAs—miR-449b and miR-455-3p—were common in both compartments, highlighting their translational potential as liquid biopsy surrogates of tumor biology. (4) Conclusions: We summarize functional evidence for leading tumor-suppressive (e.g., miR-205, miR-23b, miR-455-3p) and oncogenic (e.g., miR-21, miR-182, miR-449b) candidates, discuss their intersection with the androgen-receptor, TGF-β, WNT/β-catenin, and PI3K-AKT signaling, and outline outstanding requirements for the clinical qualification of miRNA panels in prostate cancer.

1. Introduction

Prostate cancer is recognized as the most diagnosed cancer among men worldwide, the second leading cause of cancer among men in the United States, and the third in Europe [1,2]. In 2020, an estimated 375,000 deaths were attributed to prostate cancer globally, and one in eight men are expected to be diagnosed with prostate cancer in their lifetime. The prevalence of prostate cancer ranges from less than 5% in men under 30 years of age to nearly 60% in men over 79. Despite its frequency, most men diagnosed with prostate cancer do not die from it. In the United States, the majority of the 3,300,000 men who have received a diagnosis remain alive. Between 1993 and 2013, a nearly 50% reduction in prostate cancer mortality was observed, primarily attributed to earlier diagnosis. The estimated mean cost for prostate cancer–specific treatment is USD 2935, including USD 2537 before, and USD 6661, after progression to castration-resistant prostate cancer [3]. The etiology of prostate cancer remains largely unknown, although ethnic background and family history are associated with increased incidence, suggesting a genetic implication.
MicroRNAs (miRNAs) have recently garnered significant attention, as the 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun “for the discovery of microRNA and its role in post-transcriptional gene regulation” [4]. A microRNA (miR or miRNA) is a small, non-coding RNA molecule, about 20–25 nucleotides long, that plays a key role in regulating gene expression. Instead of coding for proteins, miRs bind to messenger RNAs (mRNAs), typically at the 3′ untranslated region (3′ UTR), and either block the translation of the mRNA into protein or cause the mRNA to be degraded [5]. This means miRs act like molecular switches, helping to fine-tune which proteins get made and in what amounts. miRs have been linked to developmental, physiological, and behavioral defects in animals [5]. miRNAs occur in both animals and humans [6].
miRNAs are initially transcribed in the nucleus by Polymerase II as “pri-miRNAs,” which possess at least one hairpin region. With the involvement of the Drosha endonuclease and DGCR8 protein, the hairpin loop of pri-miRNA is cleaved to produce “pre-miRNA” [7]. Exportin 5 facilitates the transfer of pre-miRNA to the cytoplasm, where Dicer cleaves both strands near the loop, generating the miRNA–miRNA* duplex (the miRNA and its passenger strand). This duplex is then loaded onto an Argonaute protein. An ATP-dependent process releases the mature miRNA from Argonaute, while the passenger strand is removed. The resulting mature miRNA is the active form that binds to mRNA and mediates post-transcriptional repression.
In cancer, the miR regulatory function becomes especially important. Some miRs act as tumor suppressors, helping prevent uncontrolled cell growth by silencing genes that drive proliferation. Others act as oncomiRs, promoting cancer development by blocking tumor-suppressing genes. For example, if a tumor-suppressive miR is lost or downregulated, cancer cells may grow unchecked. Conversely, if an oncomiR is overproduced, it can silence key brakes on cell division. Because of this dual nature, miRs are being studied as both biomarkers (prognostic/diagnostic) and potential therapeutic targets in many types of cancer [8].
The principal goal of this review article is to provide an overview of current knowledge regarding the impact of miRNAs on prostate cancer and their potential applications in the future.

2. Methods

2.1. Systemic Review

A systematic literature review was conducted in PubMed, Google Scholar, and ResearchGate using the terms “prostate cancer,” “prostate cancer diagnosis,” “prostate cancer treatment,” and “miRNA,” with no time restrictions. This search returned 318 articles, of which 310 were excluded for failing to meet the selection criteria. An additional 16 articles were identified through reference lists. A full-text assessment was performed for all selected articles, and 24 were finally included.

2.2. Inclusion Criteria

  • Studies focusing on the impact of miRNAs on prostate cancer.
  • Peer-reviewed articles.
  • Reviews (any type), meta-analyses, clinical trials.
  • Research regarding miRNAs as a diagnostic or therapeutic tool in prostate cancer.

2.3. Exclusion Criteria

  • Publications focusing on cancer types other than prostate cancer.
  • Publications not in the English language.
  • Lack of full-text availability.
Three team members independently assessed each selected study for research type, sample size, results, and conclusions. Potential limitations, such as small sample size or bias, were acknowledged, and recommendations for further investigation with larger sample sizes were made.

3. Results and Discussion

3.1. miRNAs-Based Biomarkers

Across 24 eligible studies and 2 public GEO tissue datasets, >150 miRNAs show reproducible dysregulation in prostate cancer tissue.
Like other malignancies, prostate cancer presents a distinctive miRNA expression profile [9,10,11]. An early microarray study by Porkka et al. [12] already captured this breadth, reporting 37 tumor-suppressive losses and 14 oncogenic gains relative to normal prostate. Since then, functional screens, such as the CRISPR/Cas9 knockout series, by using a pooled CRISPR/Cas9 knockout screen, Jiang et al. [13] confirmed that loss of tumor-suppressive miR-205, miR-23b, and miR-30c accelerates LNCaP-cell proliferation, whereas the enforced expression of the oncogenic pair miR-1225-5p/miR-663a has the opposite effect. Full gene lists, fold-changes, and p values are summarized in Table 1. A lentiviral vector knockout system was used on LNCaP cells to study these miRNAs. Significant enhancement (p < 0.05) was observed in cell proliferation following knockout of miR-222, miR-224, miR-23b, miR-205, and miR-30c, whereas knockout of miR-1225-5p and miR-663a caused a notable reduction in proliferative potential (p < 0.01). Knockout of miR-221, miR-455-3p, and miR-505 did not show any significant changes (p > 0.05) in proliferation. Regarding cell invasion, knockout of miR-205, miR-221, miR-455-3p, miR-222, miR-224, miR-505, miR-23b, and miR-30c contributed to increased invasiveness in LNCaP cells, suggesting possible tumor-suppressive functions [13]. Several studies [14,15,16] emphasized miR-205 as a tumor suppressor in prostate cancer, and Verdoot et al. [17] demonstrated its role in DNA damage response following doxorubicin or cisplatin treatment, as well as in inhibiting proliferation in PC-3 and LNCaP cells.
Numerous studies [19,23,28,29] supported the notion that miR-221 and miR-222 are downregulated in prostate cancer, and additional findings suggested that the loss of miR-30c may enhance the proliferation and invasiveness of cancer cells [19]. Jiang et al. [13] first proposed that miR-663a and miR-1225-5p act as tumor promoters. Zhang et al. [20] reported that miR-335-5p can induce apoptosis in prostate cancer cells and proposed it as a potential biomarker [20,30]. Sun et al. [22] found that aggressive prostate cancers tend to overexpress oncogenic miR-21, miR-125b, miR-221, and miR-222. Nikitina et al. [21] associated overexpressed miR-21 with tumor growth, possibly by knocking down PTEN and other tumor-suppressor genes [31]). Feng et al. [32] examined the miR-200 family and noted its key role in suppressing tumor-suppressive mechanisms and regulating cell migration. Siegel et al. [28] further observed that combining these five miRNAs with routine PSA tests may improve diagnostic accuracy.
Shinawi T. et al. [33] identified 53 dysregulated miRNAs, and 250 target genes involved in Hedgehog, ErbB, and cAMP signaling pathways in prostate cancer metastasis. Their study narrowed the hub miRNAs to hsa-miR-455-3p, hsa-miR-548c-3p, and hsa-miR-582-5p, and the hub genes to NFIB, DICER1, GSK3B, DCAF7, FGFR1OP, ABHD2, NACC2, NR3C1, and FGF2. NR3C1, ABHD2, and GSK3B displayed notable mutation capacity and altered expression. The downregulation of NR3C1 was linked to patient survival beyond 150 months. Hsa-miR-582-5p targeted the NR3C1, ABHD2, and GSK3B genes and appeared to correlate with the increased expression of ABHD2 and GSK3B in prostate tissues. Earlier work by Gordanpour et al. [34] and Huang et al. [35] suggested that hsa-miR-582-5p might inhibit metastasis by repressing TGF-β signaling. Feng et al. [36] examined the role of miR-548c-3p as a cancer regulator, particularly through ErbB and Hippo pathways.
Wong A. et al. [37] explored clinical and molecular markers of long-term survival following oligometastasis-directed stereotactic body radiotherapy and highlighted that miRNAs can regulate tumor behavior. MiR-23b, which targets oncogenes and signaling molecules (PTEN, Akt, SRC, MAP3K1, TGFbR2, RRAS2), was shown to inhibit proliferation, migration, invasion, epithelial–mesenchymal transition, angiogenesis, and metastasis in animal models [38,39,40,41]. Clinical studies [38,39,40,41,42,43] reported improved overall survival in patients with various malignancies, including prostate cancer, when miR-23b was upregulated. MiR-449a and miR-449b also share multiple overlapping targets, such as CDK6, CDC25A, HDAC1, MET, and FOS [43,44,45,46]. In prostate cancer, elevated miR-449b is associated with increased recurrence risk [25], although both miR-449a and miR-449b have shown tumor-suppressive effects in vitro [43,44,45,46]. These findings highlight the complexity of miRNA pathways in prostate cancer pathogenesis.

3.2. miRNAs in Locally Advanced Prostate Cancer

Pudova et al. [24] compared node-positive (N1, n = 20) with node-negative (N0, n = 24) tumors and reported 18 differentially expressed miRNAs. Eight belonged to two oncogenic clusters—miR-183-96-182 and miR-25-93-106b—already implicated in epithelial-to-mesenchymal transition (EMT) and early dissemination. Conversely, the N0 group was enriched for tumor-suppressive species such as miR-143-5p and miR-455-3p, both linked to TGF-β antagonism. Table 2 summarizes the nine N1-enriched miRNAs, their predicted targets (PTEN, E-cadherin, FOXO1), and supporting references. The dominance of the miR-183-96-182 cluster suggests cooperative regulation of metastatic competence and pinpoints this tri-miRNA cassette as a potential liquid biopsy marker for lymph node involvement.

3.2.1. N1 Group

Among the nine miRNAs in the N1 group, miR-182-5p, miR-183-5p, and miR-96-5p belong to the miR-183-96-182 oncogenic cluster, which has been widely studied for its oncogenic properties. miR-183 contributes to tumor invasion and metastasis by targeting PDCD4, PP2A, EGR1, and PTEN [36,37,38]. These three miRNAs also appear to negatively affect FOXO3a, a tumor suppressor gene responsible for cell cycle arrest and cell death in endometrial cancer [48]. Some findings suggest that FOXO1 may act as a repressor of the androgen receptor, which is a principal oncogenic pathway in prostate cancer [49]. Siu MK et al., 2015, reported that elevated miR-96-5p in prostate cancer promotes metastasis by activating the mTOR pathway [50]. Similarly, Schaefer et al. [23], Casanova-Salas [51], and Wang et al. [52] observed increased miR-182-5p in prostate cancer tissues, differentiating them from normal tissues with nearly 100% specificity.
Two other miRNAs, miR-25 and miR-93, were also elevated in the N1 samples. These, together with miR-106, form the miR-106b-25 oncogenic cluster, which is elevated in multiple malignancies including gastric, prostatic, pancreatic neuroendocrine cancers, multiple myelomas, and neuroblastomas. This cluster, alongside the miR-17-92 oncogenic cluster, regulates TGF-β. Its inactivation is considered a key step in tumor progression because it disrupts cell apoptosis and cell cycle arrest [53]. miR-25 has been reported to be elevated in several cancers, including prostate cancer [54], and miR-25-3p levels have been specifically associated with prostate cancer [55,56]. Choi et al. [16] reported a correlation between the progression of cancer and increased miR-93-5p. Another oncogenic miRNA, miR-615-3p, is elevated in many cancers, including aggressive prostate cancer [54,55,56].

3.2.2. N0 Group

Although miRNAs often act as suppressors, their roles can be ambivalent and depend on specific biological contexts. miR-221 and miR-222 are decreased in the N1 group. Galardi et al. [18] found that these miRNAs target the cell cycle inhibitor p27, thereby influencing cancer cell proliferation. They normally regulate vascular remodeling after injury by controlling endothelial cell differentiation, migration, and proliferation [57,58]. Numerous studies have investigated these miRNAs in various cancers, including prostate cancer, where they may function as either tumor suppressors or oncogenes [18,57,58,59,60,61]. Kiener et al. [62] employed mouse and zebrafish models to investigate whether miR-221-5p controls proliferation and migration in human prostate cancer cells and observed a reduction in miR-221-3p and miR-221-5p during prostate cancer progression. Moreover, miR-221-5p appears to function as a tumor suppressor in prostate cancer cell lines, limiting tumor burden. miR-221 serves as a key regulator of a network of other miRNAs in prostate cancer and can influence cell physiology [63]. Thus, the exact biological roles and mechanisms of action of miR-221 and miR-222 in androgen-independent prostate cancer pathogenesis are not yet fully understood.
Multiple reports describe miR-223-5p as an abnormally expressed lagging strand in various solid malignant tumors, including vulvar cancer [64], non-small cell lung cancer [65], and bladder cancer [66]. Evidence suggests that miR-223-5p acts as an anti-tumor miRNA by targeting oncogenic genes such as E2F8 and ALN. The ETS-related gene (ERG), a member of the ETS family, is crucial in hematopoiesis and angiogenesis [67]. In approximately half of prostate cancer patients, the TMPRSS2-ERG fusion gene occurs [68], which may upregulate ERG and promote cell development [69]. ERG is hypothesized to drive epithelial neoplasia and cancer progression in prostate epithelium.
Wei et al. [26] investigated the correlation between miR-223-5p and ERG. In multiple prostate cancer cell lines, an inverse relationship was identified between miR-223-5p and ERG expression. Potential targets of miR-223-5p were then predicted using Targetscan, miRDB, microRNA, and PhastCons, indicating ERG as a likely target. DU145 cells were transfected with miR-223-5p mimics (miR-MM) or miR-223-5p antisense oligonucleotides (miR-AO). A downregulation of ERG was observed in miR-MM cells, while an upregulation was detected in miR-AO cells, thus supporting the negative regulation of ERG by miR-223-5p. Further experiments in DU145 and LNCaP cells, each transfected with one of three ERG siRNAs (to select the optimal one), demonstrated that silencing miR-223-5p resulted in a marked increase in ERG expression, suggesting a negative feedback loop. Knocking down ERG significantly inhibited cell proliferation, migration, and invasion in prostate cancer cell lines, emphasizing the potential oncogenic function of ERG and its regulation by miR-223-5p.

3.2.3. Androgen Receptors and miRs

Androgen receptors play an important role in the normal growth of prostate cells. Their regulatory actions and mechanisms remain incompletely understood in prostate cancer. Ostling et al. [47] investigated several miRNAs that either upregulate or downregulate androgen receptor protein levels by targeting the 3′UTR. They reverse-transfected 21 miRNAs into LNCaP and 22Rv1 cell lines and performed Western blot and qRT-PCR to analyze androgen receptor levels, finding that these miRNAs reduced the androgen receptor protein. Most also decreased PSA levels in LNCaP cells, although miR-299-3p increased PSA. miR-30d increased both PSA and androgen receptors in LNCaP cells, while miR-9 decreased PSA levels. The 22Rv1 cells can express an isoform of the androgen receptor [70,71], and several miRNAs—miR-135b, miR-147, miR-299-3p, miR-34a, and miR-644—downregulated this alternative transcript. In addition, miR-147, miR-297, miR-298, miR-299–3p, miR-421, and miR-449a reduced the androgen receptor mRNA in both LNCaP and 22Rv1 cells. miR-371–3p, miR-449b, and miR-491–5p were particularly effective in LNCaP cells, while miR-876–3p was more effective in 22Rv1. Out of the 21 miRNAs, 13 (miR-135b, miR-185, miR-297, miR-299–3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9) interacted with the 3′UTR region of the androgen receptor. Among these, miR-421, miR-449a, miR-449b, and miR-9 also reduced exogenous androgen receptor expression [70,71].
miR-34a and miR-34c are regulated by the tumor suppressor TP53, meaning that decreased levels of these miRNAs can lead to increased tumor aggression, elevated PSA, and metastasis [72]. In 47 prostate tumors, miR-34a and miR-34c levels and androgen receptor content were measured by qRT-PCR and immunostaining, respectively. An inverse correlation was found between miR-34c levels and androgen receptor immunostaining (p = 0.0082), and similarly for miR-34a (p = 0.0085). Both miRNAs directly target the 3′UTR region of the androgen receptor, influencing prostate cancer progression.

3.3. PSA vs. Circulating miRNAs in Prostate Cancer

Although the prostate biopsy is the gold standard prostate cancer diagnostic tool, and the identification of miRs in a prostate biopsy has been the focus of intense research, as outlined in Table 1 and Table 2, it is bound by several limitations [73]. Most prostate biopsies are routinely performed by taking 12 cores under the transrectal ultrasound guidance [73], with an increase in the core number found to increase the cancer detection rate by only 1.06-fold [74]. However, the major drawback lies in the possibility of generating false negatives, as the samples are often taken randomly due to the unknown location of the tumor, and patients may require repeated biopsies under MRI guidance or in combination with ultrasound for better sensitivity [73]. Non-invasive quantification of circulating miRNAs in body fluids, specifically plasma, may serve as clinically important biomarkers of prostate cancer.

3.4. Computational Analysis

In this study, three publicly available prostate cancer (PC) miRNA datasets from the Gene Expression Omnibus (GEO) were selected to identify and compare differentially expressed miRNAs in both tissue and plasma. GSE54516 (GEO set 1, 219 miRNAs, 99 patients) [75] and GSE21032 (GEO set 2, 326 miRNAs, 127 patients) [76] focused on PC tissue, whereas GSE206793 (GEO set 3, 12 miRNAs, 96 patients) [77] examined miRNAs from plasma samples. All datasets were reviewed for quality, completeness, and normalization parameters prior to analysis. Differential expression testing was performed with Transcriptome Analysis Console (TAC) software, applying p < 0.05 and a false discovery rate (FDR) < 0.05. In GSE206793, multiple binary comparisons were performed between the four available cohorts (healthy volunteers, low risk, intermediate risk, and high risk). The only comparison that yielded a statistically significant set of differentially expressed miRNAs (FDR < 0.05, |log2FC| ≥ 1) was between healthy controls (n = 5) and the high-risk prostate cancer group (n = 91). As a result, this comparison was used for downstream analysis and is reflected in the Venn diagram (Figure 1). Comparisons involving the low- and intermediate-risk groups did not meet the criteria for differential expression and were therefore excluded. For GSE54516 and GSE21032, the comparisons were straightforward as they involved prostate cancer patients and healthy/benign controls only. In both cases, the entire dataset was used to identify significantly dysregulated miRNAs using the same statistical thresholds.
As shown in Figure 1, miR-449b and miR-455-3p, discussed below, were identified in both tissue and plasma signatures, suggesting they may serve as circulating biomarkers for prostate cancer. These two miRNAs may be associated with the primary tumor site and could be indicative of prostate cancer at an early stage.

3.4.1. miR-455-3p

Cap-dependent translation is recognized as an important process in the initiation and progression of many cancers, partially through the translation of oncogenic mRNAs such as cyclin D1 and c-MYC [78]. The eIF4F complex regulates cap-dependent translation [79]. Zhao et al. [27] investigated the role of miR-455-3p in prostate cancer and noted that it targets and suppresses eIF4E. Using quantitative PCR, they assessed miR-455-3p in one benign cell line and five cancer cell lines (22Rv1, LNCaP, C4-2, PC-3, and DU145), detecting a significant reduction in miR-455-3p in cancer cells relative to benign cells. Analysis of 65 clinical prostate tissue samples (18 benign, 47 cancerous) showed a marked decrease in miR-455-3p levels in cancer tissues compared to normal tissues, suggesting a role in cancer initiation. Conversely, miR-455-3p upregulation appeared to reduce cancer cell growth. When a miR-455-3p mimic was introduced into LNCaP and PC-3 cells, their proliferation declined in vitro; the in vivo overexpression of miR-455-3p in PC-3 xenografts also suppressed tumor growth.
To confirm the inhibitory function of miR-455-3p, an antagomir was used to silence endogenous miR-455-3p, leading to enhanced cancer cell proliferation in vitro and in vivo. Further experiments indicated that miR-455-3p inhibits cap-dependent translation and prostate cancer cell proliferation via its effect on eIF4E. The introduction of a 3′ UTR–deleted eIF4E plasmid into miR-455-3p–transfected PC-3 cells reversed the inhibition of cap-dependent translation and cell growth. However, upon silencing eIF4E, the observed increase in cell activity was attenuated, suggesting that the interplay between miR-455-3p and eIF4E underlies its regulatory effects on prostate cancer cell proliferation.

3.4.2. miR 449b

Three independent cohorts agree that miR-449b is the strongest predictor of biochemical recurrence (BCR) after radical prostatectomy. In Mortensen et al. [25], a 2.8-fold increase translated to a hazard ratio (HR) of 1.9 (p = 0.003). Fendler et al. [80] later validated miR-449b (late BCR) alongside miR-10b (early BCR), while Prueitt et al. [81] highlighted miR-126 and miR-125-5p as protective. Ambs et al. [9] highlighted the role of elevated miR-449b and miR-484 in extra prostatic disease extension.
Some findings indicate that miR-449b can inhibit androgen receptor expression, which in turn suppresses androgen-driven cell proliferation [82]. Noonan et al. [83] further reported that the E2F1 transcription factor activates the transcription of the miR-449 cluster, leading to cell cycle arrest and apoptosis through the inhibition of CDK6 and CDC25A—indicative of a negative feedback mechanism against E2F1-mediated cell proliferation. This tumor-suppressive capacity of the miR-449 cluster has been observed in multiple cell lines (prostate, breast, and lung) via different mechanisms [83,84]. Additional interactions with LEF-1, a known effector of the WNT pathway, have also been proposed [85]. The miR-449 cluster may limit WNT signaling by inhibiting LEF-1 [86,87], which can reduce cancer growth, including prostate cancer cells. Furthermore, miR-449 targets the NOTCH pathway and alters cell differentiation [88]. As the NOTCH pathway promotes both epithelial-to-mesenchymal transition (EMT) and cancer progression—and is linked to reduced bone formation—LEF-1 inhibition by miR-449b could potentially promote bone metastasis in prostate cancer. Inhibiting LEF-1 can decrease osteoblast differentiation and bone density, potentially facilitating metastasis of prostate cancer cells to the skeleton [89].

4. Conclusions and Limitations

This review should be interpreted in consideration of several important limitations. Firstly, most studies relied on small cohorts, where many tissue and nearly all plasma studies included 60 patients or fewer. This constrains statistical power, especially for miRNAs present at low abundance, and makes it hard to analyze subgroups by stage or ancestry. Secondly, pre-analytical procedures varied widely. Some groups collected plasma in EDTA tubes, and others used serum; the time to process and extract kits also differed. Such differences can change hemolysis levels and miRNA yield by more than twofold, so direct comparisons must be interpreted with caution. Thirdly, discovery platforms were not uniform. Microarrays, small-RNA sequencing, and fixed qPCR panels each have distinct dynamic ranges and background correction methods, meaning that a miRNA “missing” in one dataset may be below that platform’s detection limit. And finally, there was limited external replication beyond miR-21, miR-449b, and miR-455-3p. These few candidates have been validated in three or more independent cohorts. Until these issues are addressed, any proposed biomarker panel should be considered exploratory.
Nonetheless, by examining the complex roles of various miRNAs in prostate cancer progression, this study aimed to identify their potential roles as prognostic markers and therapeutic targets, as summarized in Figure 2. Restoring the levels of miR-205, miR-30c, miR-23b, miR-455-3p, and miR-222—often found downregulated in prostate cancer—may help control cell proliferation, migration, and invasion. Conversely, inhibiting miR-21, miR-1225-5p, miR-663a, miR-449b, miR-182-5p, miR-183-5p, miR-96-5p, miR-25, miR-93, and miR-615-3p could impede disease progression. In advanced cases, miR-582-5p and miR-548c-3p, which intersect with pathways such as TGF-β, Hedgehog, and ErbB, may confer additional benefits.
The involvement of miR-34a, miR-34c, and miR-449b in androgen receptor regulation and pathways such as WNT, NOTCH, and TGF-β may also provide future therapeutic options. miR-141, miR-335-5p, and miR-449b, which correlate with patient recurrence and survival, hold promise as prognostic markers. Particularly, miR-449b is linked to a higher risk of biochemical recurrence after radical prostatectomy, while miR-141 is notably stable in blood samples. Furthermore, incorporating miR-455-3p, miR-23b, miR-200 family members, and miR-221/222 with traditional PSA testing has shown improved diagnostic sensitivity and specificity, aiding in earlier detection and enhanced risk stratification.
miRNAs offer a mechanistically informative and clinically accessible window into prostate-tumor biology. Integrative tissue-and-plasma analysis identifies miR-449b and miR-455-3p as robust, concordant biomarkers with plausible functional relevance. Standardized pipelines and large-scale trials will be essential to translate these insights into routine urologic practice.

Author Contributions

G.K., A.M.E., and J.N.T. designed the experiments; G.K., A.M.E., and J.N.T. performed the experiments; G.K., A.M.E., and J.N.T. analyzed the data. G.K., A.M.E., C.M.V., G.H., E.K., D.K., E.R., A.F., P.F., D.M., K.S., D.B., A.K., V.K., and A.M.K. wrote the manuscript. G.K., A.M.E., J.N.T., and C.M.V. critically reviewed and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are presented in the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Key Statistics for Prostate Cancer|Prostate Cancer Facts|American Cancer Society. Available online: https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html (accessed on 8 January 2025).
  2. Prostate Cancer-Uroweb. Available online: https://uroweb.org/guidelines/prostate-cancer (accessed on 11 May 2025).
  3. Kaye, D.R.; Khilfeh, I.; Muser, E.; Morrison, L.; Kinkead, F.; Urosevic, A.; Lefebvre, P.; Pilon, D.; George, D.J. Real-world economic burden of metastatic castration-resistant prostate cancer before and after first-line therapy initiation. J. Med. Econ. 2024, 27, 201–214. [Google Scholar] [CrossRef]
  4. All Nobel Prizes 2024-NobelPrize.org. Available online: https://www.nobelprize.org/all-nobel-prizes-2024/ (accessed on 11 May 2025).
  5. Bartel, D.P. Metazoan MicroRNAs. Cell 2018, 173, 20–51. [Google Scholar] [CrossRef] [PubMed]
  6. Friedman, R.C.; Farh, K.K.-H.; Burge, C.B.; Bartel, D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009, 19, 92–105. [Google Scholar] [CrossRef]
  7. Dalmay, T. MicroRNAs and cancer. J. Intern. Med. 2008, 263, 366–375. [Google Scholar] [CrossRef]
  8. Valera, V.A.; Parra-Medina, R.; Walter, B.A.; Pinto, P.; Merino, M.J. microRNA Expression Profiling in Young Prostate Cancer Patients. J. Cancer 2020, 11, 4106–4114. [Google Scholar] [CrossRef] [PubMed]
  9. Ambs, S.; Prueitt, R.L.; Yi, M.; Hudson, R.S.; Howe, T.M.; Petrocca, F.; Wallace, T.A.; Liu, C.-G.; Volinia, S.; Calin, G.A.; et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 2008, 68, 6162–6170. [Google Scholar] [CrossRef]
  10. Plaisier, C.L.; Pan, M.; Baliga, N.S. A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers. Genome Res. 2012, 22, 2302–2314. [Google Scholar] [CrossRef]
  11. Song, C.-J.; Chen, H.; Chen, L.-Z.; Ru, G.-M.; Guo, J.-J.; Ding, Q.-N. The potential of microRNAs as human prostate cancer biomarkers: A meta-analysis of related studies. J. Cell. Biochem. 2018, 119, 2763–2786. [Google Scholar] [CrossRef]
  12. Porkka, K.P.; Pfeiffer, M.J.; Waltering, K.K.; Vessella, R.L.; Tammela, T.L.J.; Visakorpi, V. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007, 167, 6130–6135. [Google Scholar] [CrossRef]
  13. Jiang, F.-N.; Liang, Y.-X.; Wei, W.; Zou, C.-Y.; Chen, G.-X.; Wan, Y.-P.; Liu, Z.-Z.; Yang, Y.; Han, Z.-D.; Zhu, J.-G.; et al. Functional classification of prostate cancer-associated miRNAs through CRISPR/Cas9-mediated gene knockout. Mol. Med. Rep. 2020, 22, 3777–3784. [Google Scholar] [CrossRef]
  14. Gandellini, P.; Folini, M.; Longoni, N.; Pennati, M.; Binda, M.; Colecchia, M.; Salvioni, R.; Supino, R.; Moretti, R.; Limonta, P.; et al. MiR-205 exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res. 2009, 69, 2287–2295. [Google Scholar] [CrossRef] [PubMed]
  15. Majid, S.; Dar, A.A.; Saini, S.; Yamamura, S.; Hirata, H.; Tanaka, Y.; Deng, G.; Dahiya, R. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 2010, 116, 5637–5649. [Google Scholar] [CrossRef]
  16. Choi, N.; Park, J.; Lee, J.-S.; Yoe, J.; Park, G.Y.; Kim, E.; Jeon, H.; Cho, Y.M.; Roh, T.-Y.; Lee, Y. MiR-93/miR-106b/miR-375-CIC-CRABP1: A novel regulatory axis in prostate cancer progression. Oncotarget 2015, 6, 23533–23547. [Google Scholar] [CrossRef]
  17. Verdoodt, B.; Neid, M.; Vogt, M.; Kuhn, V.; Liffers, S.-T.; Palisaar, R.-J.; Noldus, J.; Tannapfel, A.; Mirmohammadsadegh, A. MicroRNA-205, a novel regulator of the anti-apoptotic protein Bcl2, is downregulated in prostate cancer. Int. J. Oncol. 2013, 43, 307–314. [Google Scholar] [CrossRef]
  18. Galardi, S.; Mercatelli, N.; Giorda, E.; Massalini, S.; Frajese, G.V.; Ciafrè, S.A.; Farace, M.G. MiR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J. Biol. Chem. 2007, 282, 23716–23724. [Google Scholar] [CrossRef]
  19. Ling, X.; Han, Z.; Xia, D.; He, H.; Jiang, F.; Lin, Z.; Fu, X.; Deng, Y.; Dai, Q.; Cai, C.; et al. MicroRNA-30c serves as an independent biochemical recurrence predictor and potential tumor suppressor for prostate cancer. Mol. Biol. Rep. 2014, 41, 2779–2788. [Google Scholar] [CrossRef] [PubMed]
  20. Zhang, P.; Yang, X.; Wang, L.; Zhang, D.; Luo, Q.; Wang, B. Overexpressing miR-335 inhibits DU145 cell proliferation by targeting early growth response 3 in prostate cancer. Int. J. Oncol. 2019, 54, 1981–1994. [Google Scholar] [CrossRef]
  21. Nikitina, E.G.; Urazova, L.N.; Stegny, V.N. MicroRNAs and human cancer. Exp. Oncol. 2012, 34, 2–8. [Google Scholar] [PubMed]
  22. Sun, T.; Wang, Q.; Balk, S.; Brown, M.; Lee, G.-S.M.; Kantoff, P. The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res. 2009, 69, 3356–3363. [Google Scholar] [CrossRef]
  23. Schaefer, A.; Jung, M.; Mollenkopf, H.-J.; Wagner, I.; Stephan, C.; Jentzmik, F.; Miller, K.; Lein, M.; Kristiansen, G.; Jung, K. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int. J. Cancer 2010, 126, 1166–1176. [Google Scholar] [CrossRef]
  24. Pudova, E.A.; Krasnov, G.S.; Nyushko, K.M.; Kobelyatskaya, A.A.; Savvateeva, M.V.; Poloznikov, A.A.; Dolotkazin, D.R.; Klimina, K.M.; Guvatova, Z.G.; Simanovsky, S.A.; et al. miRNAs expression signature potentially associated with lymphatic dissemination in locally advanced prostate cancer. BMC Med. Genom. 2020, 13, 129. [Google Scholar] [CrossRef]
  25. Mortensen, M.M.; Høyer, S.; Orntoft, T.F.; Sørensen, K.D.; Dyrskjøt, L.; Borre, M. High miR-449b expression in prostate cancer is associated with biochemical recurrence after radical prostatectomy. BMC Cancer 2014, 14, 859. [Google Scholar] [CrossRef] [PubMed]
  26. Wei, Y.; Peng, J.; He, S.; Huang, H.; Lin, L.; Zhu, Q.; Ye, L.; Li, T.; Zhang, X.; Gao, Y.; et al. MiR-223-5p targeting ERG inhibits prostate cancer cell proliferation and migration. J. Cancer 2020, 11, 4453–4463. [Google Scholar] [CrossRef] [PubMed]
  27. Zhao, Y.; Yan, M.; Yun, Y.; Zhang, J.; Zhang, R.; Li, Y.; Wu, X.; Liu, Q.; Miao, W.; Jiang, H. MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol. Rep. 2017, 37, 2449–2458. [Google Scholar] [CrossRef] [PubMed]
  28. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [PubMed]
  29. Tong, A.W.; Fulgham, P.; Jay, C.; Chen, P.; Khalil, I.; Liu, S.; Senzer, N.; Eklund, A.C.; Han, J.; Nemunaitis, J. MicroRNA profile analysis of human prostate cancers. Cancer Gene Ther. 2009, 16, 206–216. [Google Scholar] [CrossRef]
  30. Wang, X.; Wu, G.; Cao, G.; Chen, X.; Huang, J.; Jiang, X.; Hou, J. MicroRNA-335 inhibits bladder cancer cell growth and migration by targeting mitogen-activated protein kinase 1. Mol. Med. Report. 2016, 14, 1765–1770. [Google Scholar] [CrossRef]
  31. Meng, F.; Henson, R.; Wehbe-Janek, H.; Ghoshal, K.; Jacob, S.T.; Patel, T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007, 133, 647–658. [Google Scholar] [CrossRef]
  32. Feng, X.; Wang, Z.; Fillmore, R.; Xi, Y. MiR-200, a new star miRNA in human cancer. Cancer Lett. 2014, 344, 166–173. [Google Scholar] [CrossRef] [PubMed]
  33. Shinawi, T.; Nasser, K.K.; Moradi, F.A.; Mujalli, A.; Albaqami, W.F.; Almukadi, H.S.; Elango, R.; Shaik, N.A.; Banaganapalli, B. A comparative mRNA- and miRNA transcriptomics reveals novel molecular signatures associated with metastatic prostate cancers. Front. Genet. 2022, 13, 1066118. [Google Scholar] [CrossRef] [PubMed]
  34. Gordanpour, A.; Nam, R.K.; Sugar, L.; Seth, A. MicroRNAs in prostate cancer: From biomarkers to molecularly-based therapeutics. Prostate Cancer Prostatic Dis. 2012, 15, 314–319. [Google Scholar] [CrossRef] [PubMed]
  35. Huang, S.; Zou, C.; Tang, Y.; Wa, Q.; Peng, X.; Chen, X.; Yang, C.; Ren, D.; Huang, Y.; Liao, Z.; et al. MiR-582-3p and miR-582-5p suppress prostate cancer metastasis to bone by repressing TGF-βsignaling. Mol. Ther. Nucleic Acids 2019, 16, 91–104. [Google Scholar] [CrossRef]
  36. Feng, C.; Li, Y.; Lin, Y.; Cao, X.; Li, D.; Zhang, H.; He, X. CircRNA-associated ceRNA network reveals ErbB and Hippo signaling pathways in hypopharyngeal cancer. Int. J. Mol. Med. 2019, 43, 127–142. [Google Scholar] [CrossRef] [PubMed]
  37. Wong, A.C.; Watson, S.P.; Pitroda, S.P.; Son, C.H.; Das, L.C.; Stack, M.E.; Uppal, A.; Oshima, G.; Khodarev, N.N.; Salama, J.K.; et al. Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT). Cancer 2016, 122, 2242–2250. [Google Scholar] [CrossRef]
  38. Zhang, H.; Hao, Y.; Yang, J.; Zhou, Y.; Li, J.; Yin, S.; Sun, C.; Ma, M.; Huang, Y.; Xi, J.J. Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nat. Commun. 2011, 2, 554. [Google Scholar] [CrossRef] [PubMed]
  39. Li, W.; Liu, Z.; Chen, L.; Zhou, L.; Yao, Y. MicroRNA-23b is an independent prognostic marker and suppresses ovarian cancer progression by targeting runt-related transcription factor-2. FEBS Lett. 2014, 588, 1608–1615. [Google Scholar] [CrossRef]
  40. Majid, S.; Dar, A.A.; Saini, S.; Arora, S.; Shahryari, V.; Zaman, M.S.; Chang, I.; Yamamura, S.; Tanaka, Y.; Deng, G.; et al. MiR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer. Cancer Res. 2012, 72, 6435–6446. [Google Scholar] [CrossRef]
  41. Zaman, M.S.; Thamminana, S.; Shahryari, V.; Chiyomaru, T.; Deng, G.; Saini, S.; Majid, S.; Fukuhara, S.; Chang, I.; Arora, S.; et al. Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS ONE 2012, 7, e50203. [Google Scholar] [CrossRef]
  42. Jin, L.; Wessely, O.; Marcusson, E.G.; Ivan, C.; Calin, G.A.; Alahari, S.K. Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-α in breast cancer. Cancer Res. 2013, 73, 2884–2896. [Google Scholar] [CrossRef]
  43. Bou Kheir, T.; Futoma-Kazmierczak, E.; Jacobsen, A.; Krogh, A.; Bardram, L.; Hother, C.; Grønbæk, K.; Federspiel, B.; Lund, A.H.; Friis-Hansen, L. MiR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Mol. Cancer 2011, 10, 29. [Google Scholar] [CrossRef]
  44. Chen, S.-P.; Liu, B.-X.; Xu, J.; Pei, X.-F.; Liao, Y.-J.; Yuan, F.; Zheng, F. MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC Cancer 2015, 15, 706. [Google Scholar] [CrossRef] [PubMed]
  45. Yang, X.; Feng, M.; Jiang, X.; Wu, Z.; Li, Z.; Aau, M.; Yu, Q. MiR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes Dev. 2009, 23, 2388–2393. [Google Scholar] [CrossRef] [PubMed]
  46. Noonan, E.J.; Place, R.F.; Pookot, D.; Basak, S.; Whitson, J.M.; Hirata, H.; Giardina, C.; Dahiya, R. MiR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 2009, 28, 1714–1724. [Google Scholar] [CrossRef]
  47. Östling, P.; Leivonen, S.-K.; Aakula, A.; Kohonen, P.; Mäkelä, R.; Hagman, Z.; Edsjö, A.; Kangaspeska, S.; Edgren, H.; Nicorici, D.; et al. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res. 2011, 71, 1956–1967. [Google Scholar] [CrossRef]
  48. Myatt, S.S.; Wang, J.; Monteiro, L.J.; Christian, M.; Ho, K.-K.; Fusi, L.; Dina, R.E.; Brosens, J.J.; Ghaem-Maghami, S.; Lam, E.W.-F. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 2010, 70, 367–377. [Google Scholar] [CrossRef]
  49. Larne, O.; Martens-Uzunova, E.; Hagman, Z.; Edsjö, A.; Lippolis, G.; den Berg, M.S.V.; Bjartell, A.; Jenster, G.; Ceder, Y. miQ--a novel microRNA based diagnostic and prognostic tool for prostate cancer. Int. J. Cancer 2013, 132, 2867–2875. [Google Scholar] [CrossRef]
  50. Siu, M.K.; Tsai, Y.C.; Chang, Y.S.; Yin, J.J.; Suau, F.; Chen, W.Y.; Liu, Y.N. Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene 2015, 34, 4767–4776. [Google Scholar] [CrossRef] [PubMed]
  51. Casanova-Salas, I.; Rubio-Briones, J.; Calatrava, A.; Mancarella, C.; Masiá, E.; Casanova, J.; Fernández-Serra, A.; Rubio, L.; Ramírez-Backhaus, M.; Armiñán, A.; et al. Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J. Urol. 2014, 192, 252–259. [Google Scholar] [CrossRef] [PubMed]
  52. Wang, D.; Lu, G.; Shao, Y.; Xu, D. MiR-182 promotes prostate cancer progression through activating Wnt/β-catenin signal pathway. Biomed. Pharmacother. 2018, 99, 334–339. [Google Scholar] [CrossRef]
  53. Petrocca, F.; Vecchione, A.; Croce, C.M. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res. 2008, 68, 8191–8194. [Google Scholar] [CrossRef]
  54. Zhao, H.; Wang, Y.; Yang, L.; Jiang, R.; Li, W. MiR-25 promotes gastric cancer cells growth and motility by targeting RECK. Mol. Cell. Biochem. 2014, 385, 207–213. [Google Scholar] [CrossRef]
  55. Hudson, R.S.; Yi, M.; Esposito, D.; Glynn, S.A.; Starks, A.M.; Yang, Y.; Schetter, A.J.; Watkins, S.K.; Hurwitz, A.A.; Dorsey, T.H.; et al. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene 2013, 32, 4139–4147. [Google Scholar] [CrossRef]
  56. Martens-Uzunova, E.S.; Jalava, S.E.; Dits, N.F.; van Leenders, G.J.L.H.; Møller, S.; Trapman, J.; Bangma, C.H.; Litman, T.; Visakorpi, T.; Jenster, G. Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene 2012, 31, 978–991. [Google Scholar] [CrossRef] [PubMed]
  57. Song, Z.; Li, G. Role of specific microRNAs in regulation of vascular smooth muscle cell differentiation and the response to injury. J. Cardiovasc. Transl. Res. 2010, 3, 246–250. [Google Scholar] [CrossRef] [PubMed]
  58. Chistiakov, D.A.; Sobenin, I.A.; Orekhov, A.N.; Bobryshev, Y.V. Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling. BioMed Res. Int. 2015, 2015, 354517. [Google Scholar] [CrossRef] [PubMed]
  59. Sun, T.; Yang, M.; Chen, S.; Balk, S.; Pomerantz, M.; Hsieh, C.-L.; Brown, M.; Lee, G.-S.M.; Kantoff, P.W. The altered expression of MiR-221/-222 and MiR-23b/-27b is associated with the development of human castration resistant prostate cancer. Prostate 2012, 72, 1093–1103. [Google Scholar] [CrossRef]
  60. Goto, Y.; Kojima, S.; Nishikawa, R.; Kurozumi, A.; Kato, M.; Enokida, H.; Matsushita, R.; Yamazaki, K.; Ishida, Y.; Nakagawa, M.; et al. MicroRNA expression signature of castration-resistant prostate cancer: The microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br. J. Cancer 2015, 113, 1055–1065. [Google Scholar] [CrossRef]
  61. Coarfa, C.; Fiskus, W.; Eedunuri, V.K.; Rajapakshe, K.; Foley, C.; Chew, S.A.; Shah, S.S.; Geng, C.; Shou, J.; Mohamed, J.S.; et al. Comprehensive proteomic profiling identifies the androgen receptor axis and other signaling pathways as targets of microRNAs suppressed in metastatic prostate cancer. Oncogene 2016, 35, 2345–2356. [Google Scholar] [CrossRef]
  62. Kiener, M.; Chen, L.; Krebs, M.; Grosjean, J.; Klima, I.; Kalogirou, C.; Riedmiller, H.; Kneitz, B.; Thalmann, G.N.; Snaar-Jagalska, E.; et al. MiR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo. BMC Cancer 2019, 19, 627. [Google Scholar] [CrossRef]
  63. Alshalalfa, M. MicroRNA Response Elements-Mediated miRNA-miRNA Interactions in Prostate Cancer. Adv. Bioinform. 2012, 2012, 839837. [Google Scholar] [CrossRef]
  64. de Melo Maia, B.; Rodrigues, I.S.; Akagi, E.M.; Soares do Amaral, N.; Ling, H.; Monroig, P.; Soares, F.A.; Calin, G.A.; Rocha, R.M. MiR-223-5p works as an oncomiR in vulvar carcinoma by TP63 suppression. Oncotarget 2016, 7, 49217–49231. [Google Scholar] [CrossRef]
  65. Ren, X.-S.; Yin, M.-H.; Zhang, X.; Wang, Z.; Feng, S.-P.; Wang, G.-X.; Luo, Y.-J.; Liang, P.-Z.; Yang, X.-Q.; He, J.-X.; et al. Tumor-suppressive microRNA-449a induces growth arrest and senescence by targeting E2F3 in human lung cancer cells. Cancer Lett. 2014, 344, 195–203. [Google Scholar] [CrossRef] [PubMed]
  66. Sugawara, S.; Yamada, Y.; Arai, T.; Okato, A.; Idichi, T.; Kato, M.; Koshizuka, K.; Ichikawa, T.; Seki, N. Dual strands of the miR-223 duplex (miR-223-5p and miR-223-3p) inhibit cancer cell aggressiveness: Targeted genes are involved in bladder cancer pathogenesis. J. Hum. Genet. 2018, 63, 657–668. [Google Scholar] [CrossRef] [PubMed]
  67. Adamo, P.; Ladomery, M.R. The oncogene ERG: A key factor in prostate cancer. Oncogene 2016, 35, 403–414. [Google Scholar] [CrossRef]
  68. Magi-Galluzzi, C.; Tsusuki, T.; Elson, P.; Simmerman, K.; LaFargue, C.; Esgueva, R.; Klein, E.; Rubin, M.A.; Zhou, M. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate 2011, 71, 489–497. [Google Scholar] [CrossRef] [PubMed]
  69. Clark, J.P.; Cooper, C.S. ETS gene fusions in prostate cancer. Nat. Rev. Urol. 2009, 6, 429–439. [Google Scholar] [CrossRef]
  70. Guo, Z.; Yang, X.; Sun, F.; Jiang, R.; Linn, D.E.; Chen, H.; Chen, H.; Kong, X.; Melamed, J.; Tepper, C.G.; et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009, 69, 2305–2313. [Google Scholar] [CrossRef]
  71. Dehm, S.M.; Schmidt, L.J.; Heemers, H.V.; Vessella, R.L.; Tindall, D.J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008, 68, 5469–5477. [Google Scholar] [CrossRef]
  72. Hagman, Z.; Larne, O.; Edsjö, A.; Bjartell, A.; Ehrnström, R.A.; Ulmert, D.; Lilja, H.; Ceder, Y. MiR-34c is downregulated in prostate cancer and exerts tumor suppressive functions. Int. J. Cancer 2010, 127, 2768–2776. [Google Scholar] [CrossRef]
  73. Marks, L.; Young, S.; Natarajan, S. MRI-ultrasound fusion for guidance of targeted prostate biopsy. Curr. Opin. Urol. 2013, 23, 43–50. [Google Scholar] [CrossRef]
  74. Ceylan, C.; Doluoglu, O.G.; Aglamis, E.; Baytok, O. Comparison of 8, 10, 12, 16, 20 cores prostate biopsies in the determination of prostate cancer and the importance of prostate volume. Can. Urol. Assoc. J. 2014, 8, E81–E85. [Google Scholar] [CrossRef]
  75. Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010, 18, 11–22. [Google Scholar] [CrossRef]
  76. Zhiyanov, A.; Engibaryan, N.; Nersisyan, S.; Shkurnikov, M.; Tonevitsky, A. Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer. Bioinformatics 2023, 39, btad051. [Google Scholar] [CrossRef]
  77. Gu, L.; Frommel, S.C.; Oakes, C.C.; Simon, R.; Grupp, K.; Gerig, C.Y.; Bär, D.; Robinson, M.D.; Baer, C.; Weiss, M.; et al. BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat. Genet. 2015, 47, 22–30. [Google Scholar] [CrossRef]
  78. Pettersson, F.; Del Rincon, S.V.; Miller, W.H. Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond. Expert Opin. Ther. Targets 2014, 18, 1035–1048. [Google Scholar] [CrossRef]
  79. Spilka, R.; Ernst, C.; Mehta, A.K.; Haybaeck, J. Eukaryotic translation initiation factors in cancer development and progression. Cancer Lett. 2013, 340, 9–21. [Google Scholar] [CrossRef] [PubMed]
  80. Fendler, A.; Jung, M.; Stephan, C.; Honey, R.J.; Stewart, R.J.; Pace, K.T.; Erbersdobler, A.; Samaan, S.; Jung, K.; Yousef, G.M. miRNAs can predict prostate cancer biochemical relapse and are involved in tumor progression. Int. J. Oncol. 2011, 39, 1183–1192. [Google Scholar] [CrossRef]
  81. Prueitt, R.L.; Yi, M.; Hudson, R.S.; Wallace, T.A.; Howe, T.M.; Yfantis, H.G.; Lee, D.H.; Stephens, R.M.; Liu, C.-G.; Calin, G.A.; et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate 2008, 68, 1152–1164. [Google Scholar] [CrossRef] [PubMed]
  82. Lizé, M.; Pilarski, S.; Dobbelstein, M. E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis. Cell Death Differ. 2010, 17, 452–458. [Google Scholar] [CrossRef]
  83. Noonan, E.J.; Place, R.F.; Basak, S.; Pookot, D.; Li, L.-C. MiR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells. Oncotarget 2010, 1, 349–358. [Google Scholar] [CrossRef]
  84. Paik, S.; Jung, H.S.; Lee, S.; Yoon, D.S.; Park, M.S.; Lee, J.W. MiR-449a regulates the chondrogenesis of human mesenchymal stem cells through direct targeting of lymphoid enhancer-binding factor-1. Stem Cells Dev. 2012, 21, 3298–3308. [Google Scholar] [CrossRef]
  85. Chesire, D.R.; Ewing, C.M.; Gage, W.R.; Isaacs, W.B. In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene 2002, 21, 2679–2694. [Google Scholar] [CrossRef] [PubMed]
  86. Chesire, D.R.; Ewing, C.M.; Sauvageot, J.; Bova, G.S.; Isaacs, W.B. Detection and analysis of beta-catenin mutations in prostate cancer. Prostate 2000, 45, 323–334. [Google Scholar] [CrossRef]
  87. Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 2012, 4, 1837–1851. [Google Scholar] [CrossRef] [PubMed]
  88. Marcet, B.; Chevalier, B.; Luxardi, G.; Coraux, C.; Zaragosi, L.-E.; Cibois, M.; Robbe-Sermesant, K.; Jolly, T.; Cardinaud, B.; Moreilhon, C.; et al. Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway. Nat. Cell Biol. 2011, 13, 693–699. [Google Scholar] [CrossRef] [PubMed]
  89. Noh, T.; Gabet, Y.; Cogan, J.; Shi, Y.; Tank, A.; Sasaki, T.; Criswell, B.; Dixon, A.; Lee, C.; Tam, J.; et al. Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner. PLoS ONE 2009, 4, e5438. [Google Scholar] [CrossRef]
Biomolecules 15 01156 g001
Figure 1. Venn diagram of differentially expressed miRNAs in prostate cancer. This schematic depicts the overlap of significantly dysregulated miRNAs from three GEO datasets: GSE54516 (219 miRNAs, 99 patients, tissue), GSE21032 (326 miRNAs, 127 patients, tissue), and GSE206793 (12 miRNAs, 96 patients, plasma). Numbers in the overlapping and non-overlapping regions illustrate the count of miRNAs unique to or shared among each dataset. Notably, miR-449b and miR-455-3p were common to tissue and plasma, highlighting their potential value for early prostate cancer detection and monitoring.
Figure 1. Venn diagram of differentially expressed miRNAs in prostate cancer. This schematic depicts the overlap of significantly dysregulated miRNAs from three GEO datasets: GSE54516 (219 miRNAs, 99 patients, tissue), GSE21032 (326 miRNAs, 127 patients, tissue), and GSE206793 (12 miRNAs, 96 patients, plasma). Numbers in the overlapping and non-overlapping regions illustrate the count of miRNAs unique to or shared among each dataset. Notably, miR-449b and miR-455-3p were common to tissue and plasma, highlighting their potential value for early prostate cancer detection and monitoring.
Biomolecules 15 01156 g001
Biomolecules 15 01156 g002
Figure 2. Schematic summarizing miRs regulated in prostate cancer and their potential clinical use.
Figure 2. Schematic summarizing miRs regulated in prostate cancer and their potential clinical use.
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Table 1. miRNAs as predictive biomarkers in prostate cancer.
Table 1. miRNAs as predictive biomarkers in prostate cancer.
miRNAExpression in Prostate CancerLocation (Plasma/Tissue/Both)Predictive RoleAuthors
miR-205DownregulatedTissueTumor suppressor; predictive of cancer progression [12,13]
miR-221DownregulatedTissuePredictive of tumor suppression and cancer progression[13,18]
miR-222DownregulatedTissuePredictive of tumor suppression and cancer progression[13,18]
miR-30cDownregulatedTissuePredictive of cancer cell proliferation and invasion[13,19]
miR-1225-5pUpregulatedTissuePredictive of tumor promotion[13]
miR-663aUpregulatedTissuePredictive of tumor promotion[13]
miR-335-5pDownregulatedTissuePredictive of apoptosis induction in prostate cancer[20]
miR-21UpregulatedTissuePredictive of aggressive prostate cancer[14,21]
miR-125bUpregulatedTissuePredictive of aggressive prostate cancer[22]
miR-182-5pUpregulatedTissuePredictive tumor growth and differentiation[23,23]
miR-183-5pUpregulatedTissuePredictive of tumor invasion and metastasis[24]
miR-96-5pUpregulatedTissuePredictive of metastatic potential[24,24]
miR-449bUpregulatedTissuePredictive of biochemical recurrence after radical prostatectomy[25]
miR-223-5pDownregulatedTissuePredictive of tumor suppression via ERG inhibition[26]
miR-455-3pDownregulatedTissuePredictive of tumor suppression via eIF4E inhibition[27]
Table 2. miRNAs as therapeutic targets in prostate cancer.
Table 2. miRNAs as therapeutic targets in prostate cancer.
miRNAExpression in Prostate CancerLocation (Plasma/Tissue/Both)Therapeutic RoleAuthors
miR-205DownregulatedTissueTumor suppressor; potential therapeutic target for restoring tumor suppression[14,30]
miR-221DownregulatedTissueTherapeutic target for inhibiting tumor progression[13,18]
miR-222DownregulatedTissueTherapeutic target for inhibiting tumor progression[13,18]
miR-30cDownregulatedTissueTherapeutic target for reducing cancer cell proliferation and invasion[13,19]
miR-1225-5pUpregulatedTissueTherapeutic target for inhibiting tumor promotion[13]
miR-663aUpregulatedTissueTherapeutic target for inhibiting tumor promotion[13]
miR-21UpregulatedTissueTherapeutic target for reducing tumor growth and PTEN knockdown[21,31]
miR-200 familyDownregulatedTissueTherapeutic target for regulating cancer cell migration and tumor suppression[32]
miR-23bDownregulatedTissueTherapeutic target for inhibiting tumor proliferation, migration, and metastasis[38,40]
miR-449a/bDownregulatedTissueTherapeutic target for inducing cell cycle arrest and apoptosis[45,46]
miR-582-5pDownregulatedTissueTherapeutic target for inhibiting TGF-β signaling and metastasis[33,35]
miR-548c-3pDownregulatedTissueTherapeutic target for regulating ErbB and Hippo signaling pathways[36]
miR-455-3pDownregulatedTissueTherapeutic target for inhibiting eIF4E and tumor growth[27]
miR-223-5pDownregulatedTissueTherapeutic target for inhibiting ERG and tumor progression[26]
miR-34a/cDownregulatedTissueTherapeutic target for reducing androgen receptor levels and tumor aggression[47,47]
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Kallinikas, G.; Ektesabi, A.M.; Vaswani, C.M.; Haronis, G.; Kallinika, E.; Kozyrakis, D.; Rodinos, E.; Filios, A.; Filios, P.; Mityliniou, D.; et al. A Brief Review of MicroRNA Profiling in Human Prostate Cancer Tissues and Plasma. Biomolecules 2025, 15, 1156. https://doi.org/10.3390/biom15081156

AMA Style

Kallinikas G, Ektesabi AM, Vaswani CM, Haronis G, Kallinika E, Kozyrakis D, Rodinos E, Filios A, Filios P, Mityliniou D, et al. A Brief Review of MicroRNA Profiling in Human Prostate Cancer Tissues and Plasma. Biomolecules. 2025; 15(8):1156. https://doi.org/10.3390/biom15081156

Chicago/Turabian Style

Kallinikas, Georgios, Amin M. Ektesabi, Chirag M. Vaswani, Georgios Haronis, Eirini Kallinika, Diomidis Kozyrakis, Evangelos Rodinos, Athanasios Filios, Panagiotis Filios, Despoina Mityliniou, and et al. 2025. "A Brief Review of MicroRNA Profiling in Human Prostate Cancer Tissues and Plasma" Biomolecules 15, no. 8: 1156. https://doi.org/10.3390/biom15081156

APA Style

Kallinikas, G., Ektesabi, A. M., Vaswani, C. M., Haronis, G., Kallinika, E., Kozyrakis, D., Rodinos, E., Filios, A., Filios, P., Mityliniou, D., Safioleas, K., Bozios, D., Karmogiannis, A., Konstantinopoulos, V., Konomi, A. M., & Tsoporis, J. N. (2025). A Brief Review of MicroRNA Profiling in Human Prostate Cancer Tissues and Plasma. Biomolecules, 15(8), 1156. https://doi.org/10.3390/biom15081156

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