Review ArticleRole of miRNAs in prostate cancer: Do we really know everything?
Introduction
Prostate cancer (CaP) is the most common male malignancy worldwide, with a prevalence of over 3.6 million and an estimated 174,650 new cases in 2019 in the USA [1,2]. CaP affects about 30% of men aged over 50 years old, but only 10% of them will be diagnosed with clinically significant disease [3]. The definitive` diagnosis of CaP is based on prostate biopsy that has to be performed when an altered PSA level and/or a suspicious Digital Rectal Examination (DRE) are detected. The main goals in CaP diagnosis are to detect cancer at an early stage and to distinguish the clinically significant disease from the indolent one in order to treat more cancer patients at an initial and localized stage, improve cure rates, and to avoid overtreatment [4]. However, the main problem with the diagnostic management of CaP is the poor accuracy of currently available tools. The positive predictive power of prostate biopsy performed for serum PSA levels greater than 2.5 to 4 ng/ml and/or abnormalities in DRE is about 24% to 37% [5], [6], [7]. Although the introduction of serum PSA evaluation in clinical practice has dramatically improved the early diagnosis and consequently the success rate of confined-organ disease treatment, its extensive use is not recommended. In fact, PSA is an organ-specific, rather than a cancer-specific, marker and, for this reason, altered PSA levels may be due to benign conditions as well as cancer. This poor specificity of PSA has brought about an increase in unnecessary biopsies and diagnoses of indolent tumours that are not life-threatening [8]. Moreover, the overtreatment of indolent disease could expose the patients to possible complications without any benefit in terms of cancer-specific survival. Albertsen et al. demonstrated that the risk of dying from a Gleason Score of 8 to 10 CaP within 10 years is about 12.1%, while this risk is minimal for low-risk disease [9]. Many different genetic alterations, as well as complex epigenetic interactions, are at the basis of the genesis and progression of CaP [10]. For these reasons, until now the molecular pathways related to the development of this cancer, and those determining aggressive or indolent tumour behaviour, were still unknown. In the last decades, basic research has been focused on the discovery of new biomarkers able both to provide an accurate and early diagnosis, and to distinguish aggressive forms from indolent ones in order to plan an individualized therapy [11].
MicroRNAs (miRNA) are short noncoding single-stranded RNA molecules, that regulate post-transcriptional gene expression by complementary binding to the 3′ untranslated region (3’-UTR) of mRNAs, which, in turn, lead to translational suppression or degradation of the mRNA target [12] (Fig. 1). MiRNAs play a crucial role in regulating several biological functions and preserving homeostasis as they carry out a wide modulatory activity on various molecular signalling pathways. About 60% of all human genes are regulated by miRNAs [13].
Because miRNAs are placed in cancer-related genomic regions or in fragile sites, and are involved in main steps of carcinogenesis since they can regulate the expression of many oncogenes and oncosuppressor genes, miRNAs have been assessed as potential biomarkers for almost every type of cancer [14,15]. In 2007, for the first time, Porkka et al. associated a particular miRNA expression profile with CaP [16].
The evidence of their key role in prostate carcinogenesis and progression, their stability in biological fluids such as serum and urine, and their resistance to various storage conditions make miRNAs promising candidates as minimally invasive diagnostic and prognostic biomarkers for CaP [17].
We performed a narrative review to describe the relationship between miRNAs and the crucial steps of CaP development and progression. The aim of this study was to improve the knowledge concerning the mechanisms underlying miRNA expression and their target genes in CaP. (Fig. 2).
Section snippets
MiRNAs biogenesis and function
Canonical miRNAs biosynthesis begins in the nucleus with the transcription of long primary transcripts, called primary-miR (pri-miR), by RNA Polymerase II/III [18]. These primary transcripts are characterized by stem-loop structures (a 3’ poly-A-tail and 5’ methylated cap) and can be up to several hundred nucleotides long. Pri-miRs are then processed by the Microprocessor complex that is composed of Drosha (an RNase III endonuclease) and DGCR-8 (DiGeorge syndrome chromosomal or critical region
Cell cycle
Aberrant cell cycle regulation is a hallmark of carcinogenesis [28] often correlated with dysfunction of the miRNAs that control the expression of cell cycle-related genes.
Some miRNA functions are already established: miR-193a-3p is known to be a tumour suppressor and is expressed less in cancerous tissues compared to Benign Prostatic Hyperplasia (BPH). A recent study demonstrates that in gain-of-function experiments, miR-193a-3p can inhibit cell growth by regulating CCND1 and promoting
Proliferation
MiRNAs have been described as being implicated in CaP cell proliferation, causing malignant development and progression. Generally, the role of miRNAs in cell proliferation of CaP was studied in prostatic tissues and/or in the prostatic cancer cell line.
In order to understand the role of miRNAs in tumour prostatic proliferation, Aakula et al. tested hundreds of miRNAs by in vitro functional assays in CaP cell lines, proving that 14 miRNAs were implicated in cell proliferation. These miRNAs were
Apoptosis
Apoptosis is a physiological form of cell death required for the removal of cells that are damaged, aged, or transformed. The mechanisms underlying apoptosis are, therefore, complex and involve many signalling pathways. In recent decades, the role of miRNAs has been studied in cancerous and healthy prostate cells or tissues, and it was observed that in both conditions some miRNAs regulate the apoptosis pathway.
Indeed, in CaP cells, miR-34a, miR-34c, miR-15a, and miR-204-5p were identified as
Epithelial mesenchymal transition
Epithelial Mesenchymal Transition (EMT) is a physiological process by which epithelial cells acquire a mesenchymal phenotype. A dysregulation of EMT is one of the key processes underlying metastatic CaP. E-cadherins are cell surface proteins designated to establish and maintain cell-cell interactions, and they are regarded as gatekeepers of the epithelial state. In CaP, it has been proved that aberrant activation of EMT is associated with lost, or reduced, expression of E-cadherins by
Metastasis
The metastasis process includes several phases that make cancer prostatic cells able to degrade the extracellular matrix (ECM), violate host tissue and invade the lymphatic and blood systems (intravasal time). Circulating tumour cells survive until they reach the metastatic site, where they leave the bloodstream (extravasal time), colonize the foreign microenvironment and begin proliferation to generate a secondary tumour [105,106]. Of millions of tumour cells that infiltrate the bloodstream,
Future perspectives
In recent years, several studies have indicated that miRNAs circulate in different biological fluids, including blood, urine and semen, and that they are detectable in cell culture media, which is useful for in vitro analysis [123]. Moreover, they could be carried with lipoproteins, encapsulated into microparticles (exosome‐like and apoptotic bodies), or linked to Argonaute proteins [124]. Circulating miRNAs, therefore, offer the potential of being utilised as non-invasive biomarkers for
Conclusion
MiRNAs represent a class of small, non-coding RNAs regulating gene expression at the post-transcriptional level. They regulate many biological functions through a wide modulatory activity on various molecular signalling pathways, and their dysregulation has been proved to be involved in carcinogenesis and the progression of CaP. Many studies have suggested that miRNAs may be promising non-invasive biomarkers in CaP, but no miRNA has yet been used as biomarker for diagnosis or prognosis of CaP
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