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Commentary

A microRNA molecular signature of aggressive prostate cancer

To engagement, prostate cancer (PCa) remains a medical claiming, being one of the nigh prevalent causes of cancer deaths in men worldwide (one). A major innovation in the management of PCa was demonstrated by the measurement of prostate specific antigen (PSA) in the serum of PCa patients in the mid-1980s; however, information technology is well known that measurement of PSA levels is associated with over-diagnosis and over-handling. Although over-treatment may be reduced by improved risk stratification where very low or depression risk PCa can be monitored past agile surveillance and intermediate or high risk PCa can be subjected to treatment, many urologists and patients are reluctant to delay treatment due to the absence of a reliable indicator of aggressive illness and thus, there is a possibility of missing handling of aggressive PCa patients (2,3). A single threshold PSA test is unable to distinguish between high and low chance PCa (4), and prostate biopsy is oftentimes unreliable for the prediction of cancer grade, equally simply a minor fraction of the prostate is sampled during a biopsy for staging (5). Several promising blood based and urinary biomarkers such as the prostate health index (PHI), 4K score and PCA3 for neoplasm aggressiveness have been identified and recommended to reduce the number of unnecessary biopsies in PSA tested men (half dozen,7). However, in order to appreciate the clinical value of these biomarkers, additional unbiased prospective studies are still required. It is anticipated that the availability of unique molecular signatures and novel biomarkers would lead to an comeback in the management of patients with aggressive PCa, and microRNAs (miRNAs) are pioneers in this expanse.

The prevailing understanding was that the genome consists of regions with piffling coding textile of importance; however, recent advances accept shown that these regions are not so barren subsequently all. A part of the and so called "non-coding" genome in fact encodes for critical cistron regulators called miRNAs that are present in stable forms in the circulation and thus, tin play an important part every bit diagnostic and prognostic biomarkers for several diseases (viii). Mature miRNAs were initially detected in the cell costless fractions of blood such as serum and plasma (8), and subsequently found in other body fluids and neoplasm tissues (9). We accept recently reviewed the diagnostic and prognostic value of miRNAs, along with several detection methodologies which provides of import insights into the use of miRNAs every bit non-invasive cancer biomarkers (ix).

Knowledge almost uptake, packaging and release of miRNAs is crucial to determine their regulatory functions, and double lipid membrane vesicles, chosen exosomes, accept been found to play a crucial role in this regard (10). The usefulness of exosome miRNAs has been evaluated by several studies including a study past Li et al. showing elevated levels of exosomal miR-141 in metastatic PCa patients in comparison to beneficial prostatic hyperplasia (BPH) patients and healthy controls (11). Similarly, Huang et al. showed that the plasma exosomal level of miR-1290 and miR-375 was associated with poor survival of castration resistant PCa patients (12). Autonomously from serum and plasma, Samsonov et al. indicated upregulation of miR-21, miR-141 and miR-574 in urinary exosomes isolated from PCa patients and healthy controls using a lectin-based agglutination method (13). Therefore, exosomal miRNAs may be utilized as non-invasive molecular signatures specific to patients with an increased risk of developing aggressive PCa, but it is difficult to differentiate intermediate grades from aggressive forms due to the heterogeneity of PCa.

To address this effect, in a recent written report published in Proceedings of the National Academy of Sciences (PNAS) (xiv), Alhasan and colleagues developed a high-throughput, spherical nucleic acid (SNA)- and microarray-based miRNA expression profiling platform, chosen the Scano-miR bioassay, to determine the exosomal miRNA expression. Authors used the Scano-miR bioassay in a discovery set of 16 serum samples from patients with varying grades of PCa, i.e., ≥eight Gleason Score for high or very loftier take chances and Gleason Score =6 for very depression or low risk PCa, and healthy individuals. Furthermore, a molecular signature score was calculated, as done by Zeng et al. previously (15), to ensure diagnostic reliability upon combining the differentially expressed miRNAs in a blind study. In this way, a molecular signature consisting of five miRNAs (miR-200c, miR-605, miR-135a*, miR-433 and miR-106a) was identified capable of differentiating indolent and ambitious forms of PCa with 89% accuracy after validation in a 2nd cohort by quantitative real time PCR (qRT-PCR) (xiv). This unique molecular signature may aid in stratifying patients who may benefit from therapy from those who may only require close monitoring through active surveillance.

In the above study, the serum expression of miR-200c was highly elevated in very high risk PCa patients suggesting its office in predicting metastasis, and similar results have been obtained in studies focussing on colorectal and gastric cancer (16,17), suggesting the function of this miRNA every bit a general marker of metastasis. In another study, miR-200c has been found to be role of a five biomarker panel for the detection of metastatic castration resistant PCa supporting the findings of Alhasan and colleagues (18). Dysregulation of miR-106a has been reported in lung and gastric cancer (xix) and has been previously linked to PCa. miR-106a was too one of the previously reported participant of several biomarker panels for loftier gamble PCa (twenty), only the other miRNAs accept not been previously associated with PCa.

PCa is very heterogeneous in nature where cancer specific survival charge per unit is higher in patients with a depression gamble of disease progression compared to those with aggressive disease. The investigation carried out by Alhasan and colleagues atomic number 82 to the discovery of a novel miRNA signature capable of differentiating indolent from aggressive forms of PCa at a college rate than typical Gleason scoring of biopsy samples, representing a unproblematic diagnostic tool without the demand for surgical intervention. The Scano-miR bioassay does not rely on enzymatic amplification of a specific target as many of the electric current miRNA detection methods do, and therefore, allows multiplexing and detection of multiple miRNAs at the femtomolar levels in single samples. In addition, pathway analysis was too performed to identify targets of the miRNA panel and some of the targets were establish to be known drivers of tumorigenesis.

So far, specific miRNA expression patterns have been proposed for PCa subclasses, but further studies are required and several questions need to be addressed to assist the establishment of miRNA signatures for cancer diagnosis and prognosis. Some of these necessitate an understanding of the relationship betwixt circulating and neoplasm derived miRNAs, their mechanism of uptake and release, their response to inflammation and modifications, and finally their role in tumorigenesis and metastasis. Although several new techniques have improved the specificity and sensitivity of miRNA detection, the lack of referenced procedures for sample preparation, RNA extraction, endogenous control selection, sample size adding, etc. makes information technology difficult to compare results betwixt independent studies. The major claiming is to overcome these hurdles and identify reliable miRNA biomarkers for the stratification of cancer patients. The development of digital PCR would remove the dependence on a miRNA normalization control which is non yet established for qRT-PCR, where an exogenous control is used mostly. Besides, digital counting technologies such as adjacent-generation sequencing (NGS) and the NanoString nCounter miRNA Expression Assay may exist used for miRNA profiling. NGS allows the discovery of new miRNAs and confirmation of already known miRNAs as opposed to microarrays and qRT-PCR, and overcomes the limitations of background point, microarray console difference and cantankerous-hybridization issues associated with the use of microarrays. The NanoString nCounter organisation is some other new hybridization-based technology which directly detects miRNAs of interest using target specific, colour-coded probes without the need for opposite transcription or amplification by qRT-PCR (twenty). All these advancements in the area of biomarker inquiry and inclusion of other criteria such patient age, PSA level, clinical neoplasm stage, Gleason Score, etc. for risk assessment from a PCa perspective followed by multivariate analyses, will not only help in accurate cancer detection, but will too facilitate the development of novel strategies for cancer therapy.

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Acknowledgments

Funding: This piece of work is supported by the Cancer Australia Priority-Driven Collaborative Grant [1068321 (241544-0358/51)]. Dr. Batra is supported by an NHMRC Career Development Fellowship. Ms. Matin is supported by the QUT Postgraduate Inquiry Award (QUTPRA) and QUT HDR Tuition Fee Sponsorship.

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Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Peng Zhang (Section of Urology, Union Hospital, Tongji Medical College, Huazhong Academy of Science and Technology, Wuhan, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.01.21). The authors take no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of whatever role of the piece of work are appropriately investigated and resolved.

Open up Access Statement: This is an Open Access article distributed in accord with the Creative Eatables Attribution-NonCommercial-NoDerivs iv.0 International License (CC Past-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original piece of work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this commodity every bit: Matin F, Batra J. A microRNA molecular signature of aggressive prostate cancer. Transl Cancer Res 2017;6(Suppl 1):S12-S14. doi: x.21037/tcr.2017.01.21

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