miRNAs as Biomarkers in Disease: History
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Contributor:
Carmen Elena Condrat
,
Dana Claudia Thompson
,
Madalina Gabriela Barbu
,
Oana Larisa Bugnar
,
Andreea Boboc
,
Dragos Cretoiu
,
Nicolae Suciu
,
Sanda Maria Cretoiu
,
Silviu Cristian Voinea

MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. 

  • miRNA
  • biomarker
  • diagnosis
  • prognosis
  • cancer

1. Introduction

microRNAs (miRNAs) represent a class of small, non-coding RNAs comprising of 17–25 nucleotides [1], whose main role is to regulate mRNA by leading to its degradation and also to adjust the protein levels [1][2][3][4]. Their discovery was first published in 1993 and they were described as “mediators of temporal pattern formation” in Caenorhabditis elegans [5][6][7][8][9]. Previous studies have shown that miRNA encoding sequences form up to 1% of the human genome [10].
Biogenesis of miRNA begins in the nucleus, where the transcription of its precursor, primary miRNA or pri-miRNA takes place under the influence of RNA polymerases II and III [11][12]. The resulting molecule is a hairpin-like structure, which contains a loop at one end [11]. This primordial mi-RNA precursor that is usually made up of hundreds of nucleotides is then processed consecutively by two RNase III enzymes [13][14][15]. The first enzyme to act upon the pri-miRNA, which still resides in the nucleus, is called Drosha or DCGR8, and turns it into a new hairpin-like structure of approximately 70 nucleotides, the Precursor-miRNA or pre-miRNA. The latter is then transported to the cytoplasm, with the help of Exportin-5, where it is cleaved again by the Ago2/Dicer complex leading to the short, mature miRNA double strands [16].

2. The Potential of miRNAs as Biomarkers

Biomarker is a term that defines different types of objective indicators of health or disease. Throughout history, and according to human technological advancements, these indicators have turned increasingly more precise and reliable. Some of the first biomarkers were discovered in ancient times and were represented by the medical signs, such as pulse, the looks and even the taste of urine.
Nowadays, the medical community refers to biomarkers as being certain molecules, usually proteins, detected in the various fluids of the human body, through specific means in medical laboratories. The best known protein biomarkers measurable in the blood are troponin for the diagnosis of myocardial infarction, carcinoembryonic antigen (CAE) for different types of cancer, aminotransferases ALT and AST for liver diseases and the prostate-specific antigen (PSA) for the diagnosis and prognosis of prostate cancer [2]. Recently, however, detecting new and improved protein biomarkers has turned out to be a time consuming and expensive operation, due to the low amount of clinically significant proteins, the complexity of their structure and the struggle in finding accurate detection methods.
In order to attain the desiderates of personalized medicine, new and more accurate biomarkers need to be discovered. An ideal biomarker needs to fit certain criteria. First of all, it needs to be easily accessible, which means that it needs to be discovered and measured through minimally invasive procedures. Another important criterion is the specificity to the investigated pathology, followed by sensitivity (its presence should be detected preferably before the clinical symptoms have appeared and should vary according to the disease progression or response to treatment). Last, but not least, it should be translatable from research to clinic [17].
Researchers have discovered the existence of free nucleic acids in the blood for about 60 years [18][19][20][21][22], while DNA and RNA from tumors are frequently encountered in the plasma of cancer patients [23][24][25][26]. It was considered for a while that RNA molecules could not be used as biomarkers from blood samples, because of the elevated levels of nucleases found in plasma [27], but the idea was dismissed once it was discovered that miRNAs were stable in samples of fixed tissues [28].
miRNAs have first been established as biomarkers for cancer in 2008, when Lawrie et al. utilized them for the examination of diffuse large B-cell lymphoma in the serum of patients [29][30], and ever since, their potential use as biomarkers has been mentioned in literature for numerous diseases.
This novel class of molecules possesses an array of advantages that could turn them into ideal candidates for biomarkers in a variety of afflictions. As mentioned before, the ideal biomarker needs to be easily accessible, a condition that applies to miRNAs that can easily be extracted through liquid biopsies from blood, urine and other bodily fluids. It also has a high specificity for the tissue or cell type of provenance and it is sensitive in the way that it varies according to the disease progression, being used in several studies for the differentiation of the cancer stages [31] and even for the measurement of the therapy responsiveness [32]. Moreover, the technologies for the detection of nucleic acids already exist and the development of new assays requires less time and lower costs in comparison to producing new antibodies for protein biomarkers.
Another advantage of miRNAs lies in their potential for being used as multimarker models for accurate diagnosis, guided treatment and evaluating responsiveness to treatment. While running many protein markers may be both expensive and time-consuming, using multimarker panels composed of numerous miRNAs may provide a non-invasive method for diagnosis and prediction of disease progression. For instance, identifying the urinary miRNA signature of lupus nephritis has promoted the early detection of renal fibrosis [33]. This is especially important in cancer, a thoroughly heterogenous disease, where a multimarker approach would be preferable. To this extent, a nine-miRNA multimarker panel for breast carcinoma has already been shown to significantly improve the reliability of breast cancer diagnosis [34].
However, the research of miRNAs as biomarkers is still in its early stages, therefore at the moment, the findings generally lack reproducibility. There are several discordances reported between different teams that have analyzed the same tumors [35]. In order to resolve this issue, standardized protocols must be developed both for the initial stages of the process, like sample collection, transport, and storage, as well as data analyzing for the diversity of technological methods used.

3. miRNA Identification Techniques

In order to aid the diagnostic process and optimize treatment plans, research has delved into molecular testing, aiming to develop an efficient and cost-effective method for detecting miRNAs involved in some of the most common diseases worldwide, while also trying to identify new such molecules associated with these pathologies. Nevertheless, this quest has proven to be rather challenging, mainly due to the fact that the field of miRNAs itself is relatively new, and therefore traits such as detection limits, range of concentrations in body fluids, modulation depending on various parameters (age, gender, health/disease) are not yet clearly established [36].
The gold-standard for miRNA quantification is quantitative reverse transcriptase PCR (RT-qPCR) [36][37][38]. Stem-loop reverse transcription (RT)-based TaqMan microRNA assay is the main PCR technique used in research, with the advantage of having high sensitivity and specificity rates [39]. This is a two-step method, the first step requiring the binding of miRNA molecules by primers at the 3′ end in order to proceed to stem-loop reverse transcription [40]. For the second step of the technique, real-time PCR is used to quantify the miRNAs targeted [40]. Other available options are direct RT-based and poly (A) tailing-based SYBR miRNA assays [39]. The downside to these techniques is that sensing errors for the samples used can sometimes happen and also, during the amplification steps, there is high risk of contamination [36].
Northern blot hybridization represents another widely used alternative for quantitative assessments of miRNAs. This method involves the separation of the total amount of RNA on polyacrylamide gel that possesses the property of denaturation, followed by its transfer on a nylon membrane. After that, the RNA undergoes a process of UV cross-linking and, lastly, it is hybridized using a radioactive substance [41][42][43][44]. However, this technique tends to be strenuous, it necessitates large quantities of RNA and it has sometimes been reported to omit rare types of miRNA [44]. Under these circumstances, efforts have been made in order to improve the method, therefore leading to the possibility of using lower amounts of RNA and also shortening the execution time of the technique [45][46][47].
Two other methods are also in use for the same purpose of identifying the miRNAs. In situ hybridization or ISH is a technique that utilizes radioactive, fluorescent or dioxygenin probes to bind the desired RNA, therefore comparing the expression of miRNAs in various cells [48]. The disadvantages of ISH, however, are still significant and include laborious steps and long processes, with a predisposition towards errors [48]. The second method is next-generation sequencing or NGS. Despite the fact that this is a highly accurate technique that has the ability to detect single miRNAs with the precision of one nucleotide, its high costs lead to a limitation of this technique’s wider accessibility [44].

4. miRNAs in Cancer

Cancer is the most important cause of mortality worldwide. Even though detection in its early stages could lead to a better outcome for the survival of the patient, unfortunately, late detection still remains a major concern nowadays, leading to poor prognosis and a high mortality rate [49]. As a result, and in order to overcome this problem in the age of personalized medicine, new and more sensitive diagnosis methods, such as biomarkers, need to be developed.
Numerous reports have published throughout the years, hundreds of cases of deregulated miRNAs found in the plasma and serum of cancer patients, in comparison to healthy subjects [50] and a lot more studies have nominated circulating miRNAs as potential biomarkers for the diagnosis and prognosis of cancer [50][51][52][53]. The role that circulating miRNAs are playing in cancer is controlling the oncogenes (which is achieved through tumor suppressor miRNAs) and the tumor suppressors (through oncomiRs) [54]. Usually, the oncomiRs tend to be excessively represented (for example miR-17-92 or miR-21 clusters) [55][56], while the miRNAs with tumor suppression function (let-7 cluster), are expressed insufficiently [57]. These discoveries have been made experimentally, by inhibition or inducement of their function.
There are, however, miRNAs that can act both as suppressors or oncomiRs. For example, miR-155 was first considered an oncomiR for lymphoma and pancreatic cancer [58][59], but other evidence suggests that in the cases of ovarian and gastric cancers and melanoma, its expression is inhibited, therefore acting like a tumor suppressor [60][61][62].
There are various causes of the abnormal expression of circulating miRNAs in cancer. Around 50% of the miRNA coding genes are located in areas of the genome that are associated with cancer, which are translocated or amplified in malignancies [63]. Another reason is represented by the function variation of the enzymes involved in the biosynthesis of miRNA, like Drosha and Dicer 1 [64]. A decrease in the levels of these enzymes has been reported in the case of bladder [65] and ovarian cancers [66], while elevated levels are encountered in gastric [67] and cervical squamous cell neoplasms [68]. Lastly, the alteration of circulating miRNAs in cancer could also be caused by transcriptional errors of pri-miRNA [64].
Further on, this research will describe several types of cancer and how their miRNA profiles could potentially lead to medical advancements in terms of an early diagnosis and a better profiling of these malignancies. A brief summary of some of the most important findings analyzed  in Table 1.
Table 1. MicroRNA (miRNA) regulation in cancer.
miRNA Disease Regulation Main Characteristics Reference
miR-10b Breast Cancer Upregulated Overexpressed only in metastatic disease
In non-metastatic disease—cell invasion and metastasis inductor
High levels correlated to disease progression and poor outcome		 [69][70][71]
miR-196a Breast Cancer Upregulated Oncogenic role
Alters apoptosis and angiogenesis
High levels associated with advanced disease		 [72][73][74][75]
miR-4417 Breast Cancer Downregulated Prognostic tool for TNBC
Levels correlated to the evolution of the disease		 [76][77]
miR-200 cluster Ovarian Cancer Upregulated Low levels associated with cell invasion and metastasis
Low levels predict poor outcomes and disease recurrence
Angiogenesis inhibitors		 [78][79][80][81]
miR-506 Ovarian Cancer Dysregulated Cell invasion, migration and EMT inhibitor
High levels confer a good prognosis		 [82]
let-7 cluster Ovarian Cancer Dysregulated Suppressors of tumor growth and cell invasion [80][83][84]
miR-183 Ovarian Cancer Dysregulated Overexpressed in low metastatic ovarian cancer [85]
miR-22 Ovarian Cancer Dysregulated Overexpressed in low metastatic ovarian cancer [85]
miR-21a Cervical Cancer Upregulated Inflammation and proliferation stimulator
Apoptosis inhibitor		 [86]
miR-944 Cervical Cancer Upregulated Levels associated with advanced FIGO stage, bulky tumor size, lymph node metastasis
Poor prognostic factor
Higher levels in HPV-positive cervical cancer		 [87][88][89]
miR-138 Cervical Cancer Downregulated Tumor suppressor role
Apoptosis stimulator
Negatively associated with lymph node metastasis and advanced FIGO stage		 [90][91][92]

This entry is adapted from the peer-reviewed paper 10.3390/cells9020276

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