Relation of Circulating MicroRNAs as Biomarkers in few Diseases

The abundance of circulating miRNAs which are small non-coding RNAs involved in posttranscriptional regulation of gene expression in body fluids of patients with cancers, cardiovascular diseases, neurological diseases, autoimmune and infectious diseases hold great promise to identify stable and specific biomarkers, which may be useful for early diagnosis as well as to predict the clinical outcome and treatment response. Because of an aberrant miRNA expression, emerging theme for a wide variety of diseases, highlighting the fundamental role played by miRNAs in both physiological and pathological states. Recent studies have reported significant levels of miRNAs in serum and other body fluids, raising the possibility that circulating miRNAs could serve as useful clinical biomarker. We review the disease and cancer-specific profiles of circulating microRNAs. We also discuss possible functions of circulating microRNAs and their potential as non-invasive biomarkers.


Introduction
Research of microRNA (miRNA) in cancer, cardiovascular and neurological diseases is an emerging field with potential novel applications in diagnostics and therapy. [1]These noncoding RNA with 18-25 nucleotides function in RNA silencing and post-transcriptional regulation of gene expression.More than 19,000 entries of miRNAs exists in the database from 168 species and 1,612 of them belongs to homo sapiens. [2]ogenesis and origin of miRNA miRNA regulates gene expression by promoting mRNA degradation or by attenuating protein translation.It is estimated by computational prediction that more than 60% of mammalian mRNAs are targeted by at least Circulating MicroRNAs as Biomarkers miRNAs could be valuable biomarkers as revealed by ROC curve analysis.
Even though serum miRNA-122a levels correlates as a marker for hepatocellular cancer, it is not superior to alfa-feto protein as a diagnostic tool. [12]In lung cancers including stage-I disease the plasma levels of miR-155, 197 and miR-182 severe significantly elevated compared to controls. [13]Sixty three miRNAs that were absent in the controls were found in the sera of non-small cell lung cancer patients (NSCLC). [14]Kannan and colleagues found that 380 miRNAs were dysregulated in the tissues of colorectal cancer (CRC).
The two most upregulated miRNAs 31and 135b and most downregulated miR-NAs 1and 133a could identify CRC with 100% sensitivity and 80% specificity. [15]In CRC stages III and IV miR-31 was more upregulated compared to stages I and II.Whereas in the plasma group miR-21 differentiated CRC patients from controls with 90% sensitivity and specificity. [16]miR-133 and 155a have been shown to be the best combination biomarkers in identifying oral squamous cell carcinoma. [17]In gastric cancer, the serum levels of upregulated miRNAs miR-21 and 106 b are higher before surgical resection and reduces significantly after resection. [18]Serum miR-21, 146a and 148a are closely associated with gastric cancer pN stage and could be biomarker candidates to predict lymph node metastasis. [19]Plasma levels of miR-21, 210, 155 and miR-196a can differentiate pancreatic adenocarcinoma. [20] adult leukemia there is a decrease in miR-92a levels in the plasma.A specific profile is also observed in CLL and can help differentiate from multiple myeloma and hairy-cell leukemia.The miR marker for CLL correlates well with ZAP-70 status used as a prognostic marker and is also useful to stratify CLL. [21]miRNAs 425-5p and 93-5p are found abundantly in plasma following radiotherapy of HNSCC and may represent as novel biomarkers for therapy monitoring.Application of circulating miRNAs in cancer.

Circulating microRNA in cardiovascular diseases
Since the discovery of circulating biomarkers, a vast literature exists on its role in relation to cardiovascular disease such as myocardial infarction, heart failure atherosclerosis and hypertension. [22]In early studies four cardiac miRNAs namely miR-208a, miR-499, miR-1, and miR-133 are found to be consistently elevated in plasma of AMI patients within hours after the onset of infarction. [23]miR-1,miR-133a, and more particularly miR-208a may even be more sensitive than the classic biomarker cTnI. [24]Reduced levels of miR-126, miR-15a, miR-29b, and miR-223 and elevated levels of miR-28-3p were reported in this study.Levels of cTN-I and NT-pro-BNP were positively correlated with miR-21 and negatively correlated with miR-126.Integrating specific pattern of miRNA levels with NT-pro- BNP and/or cardiac troponin may improve the diagnosis of cardiovascular diseases. [25]ompared to the other microRNAs, miR-208a biomarkers can be used for early detection of AMI and MiR-1 and miR-133 may also serve to diagnose AMI. [26]miR-1 and miR-133a levels may be correlated with muscle creatine kinase levels and cTnI levels in plasma and are affected by pathology of other organs, as these miRNAs levels have also been found to increase in lung cancer and colorectal cancer.
The combined assessment of the 2 myo-miRs miR-208a and miR-499 may provide an attractive signature to diagnose both acute and very recent cardiac injury miR-208, whereas miR-499 due to its role in the inflammatory process can trace myocardial injury. [27]In one of the most accepted studies, the lower levels of miR-126 were also found in atherosclerotic CAD and in patients with type 2 diabetes mellitus and may reflect the condition of vascular endothelial cells in HF patients.miR-126, miR-92a and miR-17 are determined as the most promising miRNA biomarkers in diagnosis of patients with CAD. [28]

Circulating miRNAs as biomarkers in neurodegenerative disorders
Studies show the association between circulating biomarkers packed in carriers and suspended in the fluid, and neuro degenerative diseases. [29]Study on the PBMCs identified significantly under-expressed miRNAs and showed miR-103 and miR-107 suppress Cofilin translation with the increased level of active Cofilin protein, which leads in the Cofilin rods formation. [30]other study using qRT-PCR, suggested that miR-1, miR-22-5p and miR-29 expression levels in total peripheral blood allow to distinguish non-treated PD from healthy subjects, and that miR-16-2-3p, miR-26a-2-3p and miR30a differentiate treated from untreated patients. [31]Among all the known miRNAs, some regulate the neuron development process, such as neurogenesis, synaptic formation, and stem cell differentiation such as miR-9, miR-124a, miR-124b, miR-135, and miR-219.Circulating miR-223 is the marker for acute ischemic stroke. [32]miR-132 and miR-212 are involved in several abnormalities like synaptic plasticity and connectivity in Schizophrenia and in neuronal cultures, the mature miR-132 stability is affected by NMDA inhibition.

Circulating microRNA in skin and autoimmune disease
As the diseases affecting the skin and immune system are closely related the circulating biomarkers are found to work well in their diagnosis and prognosis. [33]Serum miR -21 levels were significantly up-regulated, correlating with serum IgG levels in dermatomyositis.Serum levels of miR-223 and miR-7 were down-regulated , while serum miR-142-3p and miR-92 was not changed in dermatomyositis patients. [34]Psoriatic patients have positive association with cardiovascular diseases, so that the expression of cell-free circulating microRNA-33 and mi-croRNA-126 in plasma from psoriatic patients and the relationship with clinical parameters have been identified.Similarly, Pivarcsi and colleagues recently reported up -or downregulation of miR-128a, let-7d, miR-142-3p and miR-181a in sera from psoriasis patients compared with normal subjects. [35] another study Serum miR-150 levels were found to be decreased in Systemic Sclerosis (SSc) patients. [36]atients with lower serum miR-150 levels had more severe clinical manifestations.Patients with lower serum miR-196a levels had a significantly higher ratio of diffuse cutaneous scleroderma (dSSc) limited cutaneous sclerodermal lesion, a higher modified Rodnan total skin thickness score, and a higher prevalence of pitting scars than those with higher miR-196a levels. [37]atients with SSc showed miR-142-3p levels which were significantly higher than those in patients with systemic lupus erythematosus, dermatomyositis and scleroderma. [38]Serum level of miR-142-3p correlated with the severity of SSc fibrosis and may be useful diagnostic markers for the presence of SSc and differentiation of SSc from scleroderma spectrum disorder. [39,40] sease miRNA type

Cardiovascular disease
Acute myocardial infarction miR-

Circulating microRNA and viral and bacterial infections
Viral and bacterial infections have been associated with cf-microRNA and there is significant development of many biomarkers for their early detection.Presence of circulating miR-BART17-5p and EBV DNA in a larger series of nasopharyngeal carcinoma (NPC) plasma samples have been shown. [41,42]Serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with chronic hepatitis C infection (CHC). [43]erum levels of miR-122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels. [44]Three microRNAs with higher expression in active tuberculosis patients have been positively evaluated for use as a biomarker namely miR-155, in stimulated PBMCs. [45]and miR-29a in pooled serum. [46](Table 2).In addition to expression analysis, microRNA single nucleotide polymorphism (SNP) analysis has revealed a correlation between SNPs in miR-146a (rs2910164) and miR-499 (rs3746444) and increased pulmonary tuberculosis susceptibility in certain populations.

Conclusion
Extensive research on miRNA biomarkers in exosomes are providing potential information on diagnosis, management and prognosis of diseases.Many challenges exists in studying miRNAs and more sensitive methods to detect them are being developed.

Fig 1 .
Fig 1.Schematic view of free Micro RNA in certain disease

Table 1 .
Circulating micro-RNA association with clusters of diseases