MicroRNAs as Circulating Biomarkers

12097693_lMicroRNAs (miRNAs) are short strands of RNA averaging between 19-24 nucleotides in length that were first discovered in C.elegans and subsequently shown to exist in species ranging from algae to humans (1). Speculated to be merely “junk” more than a decade ago, miRNAs have emerged as powerful regulators of a wide array of cellular processes because of their influence on gene expression at the posttrancriptional level. Dysregulation of these miRNAs is also associated with life-threatening conditions such as cancer and cardiovascular disease, which points to a potential use of miRNAs in diagnosis and treatment. Recently, it has been demonstrated that miRNAs are present in circulating blood plasma, protected from degradation by inclusion in lipid or lipoprotein complexes. This opens up the possibility to exploit miRNA as a useful diagnostic tool in clinical samples.

For combating tough diseases like cancer and heart disease, it is imperative but challenging to identify key biomarkers at early stages of the disease from samples that are easily obtained by the least invasive methods. A biomarker by definition is a measurable substance in an organism that can be used to diagnose a medical condition. An ideal biomarker fulfills a number of criteria, such as accessibility through noninvasive methods (e.g., bodily fluids); a high degree of specificity and sensitivity; the ability to differentiate pathologies, allowing early detection; sensitivity to relevant changes in the disease; a long half-life within the sample; and the capability for rapid and accurate detection. Because circulating miRNAs are able to fulfill a number of those criteria, several groups have reported on the use of miRNAs as circulating biomarkers for diagnosis or prognosis of several types of cancer and heart diseases. Some of the features that make miRNAs desirable as biomarkers are that miRNAs are stable in various bodily fluids; the sequences of most miRNAs are conserved among different species; the expression of some miRNAs is specific to tissues or biological stages, and the level of miRNAs can be easily assessed by commonly used methods such as polymerase chain reaction (PCR), which allows for signal amplification.

Differential expression of several miRNAs in plasma, serum, urine, and saliva has already been linked to various diseases. Notably, serum levels of miR-141, have been used to discriminate patients with advanced prostate cancer from healthy individuals, the ratio of miR-126 and miR-182 in urine samples can be used to detect bladder cancer and decreased levels of miR-125a and miR-200a in saliva is associated with oral squamous cell carcinoma (2,3). Four cardiac miRNAs (miR-208a, miR-499, miR-1, and miR-133) are found to be consistently elevated in the event of myocardial injury and closely linked with acute myocardial infarction. Candidate miRNAs have also been identified for related cardiovascular diseases such as heart failure, atherosclerosis, hypertension and Type-2 diabetes.

An important focus of the biomedical field has been to identify informative biomarkers that will aid understanding of disease progression and perhaps be useful in developing therapeutic measures. Overall, miRNAs might have more to offer as circulating biomarkers when compared to protein biomarkers. However, they require the same stringent validation processes as protein-based biomarkers to demonstrate their specificity and selectivity. An important challenge in developing miRNA-based biomarker is overcoming the issues associated with accurate measurement. This necessitates building better reagent sets to obtain more comprehensive and accurate miRNA measurements. There is also an urgent need to set up a standardization process for sample preparation and develop a more accurate method to assess the quality and quantity of miRNA.

  1. Youngman, E.M. and Claycomb, J.M. (2014) From early lessons to new frontiers: the worm as a treasure trove of small RNA biology. Front. Genet. 27,416.
  2. Cheng, G. (2015) Circulating miRNAs: Roles in cancer diagnosis, prognosis and therapy. Adv. Drug Deliv. Rev. 81C, 75–93.
  3. Tijsen, A.J., Pinto, Y.M. and Creemers, E.E. (2012) Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 303, H1085-95.
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Radhika Ganeshan

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