What is microRNA?
MicroRNAs (miRNAs) are a group of small non-coding RNAs that are found in tissue samples of animals, plants, and some viruses. Since the discovery of circulating and extracellular miRNAs, there has been a rapid expansion of studies on miRNAs in biofluids like cerebrospinal fluid, plasma, serum, and urine. miRNAs are similar to small interfering RNAs (siRNAs). However, miRNAs originate from RNA transcripts forming short hairpins while siRNAs are from longer parts of double-stranded RNA. miRNAs are plentiful in mammalian cells and seem to target approximately 60% of these genes. miRNAs are thought to have important biological functions as they are evolutionary conserved. A good example is where there is conservation of 90 families of miRNAs as seen in the common ancestor of fish and mammals. The majority of these conserved miRNAs have been shown to play important roles.
Roles of miRNA
miRNA plays a role in RNA silencing and gene expression as post-transcriptional regulators. Within mRNAs, miRNAs function by base-pairing with the complementary molecules causing mRNA molecules to be silenced through cleavage of mRNA strand, destabilization of mRNA, or reduced efficiency of mRNA translation by ribosomes. Despite the low numbers of miRNA, it is estimated that the miRNAs regulate approximately more than 33% of the cellular transcriptome. Therefore, it should be no surprise that the miRNAs have crucial functions in the developmental and cellular processes that have been thought to be involved in many human diseases.
Since miRNAs are relatively stable in biofluids and have a wide range of biological potential, these molecules are suited to be used as non-invasive biomarkers in diagnosis, drug safety, and pre-clinical toxicity. Many studies have proven that secreted miRNAs are involved in conditions such as organ damage, cancers, and coronary heart disease. While the exact role of circulating miRNAs is mostly unknown, they have been observed to be protected from RNAse degradation through the inclusion in membranous particles or protein complexes.
Since miRNA plays a role in the normal functioning of eukaryotic cells, miRNA dysregulation is therefore linked to disease. For example:
a) Hereditary Diseases
It has been found that a mutation in the region of miR-96 results in progressive hearing loss.
Hereditary keratoconus with anterior polar cataract is seen in mutation in the region of miR-184.
Growth and skeletal defects can be seen in those with deletion of miR-17 to 92 cluster.
Chronic lymphocytic leukemia was one of the first human diseases that has been associated with miRNA dysregulation. Other miRNAs that have also been linked to cancer are called “oncomirs”. miRNAs are involved in pathways that are crucial in B-cell development such as B-cell receptor signaling, cell-cell interaction, B-cell migration or adhesion, and production or class-switching of immunoglobulins. They also influence the generation of marginal zone, follicular, plasma, B1, and memory B cells.
Another clinical trial is using miRNA as a screening assay for the detection of colorectal cancer in the early stages.
miRNAs can also be used to determine prognosis in cancers based on their expression level. For example, a study on non-small-cell lung carcinoma determined that a low level of miR-324a levels is an indication of poor prognosis. In colorectal cancer, a low level of miR-133b and high level of miR-185 is linked with metastasis resulting in poor prognosis.
c) Heart Disease
Studies have found that there are specific changes in the expression levels of miRNAs in diseased hearts which points to the involvement of miRNAs in cardiomyopathies.
miRNAs can also be used to determine the prognosis and risk stratification of cardiovascular diseases.
In animal models, miRNAs have been associated with the regulation and metabolism of cholesterol.
d) Nervous System
miRNAs are thought to be involved in the function and development of the nervous system.
Neural miRNAs such as miR-124, miR-132 and miR-134 are involved in dendritogenesis.
Other neural miRNAs are involved in the formation of the synapses. miR-134 and miR-138 are thought to be included in the process of synapse maturation.
Studies have found that conditions such as bipolar disorder, schizophrenia, anxiety disorders, and major depression have altered miRNA expression.
miRNAs have a vital role in the differentiation of stem cell progenitors into adipocytes. Studies have found that the expression of miRNAs 155, 221, and 222 can inhibit adipogenesis paving a possible genetic treatment for obesity.
miRNAs of the let-7 family was found to accumulate in tissues as aging occurs. Based on animal models, the excessive expression of let-7 class miRNAs resulted in accelerated aging, insulin resistance, and therefore increases the risk of obesity and diabetes. When let-7 was inhibited, it resulted in an increase in insulin sensitivity and resistance to high-fat-diet-induced obesity. This means the inhibition of let-7 may prevent, reverse, and cure obesity and diabetes.
Although miRNAs have great promise in the screening, diagnosis, treatment, and prevention of various pathological conditions, more research, and clinical trials will be needed in the study of miRNAs to further explore and discover the potential of miRNAs.
microRNA. Wikipedia. Accessed 8/22/2018. https://en.wikipedia.org/wiki/MicroRNA#Disease
Blondal T, Nielsen SJ, Baker A, et al. Assessing sample and miRNA profile quality in serum and plasma or other biofluids. Methods. 2013; 59(1): S1-S6.