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MicroRNA and Disease

By , MD, PhD

MicroRNAs or miRNAs represent an important class of small regulatory RNAs that are intrinsic to post-transcriptional gene control. They are approximately 22 nucleotides in length and regulate the expression of as much as 30% of all mammalian protein-encoding genes.

Although they have important roles in healthy individuals, miRNAs have also been implicated in a wide range of diseases – including different types of cancers, heart conditions and neurological diseases. As a consequence, miRNAs are intensely studied as promising candidates for diagnostic and prognostic biomarkers, as well as predictors of drug response.

The role of miRNAs in malignancies

Experimental approaches have shown that some miRNAs act as tumor suppressors, and other ones as oncogenes; hence they have important roles in cancer development, progression of the disease and its prognosis. Dysregulation of miRNAs is linked to the development of cancer.

The first example of a miRNA as an oncogene is miR-155, which is processed from the non-coding B-cell integration cluster RNA. This was first identified as a common integration site in lymphoma induced by avian leukosis virus (ALV). Later it was found that miR-155 expression is elevated in Hodgkin lymphoma samples and cell lines, as well as in juvenile Burkitt's lymphoma.

The human ortholog of lin-4, miR-125b-1, has been implicated in the development of leukemia (especially at an early step in leukemogenesis). This miRNA is also located in a fragile genomic region which is deleted in patients with breast, cervical, ovary and lung cancers. miR-15a and miR-15-1 are involved in the development of chronic lymphocytic leukemia.

A cluster of six miRNAs, named mir-17-92 cluster, is located within a region on chromosome 13 that is typically amplified in human B-cell lymphomas. It has been shown that this cluster (but not the individual miRNAs) can promote tumor growth by inhibiting apoptosis in malignancies. Members of this cluster are overexpressed in colon, prostate and pancreatic tumors.

miRNA expression signatures can differentiate between human malignancies according to their developmental origin, which has important clinical implications. Therefore these small RNAs with high stability may prove useful for clinical diagnosis, as well as represent an alternative way to evaluate cancer progression and prognosis.

miRNAs and cardiovascular disease

The roles of miRNAs in cardiac hypertrophy and heart failure have been demonstrated in several clinical studies. Specific miRNAs are disregulated in the diseased heart; furthermore, up- and down-regulation of miRNAs are necessary and often sufficient to explain different heart diseases.

A myriad of miRNAs are found to be regulated during cardiac hypertrophy and two, miR-1 and miR-133, play a key role in inhibiting it. Overexpression of miR-195 during cardiac hypertrophy results in pathological cardiac growth and heart failure, while miR-199a is expressed in cardiomyocytes where it maintains cell size and plays a role in the regulation of cardiac hypertrophy.

miRNAs are also important regulators of cardiac fibrosis and are involved in structural heart disease. Some specific miRNAs (such as miR-1) are implicated in the development of arrhythmia, thus it may be a potential antiarrhythmic target. Several miRNAs (miR-21, miR126, miR-221 and miR-222) represent important modulators of vessel remodeling.

miRNA in other conditions

Recent research has shown that miR-33 controls cholesterol homeostasis based on knockdown experiments using antisense technology. The overexpression of this miRNA decreases cellular cholesterol efflux to apolipoprotein A-I (ApoA-I), which is a key step in regulating reverse cholesterol transport.

miR-375 is considered to be a regulatory inhibitor of insulin secretion and may also constitute a novel drug target for the treatment of type 2 diabetes. Several observations underscore the importance of miR-122 in liver disease. miRNAs are also implicated in the proper functioning of human immune system.

Sources

  1. http://hannonlab.cshl.edu/publications/HeandHannonNRG2004.pdf
  2. http://physiolgenomics.physiology.org/content/33/2/139
  3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087823/
  4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151131/
  5. http://www.sciencedirect.com/science/article/pii/S2211383511000116
  6. O'Donnell KA, Mendell JT. Dysregulation of microRNAs in human malignancy. In: Appasani K. MicroRNAs: From Basic Science to Disease Biology. Cambridge University Press, 2008; pp. 295-308.

Further Reading

Last Updated: Jan 26, 2015

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