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European Biopharmaceutical Review

New Possibilities

 

There has been much excitement in the scientific community since the discovery of mammalian microRNA (miRNA) in 2001. Since that time, numerous studies have demonstrated that miRNAs are expressed in a cell and tissue specific manner, and their expression is deregulated in a number of diseases, including cancer, cardio vasculature disease and psychiatric disorders. Now, miRNAs are found to be present in the bloodstream in a stable form and the development of serum-based miRNAs as biomarkers of disease is eagerly anticipated.

miRNA; SMALL GENETIC REGULATORS

miRNAs are small, regulatory, noncoding RNAs. miRNAs are processed from longer precursors to produce the approximately 21 nucleotide active, mature miRNAs. The mature miRNA binds to conserved sequences on messenger RNAs, resulting in repression of protein synthesis. miRNAs have an important role in the development and differentiation of various cells and tissues. They are typically produced at high levels during early development and their expression drops as cells and tissues become differentiated. miRNAs are produced in a cell- and tissue-specific fashion and are predicted to regulate up to one-third of all genes.

miRNA expression is deregulated in a number of diseases including cancer, cardiovascular disease and psychiatric disorders. Cancer was the first disease to be identified with altered miRNA expression. The expression of two miRNAs – miR-15 and miR-16 – was found to be reduced in chronic lymphocytic leukaemia (1). By profiling tumour and normal tissue, miRNA expression was shown by many investigators to be deregulated in other types of cancer. In fact, miRNA is deregulated in all cancers studied to date. Many cancers have increased miRNA expression, while in others the miRNA expression is reduced. miRNAs may act as both oncogenes or tumour suppressors in cancer. For example, the miRNA let-7a is commonly reduced in lung cancer, and this reduction contributes to increased levels of its target, the oncogene Ras. miRNAs exhibit a unique expression pattern or signature in a given tumour and many believe that the miRNA gene expression signature will be a useful diagnostic or prognostic indicator of disease (2,3).

Stress-responsive miRNAs, such as miR-21 andmiR-195, are up-regulated during cardiac disease. Two major cardiac miRNAs – miR-30 and miR-133 – are downregulated during cardiac disease, resulting in increased levels of proteins involved in fibrosis, a hallmark of various forms of heart disease. Changes in miRNA expression or alterations in the miRNA target genes have been identified in a number of neurological disorders including Tourette’s syndrome, Parkinson’s disease, schizophrenia, Alzheimer’s and Huntington’s disease.

miRNAS IN THE BLOODSTREAM

The vast majority of miRNA studies have been performed in human and animal tissues, cell lines, plants and viruses. Within the past year, there have been a total of seven papers published that have studied the miRNA expression in human plasma or serum (see Table 1) (4-10). Previously, other nucleic acids, including DNA and messenger RNA, were detectable in the bloodstream (11,12). The discovery of serum miRNAs was surprising because, like other nucleic acids, there was no reason to believe that they should be present in the bloodstream. An exact role, if any, for nucleic acids in the blood is a mystery. Serum nucleic acids may represent the by-product of cell lysis, with the blood-based nucleic acids eventually being metabolised without rendering any biological activity. Others have proposed that serum nucleic acids may represent a means for transfer of genetic information from cell-to-cell via the bloodstream (13).


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Thomas D Schmittgen is an Associate Professor of Pharmacy at the Ohio State University in Columbus, Ohio where his research focuses on the role of noncoding RNAs in cancer. Thomas has been working in the field of miRNA for seven years and developed the first real-time quantitative PCR assay to detect miRNA in 2004. He is currently working to develop miRNA-based biomarker assays for the early detection of pancreatic cancer.

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