Using microRNAs (miRNAs) as therapeutic agents in cancer: targeting the link between the downregulation of miRNAs and oncogenesis
Nathan, Ajay Sridhar
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With the worldwide prevalence of cancer, this disease has constituted a major public health problem for many years without great success in the development of treatment. This is due in part to the large genetic heterogeneity that exists, even between cancers of the same class. The current standard of care focuses on targeting shared elements such as rapid cell division, yet treatments like chemotherapy have tremendous cytotoxic and off-target adverse effects. Recently, a different link has been discovered that is shared by cancers of diverse types: the disruption in the regulation and expression of microRNAs (miRNAs). miRNAs, produced endogenously from discrete genes that exist for them, have been shown to be master regulators of diverse processes, including growth and division. They serve to downregulate or silence the expression of certain genes at the post-transcriptional level, with each miRNA regulating multiple target messenger RNAs. This provides an important therapeutic potential because the correction in the expression of any one miRNA, especially if it has tumor-suppressive functions, has the ability to inhibit cancer formation, growth, and metastasis by multiple related pathways. The mechanisms by which the expression of miRNA is altered in cancer are reciprocal; that is, the processes that lead to oncogenesis alter the production of miRNA and altered production of miRNA can lead to increased tumorigenicity. In particular, it has been found that miRNA is globally downregulated in most cancers. The downregulation of miRNA can arise incidentally because of chromosomal abnormalities that occur with cancer, or miRNA can be directly repressed through transcriptional control, epigenetic modification, or disruption in the biogenic production process. When miRNAs are downregulated, the condition can contribute to the main hallmarks of cancer: uncontrolled growth, angiogenesis, metastasis, and evasion of anti-growth and apoptotic signals. A therapeutic strategy that has been investigated in numerous preclinical studies is miRNA replacement therapy, and this treatment has been shown to be extremely efficacious with a wide range of candidates and targets in diverse cancer systems. However, these advances have only led to two clinical trials, partly because of the lack of efficacious delivery methods. Nevertheless, with the rapid advances being made in gene therapy to address these shortcomings, a translation of these benefits from the bench-to-bedside is almost certain.
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