Abstract
The discovery of small RNA molecules with the capacity to regulate messenger RNA (mRNA) stability and translation (and consequently protein synthesis) has revealed an additional level of post-transcriptional gene control. MicroRNAs (miRNAs), an evolutionarily conserved class of small noncoding RNAs that regulate gene expression post-transcriptionally by base pairing to complementary sequences in the 3' untranslated regions of target mRNAs, are part of this modulatory RNA network playing a pivotal role in cell fate. Functional studies indicate that miRNAs are involved in the regulation of almost every biological pathway, while changes in miRNA expression are associated with several human pathologies, including cancer. By targeting oncogenes and tumor suppressors, miRNAs have the ability to modulate key cellular processes that define the cell phenotype, making them highly promising therapeutic targets. Over the last few years, miRNA-based anti-cancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies, aiming at enhancing tumor cell killing and, ideally, promoting tumor regression and disease remission. Here we provide an overview on the involvement of miRNAs in cancer pathology, emphasizing the mechanisms of miRNA regulation. Strategies for modulating miRNA expression are presented and illustrated with representative examples of their application in a therapeutic context.
Highlights
Over the last decade, miRNAs have emerged as important players in the highly complex world of gene regulation
The first indication that miRNA dysregulation could play a role in cancer was provided by Calin and colleagues, who demonstrated that two clustered miRNA genes, miR-15a and miR-16-1, were located in a region of the 13q14 locus that is commonly deleted in patients diagnosed with B-cell chronic lymphocytic leukemia (CLL) [31]
The loss of miR-15a and miR-16-1, due to chromosomal deletion of the locus 13q14 or germline mutation in their primary precursor, was associated with the development of the indolent form of CLL [31]. Both miRNAs were found to regulate posttranscriptionally the expression of Bcl-2, an anti-apoptotic protein that is widely overexpressed in CLL [39], which supports the role of these miRNAs as tumor suppressors in CLL
Summary
MiRNAs have emerged as important players in the highly complex world of gene regulation. A large number of studies involving transcriptomic, proteomic and bioinformatic approaches indicate that these small RNA molecules can regulate over 30% of all protein-coding genes and play a pivotal role in the most basic cellular processes—such as embryonic development, cell differentiation, metabolism, proliferation and cell death—in a wide range of invertebrate and vertebrate organisms, including humans [1,2,3,4]. Since the miRNA milieu has a broad effect over diverse genetic and molecular pathways, it is not surprising that abnormal miRNA expression has been associated with several human diseases, including cardiovascular and neurological disorders [10,11], diabetes [12] and cancer [13].
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