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. 2013 Sep 30;6(10):1195-220.
doi: 10.3390/ph6101195.

MicroRNAs as Molecular Targets for Cancer Therapy: On the Modulation of MicroRNA Expression

Pedro M Costa  1 , Maria C Pedroso de Lima
Affiliations

MicroRNAs as Molecular Targets for Cancer Therapy: On the Modulation of MicroRNA Expression

Pedro M Costa et al. Pharmaceuticals (Basel). .

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.

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Figures

Figure 1
Figure 1
MicroRNAs as tumor suppressors and oncogenes. (a) In normal cells, miRNA transcription, processing and binding to complementary sequences in the target mRNA lead to the repression of their target genes, by either mRNA translation inhibition or mRNA degradation. (b) The reduced expression of a miRNA that acts as a tumor suppressor, as a result of chromosomal deletion or defects at any stage of miRNA biogenesis (indicated by question marks) leads to the increased synthesis of the miRNA-target oncoprotein (purple squares), and ultimately to the development of an oncogenic phenotype. (c) The increased expression of a miRNA that acts as an oncogene, as a result of (among others) amplification of the miRNA gene or constitutive promoter activation (indicated by question marks), leads to the repression of a miRNA-target tumor-suppressor gene (pink), which favors the development of an oncogenic phenotype. ORF: open reading frame; mGpppG: 7-methylguanosine. Reproduced with permission from [38].
Figure 2
Figure 2
Strategies that are mostly employed to modulate miRNA expression. Constructs used to re-express or silence mature miRNAs: virally-mediated nuclear expression of pri-miRNA mimics or shRNAs, cytoplasmic delivery of double-stranded miRNA mimics, anti-miRNA oligonucleotides and peptide nucleic acids.
Figure 3
Figure 3
SNALP internalization in human U87 GBM and HEK293T embryonic kidney cells, caspase 3/7 activation, tumor cell proliferation and biodistribution of systemically-administered SNALP-formulated FAM-labeled oligonucleotides. (a) For evaluation of SNALP internalization, U87 and HEK293T cells were incubated with CTX-coupled (CTX) or nontargeted (NT) liposomes encapsulating FAM-labeled anti-miR-21 oligonucleotides (for 4 hours at 37°C), at a final oligonucleotide concentration of 1 μM. Cells were then rinsed twice with PBS, stained with DNA-specific Hoechst 33342 (blue) and then observed by confocal microscopy. (b) For evaluation of caspase 3/7 activation, U87 cells were incubated with CTX-coupled liposomes encapsulating anti-miR-21 or scrambled oligonucleotides for 4 hours, washed with PBS and further incubated for 24 hours with fresh medium. Cells were subsequently exposed to 15 μM of sunitinib for 24 hours, rinsed with PBS, after which caspase 3/7 activation was evaluated by the SensoLyte homogenous AMC caspase-3/7 assay (AnaSpec, San Jose, CA, USA). Results, presented as relative fluorescence units (RFU) with respect to control untreated cells, were normalized for the number of cells in each condition. Scrambled/anti-miR-21 1 μM + S15: cells transfected with scrambled or anti-miR-21 oligonucleotides and further incubated with 15 μM sunitinib. ** p < 0.01 compared to cells incubated with SNALP-formulated scrambled oligonucleotides and further treated with 15 μM sunitinib. (c) Flow cytometry analysis (fluorescence intensity plots) of tumor homogenates from animals injected intravenously with CTX-coupled and NT liposomes encapsulating FAM-labeled siRNAs or saline solution (PBS). # p < 0.05 compared to animals injected with a similar amount of NT SNALP-formulated siRNAs. Results are presented as mean ± standard deviation of at least three different experiments.
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References

    1. Alvarez-Garcia I., Miska E.A. Microrna functions in animal development and human disease. Development. 2005;132:4653–4662. doi: 10.1242/dev.02073. - DOI - PubMed
    1. Ambros V. The functions of animal micrornas. Nature. 2004;431:350–355. doi: 10.1038/nature02871. - DOI - PubMed
    1. Croce C.M. Causes and consequences of microrna dysregulation in cancer. Nat. Rev. Genet. 2009;10:704–714. doi: 10.1038/nrg2634. - DOI - PMC - PubMed
    1. Stark A., Brennecke J., Bushati N., Russell R.B., Cohen S.M. Animal micrornas confer robustness to gene expression and have a significant impact on 3'utr evolution. Cell. 2005;123:1133–1146. doi: 10.1016/j.cell.2005.11.023. - DOI - PubMed
    1. Liu N., Olson E.N. Microrna regulatory networks in cardiovascular development. Dev. Cell. 2010;18:510–525. doi: 10.1016/j.devcel.2010.03.010. - DOI - PMC - PubMed