Key Points
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The rationale for using microRNAs (miRNAs) as anticancer drugs is based on two major findings: miRNA expression is deregulated in cancer compared with normal tissues and the cancer phenotype can be changed by targeting miRNA expression.
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One of the most appealing properties of miRNAs as therapeutic agents is their ability to target multiple genes, frequently in the context of a network, making them highly efficient in regulating distinct biological cell processes relevant to normal and malignant cell homeostasis
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There are two main strategies to target miRNA expression in cancer. Direct strategies involve the use of oligonucleotides or virus-based constructs to either block the expression of an oncogenic miRNA or to substitute for the loss of expression of a tumour suppressor miRNA. The indirect strategy involves the use of drugs to modulate miRNA expression by targeting their transcription and their processing.
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Several in vitro and in vivo studies using locked nucleic acid (LNA) antimiR have shown feasibility and high efficiency of this approach. A Phase I trial in humans using LNA anti-miR-122 is ongoing. This study will provide valuable information about pharmacokinetics and safety profiles.
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The challenges for developing miRNA-based therapeutics are the same as for siRNA therapeutics and comprise delivery, potential off-target effects and safety concerns.
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Reprogramming aberrant miRNA networks in cancer could be achieved by modulating several of the key miRNAs in a network using known drugs, including chemotherapy agents or biocompounds.
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miRNA effects are currently largely interpreted as the result of miRNA–mRNA 3′untranslated region (UTR) interactions that cause target post-translational inhibition or degradation. However, focusing on this mechanism to design miRNA therapeutics is likely to prove too simplistic, owing to the emerging miRNA mechanisms, which include decoy activity and 5′ UTR and direct DNA regulatory activities.
Abstract
MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.
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Glossary
- Antisense
-
The term antisense is generally used for nucleic acid-based approaches that interferes, in a sequence-selective way, with the processing of RNA from its transcription via mRNA to protein or with the effects of other forms of functional RNA.
- Phosphorothioate
-
An oligonucleotide in which the oxygen atom normally linking two consecutive nucleotides has been replaced with sulphur, which resists degradation by cellular enzymes. The phosphorothioate backbone, although reducing affinity to the target RNA, confers considerable stability to nuclease degradation and is essential for in vivo delivery of antisense oligonucleotides to tissues, as the phosphorothioate promotes protein binding and delays plasma clearance.
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Garzon, R., Marcucci, G. & Croce, C. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9, 775–789 (2010). https://doi.org/10.1038/nrd3179
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DOI: https://doi.org/10.1038/nrd3179
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