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MicroRNAs as therapeutic targets in human cancers

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MicroRNAs (miRNAs) are evolutionarily conserved, small, regulatory RNAs that negatively regulate gene expression. Extensive research in the last decade has implicated miRNAs as master regulators of cellular processes with essential role in cancer initiation, progression, and metastasis, making them promising therapeutic tools for cancer management. In this article, we will briefly review the structure, biogenesis, functions, and mechanism of action of these miRNAs, followed by a detailed analysis of the therapeutic potential of these miRNAs. We will focus on the strategies presently used for miRNA therapy; discuss their use and drawbacks; and the challenges and future directions for the development of miRNA‐based therapy for human cancers. WIREs RNA 2014, 5:537–548. doi: 10.1002/wrna.1229

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MicroRNA (miRNA)‐based therapeutics for management of cancer. miRNA inhibition therapy for oncomiRs includes antisense anti‐miRs [anti‐miRNA oligonucleotides (AMOs), modified AMOs, locked nucleic acid (LNA)‐based AMOs, and antagomirs), small‐molecule inhibitors, miRNA sponges, and miRNA masks. miRNA replacement therapy for tumor‐suppressive miRs includes miRNA mimics, small‐molecule enhancers, and expression vectors. These approaches act at different stages of miRNA biogenesis, including processing, maturation, and strand selection.
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MicroRNA (miRNA) deregulation in human cancers. miRNA genes frequently undergo chromosomal deletions or translocations, epigenetic regulation, alterations in miRNA promoter activity by oncogenes and tumor suppressor genes, or alterations in the miRNA processing machinery resulting in widespread deregulation in their expression. Consequently, oncogenic miRNAs are upregulated, while tumor‐suppressive miRNAs are downregulated. This alteration at the miRNAome leads to aberrant changes in the transcriptome and proteome, causing cellular transformation and tumor progression.
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MicroRNA (miRNA) delivery options into the cells. Schematic representation of different delivery approaches currently investigated for the delivery of miRNA‐based therapeutics in cancer cells. Synthetic miRNAs can be delivered naked with different chemical modifications, conjugated with natural or synthetic polymers, conjugated with cholesterol molecules, complexed with liposomes, and encapsulated in nanoparticles using DNA–plasmid expression vectors or via viral expression vectors.
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