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      MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside

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          Abstract

          Non-coding RNAs represent a significant proportion of the human genome. After having been considered as ‘junk’ for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g . cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.

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          Most cited references129

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          Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

          MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.
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            Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.

            During C. elegans development, the temporal pattern of many cell lineages is specified by graded activity of the heterochronic gene Lin-14. Here we demonstrate that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4. The lin-14 3'UTR is both necessary and sufficient to confer lin-4-mediated posttranscriptional temporal regulation. The function of the lin-14 3'UTR is conserved between C. elegans and C. briggsae. Among the conserved sequences are seven elements that are each complementary to the lin-4 RNAs. A reporter gene bearing three of these elements shows partial temporal gradient activity. These data suggest a molecular mechanism for Lin-14p temporal gradient formation: the lin-4 RNAs base pair to sites in the lin-14 3'UTR to form multiple RNA duplexes that down-regulate lin-14 translation.
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              Switching from repression to activation: microRNAs can up-regulate translation.

              AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
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                Author and article information

                Contributors
                Jens.Hanhe@icr.ac.uk
                Journal
                Target Oncol
                Target Oncol
                Targeted Oncology
                Springer International Publishing (Cham )
                1776-2596
                1776-260X
                25 May 2020
                25 May 2020
                2020
                : 15
                : 3
                : 261-278
                Affiliations
                [1 ]GRID grid.18886.3f, ISNI 0000 0001 1271 4623, Division of Molecular Pathology, , The Institute of Cancer Research, ; London, UK
                [2 ]GRID grid.18886.3f, ISNI 0000 0001 1271 4623, Centre for Evolution and Cancer, , The Institute of Cancer Research, ; London, UK
                [3 ]Medical Department, Division of Oncology, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
                [4 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Division of Medical Oncology, , Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ; Milan, Italy
                [5 ]GRID grid.20501.36, ISNI 0000 0000 8767 9052, Clinic of Gastroenterology, , Medical University, ; Varna, Bulgaria
                [6 ]GRID grid.5072.0, ISNI 0000 0001 0304 893X, Department of Medicine, , The Royal Marsden NHS Foundation Trust, ; London, UK
                Author information
                http://orcid.org/0000-0002-1425-7486
                Article
                717
                10.1007/s11523-020-00717-x
                7283209
                32451752
                e008d4ec-5272-483a-9149-d313831ead22
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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                © Springer Nature Switzerland AG 2020

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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