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      Melatonin targeting non-coding RNAs in cancer: Focus on mechanisms and potential therapeutic targets

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          Abstract

          <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d12522683e182">Despite, melatonin is mainly known as a regulatory factor for circadian rhythm, its notable role in other fundamental biological processes, such as redox homeostasis and programmed cell death, has been found. In this line, a growing body of evidence indicated that melatonin could apply an inhibitory effect on the tumorigenic processes. Hence, melatonin might be considered an efficient adjuvant agent for cancer treatment. Besides, the physiological and pathological functions of non-coding RNAs (ncRNAs) in various disease, particularly cancers, have been expanded over the past two decades. It is well-established that ncRNAs can modulate the gene expression at various levels. Thereby, ncRNAs can regulate the numerous biological processes, including cell proliferation, cell metabolism, apoptosis, and cell cycle. Recently, targeting the ncRNAs expression provides a novel insight in the therapeutic approaches for cancer treatment. Moreover, accumulating investigations have revealed that melatonin could impact the expression of different ncRNAs in a multiple disorders, including cancer. Therefore, in the precent study, we discuss the potential roles of melatonin in modulating the expression of ncRNAs and the related molecular pathways in different types of cancer. Also, we highlighted its importance in therapeutic application and translational medicine in cancer treatment. </p>

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          Most cited references157

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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              Origins and Mechanisms of miRNAs and siRNAs.

              Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.
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                Author and article information

                Contributors
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                Journal
                European Journal of Pharmacology
                European Journal of Pharmacology
                Elsevier BV
                00142999
                July 2023
                July 2023
                : 950
                : 175755
                Article
                10.1016/j.ejphar.2023.175755
                37119959
                73e7159a-89f3-4321-a7e3-3104c4094987
                © 2023

                https://www.elsevier.com/tdm/userlicense/1.0/

                https://doi.org/10.15223/policy-017

                https://doi.org/10.15223/policy-037

                https://doi.org/10.15223/policy-012

                https://doi.org/10.15223/policy-029

                https://doi.org/10.15223/policy-004

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