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Targeting Cancer through RNA Biology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 July 2018) | Viewed by 46363

Special Issue Editor


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Guest Editor
Faculty of Health and Applied Sciences, University of the West of England, Bristol BS16 1QY, UK
Interests: RNA biology; RNA binding proteins; alternative splicing; splice factors; splice factor kinases; mRNA translation; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last four decades the field of molecular biology has expanded at an incredible rate, to the extent that it is a real challenge to keep up with new developments. Specific areas of interest have emerged and grown, to mention but a few: genomics, epigenetics, cell signalling, cell biology and RNA biology. What do we mean by RNA biology? It is a complex mixture of topics; the versatile nature of RNA structure, ribozymes, RNA-binding proteins, and a huge assortment of co- and post-transcriptional processes that help to regulate gene expression. In the cell nucleus we contend with alternative polyadenylation sites, RNA editing, alternative splicing, regulated RNA export, and epigenetic processes in which RNA molecules play a key part; and in the cytoplasm, mRNA localisation, regulated mRNA translation, and mRNA stability. As if that weren’t enough, we also have to consider a myriad of noncoding RNAs, both long and short. Noncoding RNAs are involved in epigenetic regulation, and the regulation in cis of mRNA translation and decay. All of these processes contribute immensely to the regulation of gene expression in development and in disease. Of particular note in humans is that over 94% of genes are alternatively spliced, and one in six disease-associatedmutations perturb pre-mRNA splicing.

Given these layers of complexity it is not surprising to find that RNA biology can and does go wrong in cancer. There is increasing interest in looking at RNA biomarkers, notablythe presence of specific cancer-associated microRNAs in the blood or urine. The expression of splice factors and the alternative splicing of key cancer-associated genes is frequently altered. Therefore a growing assortment of novel anti-cancer strategies are being developed that target RNA-mediated processes. These include the manipulation of alternative splicing through oligonucleotides and splice factor kinase inhibitors, and the manipulation of mRNA translation and nonsense-mediated decay. The purpose of this special issue is to draw attention to the significant new possibilities that RNA biology offers in the fight against cancer.

Prof. Dr. Michael R. Ladomery
Guest Editor

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Keywords

  • RNA structure
  • Ribozymes
  • RNA-binding proteins
  • Cotranscriptional and posttranscriptional processing
  • Alternative splicing, splice factors, and splice factor kinases
  • mRNA localisation, translation and decay
  • Short and long noncoding RNAs

Published Papers (7 papers)

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Research

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15 pages, 14094 KiB  
Article
Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction
by Tong-Hong Wang, Chuen Hsueh, Chin-Chuan Chen, Wan-Syuan Li, Chau-Ting Yeh, Jang-Hau Lian, Junn-Liang Chang and Chi-Yuan Chen
Int. J. Mol. Sci. 2018, 19(9), 2687; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092687 - 10 Sep 2018
Cited by 34 | Viewed by 3926
Abstract
Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed [...] Read more.
Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin’s anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin’s antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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12 pages, 2061 KiB  
Article
DEAD-Box Protein RNA-Helicase DDX6 Regulates the Expression of HER2 and FGFR2 at the Post-Transcriptional Step in Gastric Cancer Cells
by Toshihiro Tajirika, Yoshihisa Tokumaru, Kohei Taniguchi, Nobuhiko Sugito, Nobuhisa Matsuhashi, Manabu Futamura, Kazuyoshi Yanagihara, Yukihiro Akao and Kazuhiro Yoshida
Int. J. Mol. Sci. 2018, 19(7), 2005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19072005 - 09 Jul 2018
Cited by 16 | Viewed by 4273
Abstract
The human DEAD/H-box RNA helicase DDX6 (RCK/p54) is a protein encoded by the fusion gene from the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma cell line RC-K8. DDX6 has a variety of functions such as translation initiation, pre-mRNA splicing, and ribosome assembly. [...] Read more.
The human DEAD/H-box RNA helicase DDX6 (RCK/p54) is a protein encoded by the fusion gene from the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma cell line RC-K8. DDX6 has a variety of functions such as translation initiation, pre-mRNA splicing, and ribosome assembly. However, details of the regulatory mechanism governing DDX6 and the functions of DDX6 are largely unknown. Previously, we reported that DDX6 is overexpressed in most malignant cell lines and clinical colorectal tumor samples and that DDX6 positively contributes to the pathogenesis of various cancers. In the current study, we aimed at revealing the function of DDX6 in HER2 and FGFR2 related human gastric cancer (GC) by using clinical samples and GC cell lines. DDX6 protein was overexpressed in about 60% of the clinical samples; HER2, in 35%; and FGFR2, in 30%, (n = 20). Interestingly, the DDX6 protein was overexpressed in all HER2-positive samples (n = 7), and in 83% (5 of 6) of the FGFR2-positive samples, which could reflect the contribution of DDX6 to the expression of HER2 and FGFR2. In the GC cell line MKN7, which has HER2 amplification, the knockdown of DDX6 by siR-DDX6 led to the decreased expression of the HER2 protein. On the other hand, the knockdown of HER2 did not influence the DDX6 expression. Similar results were also obtained for the KATO-III and HSC39 cell lines having amplified FGFR2 expression. The increased expression of DDX6 induced a significantly increased expression of the HER2 protein without increasing the mRNA expression. The results of an RNP Immunoprecipitation (RIP)-assay using GC cells indicated that the DDX6 protein acted as an RNA-binding protein for HER2 and FGFR2 mRNAs and positively regulated their post-transcriptional processes. These findings demonstrated that DDX6 was an upstream molecule that positively regulated the expression of HER2 and FGFR2 at the post-transcriptional step in GC cells. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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Review

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15 pages, 641 KiB  
Review
Targeting Splicing in Prostate Cancer
by Effrosyni Antonopoulou and Michael Ladomery
Int. J. Mol. Sci. 2018, 19(5), 1287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051287 - 25 Apr 2018
Cited by 18 | Viewed by 5211
Abstract
Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA, KLF6, BCL2L2, ERG, and AR. We discuss opportunities [...] Read more.
Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA, KLF6, BCL2L2, ERG, and AR. We discuss opportunities to develop novel therapies that target specific splice isoforms, or that target the machinery of splicing. Therapeutic approaches include the development of small molecule inhibitors of splice factor kinases, splice isoform specific siRNAs, and splice switching oligonucleotides. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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26 pages, 2120 KiB  
Review
Messenger RNA Life-Cycle in Cancer Cells: Emerging Role of Conventional and Non-Conventional RNA-Binding Proteins?
by Lucie Coppin, Julie Leclerc, Audrey Vincent, Nicole Porchet and Pascal Pigny
Int. J. Mol. Sci. 2018, 19(3), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19030650 - 25 Feb 2018
Cited by 39 | Viewed by 11798
Abstract
Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, [...] Read more.
Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life-cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA-based therapies. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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28 pages, 308 KiB  
Review
Alternative Splicing as a Target for Cancer Treatment
by Nancy Martinez-Montiel, Nora Hilda Rosas-Murrieta, Maricruz Anaya Ruiz, Eduardo Monjaraz-Guzman and Rebeca Martinez-Contreras
Int. J. Mol. Sci. 2018, 19(2), 545; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020545 - 11 Feb 2018
Cited by 79 | Viewed by 7231
Abstract
Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination [...] Read more.
Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination of splicing sites, exonic or intronic sequences, mutually exclusive exons or retained introns could be selected during alternative splicing to generate different mature mRNAs that could in turn produce distinct protein products. Alternative splicing is the main source of protein diversity responsible for 90% of human gene expression, and it has recently become a hallmark for cancer with a full potential as a prognostic and therapeutic tool. Currently, more than 15,000 alternative splicing events have been associated to different aspects of cancer biology, including cell proliferation and invasion, apoptosis resistance and susceptibility to different chemotherapeutic drugs. Here, we present well established and newly discovered splicing events that occur in different cancer-related genes, their modification by several approaches and the current status of key tools developed to target alternative splicing with diagnostic and therapeutic purposes. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
225 KiB  
Review
Therapeutic Applications of Targeted Alternative Splicing to Cancer Treatment
by Jung-Chun Lin
Int. J. Mol. Sci. 2018, 19(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010075 - 28 Dec 2017
Cited by 33 | Viewed by 5039
Abstract
A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain [...] Read more.
A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain comprehensive insights into the impacts of AS events on cancer biology and therapeutic developments, this paper highlights recent findings regarding the therapeutic routes of targeting alternative-spliced isoforms and splicing regulators to treatment strategies for distinct cancers. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
1232 KiB  
Review
The Roles of microRNAs in Regulating the Expression of PD-1/PD-L1 Immune Checkpoint
by Qingshui Wang, Wei Lin, Xiaoqiong Tang, Suhuan Li, Libin Guo, Yao Lin and Hang Fai Kwok
Int. J. Mol. Sci. 2017, 18(12), 2540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122540 - 27 Nov 2017
Cited by 89 | Viewed by 8140
Abstract
Engagement of programmed death-ligand 1 (PD-L1) with its receptor programmed death 1 (PD-1) on T cells has been speculated to play a major role in suppressing the immune system, which helps tumor cells evade anti-tumor immunity. With the development of whole genome sequencing [...] Read more.
Engagement of programmed death-ligand 1 (PD-L1) with its receptor programmed death 1 (PD-1) on T cells has been speculated to play a major role in suppressing the immune system, which helps tumor cells evade anti-tumor immunity. With the development of whole genome sequencing technologies, microRNAs have gained more attention as an important new layer of molecular regulation. Recent studies have revealed that altered expression of microRNAs play a pivotal role in immune checkpoint and various cellular processes in cancer. In this review, we focused on the latest progress about microRNAs research which involves the regulation of PD-1/PD-L1 immune checkpoint. Full article
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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