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RNA Splicing in Cancer and Targeted Therapies
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RNA Splicing in Cancer and Targeted Therapies

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (5 July 2023) | Viewed by 30843

Special Issue Editors

Dr. Mohammad Rahman

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: RNA splicing; mutations in splicing factors; nonsense-mediated mRNA decay (NMD); splice-switching antisense oligonucleotides
Dr. Ledong Wan

E-Mail Website
Guest Editor
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
Interests: RNA splicing in cancer; pancreatic cancer; antisense oligonucleotides

Special Issue Information

Dear Colleagues,

Alternative RNA splicing has been highlighted as a critical driver of tumorigenesis in the past few decades. The advancement of high-throughput sequencing has allowed us to identify genome-wide aberrantly spliced genes in tumor versus normal tissues. It is now well-established that splicing dysregulation can affect genes involved in virtually every one of the hallmarks of cancer. Although therapeutic approaches modulating aberrant splicing in several genetic diseases are reaching the clinic, this is still in progress in cancer therapies. Pharmacological inhibition of alternative splicing using small molecules/drugs, and RNA-based therapeutics, such as splice-switching oligonucleotides, RNA aptamer, RNA interference, decoy oligonucleotides, etc., have shown promising outcomes in cancer cells. However, there are still many challenges to overcome, such as specificity, potency, toxicity, delivery, off-target effects, drug resistance, etc. In this Special Issue, we welcome manuscripts that can extend our understanding of the mechanisms of cancer-associated alternative splicing, identification of aberrant splicing targets, oncogenic somatic mutations in splicing factors, functional characterization, and development of potential therapeutic strategies targeting splicing. We look forward to your contributions.

Dr. Mohammad Rahman
Dr. Ledong Wan
Guest Editors

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Keywords

  • RNA splicing
  • RNA-binding proteins
  • high-throughput sequencing
  • aberrant splicing and tumorigenesis
  • mutations affecting splicing cis-elements
  • oncogenic somatic mutations in splicing factors
  • splicing and RNA stability
  • nonsense-mediated mRNA decay (NMD)
  • targeted splicing modulation
  • splice-modifying compounds

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 186 KiB  
Editorial
RNA Splicing in Cancer and Targeted Therapies
by Md Rafikul Islam, Preeti Nagar, Shegufta Tasneem Neetole, Ledong Wan and Mohammad Alinoor Rahman
Genes 2023, 14(11), 2020; https://doi.org/10.3390/genes14112020 - 29 Oct 2023
Viewed by 2317
Abstract
Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has highlighted RNA splicing as a critical mediator of gene expression and proteome diversity, also being important in [...] Read more.
Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has highlighted RNA splicing as a critical mediator of gene expression and proteome diversity, also being important in many developmental and biological processes [...] Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)

Research

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15 pages, 3987 KiB  
Article
Short-Term Hypoxia in Cells Induces Expression of Genes Which Are Enhanced in Stressed Cells
by Inga Peciuliene, Egle Jakubauskiene, Laurynas Vilys, Ruta Zinkeviciute, Kotryna Kvedaraviciute and Arvydas Kanopka
Genes 2022, 13(9), 1596; https://doi.org/10.3390/genes13091596 - 6 Sep 2022
Cited by 4 | Viewed by 2048
Abstract
All living organisms must respond to, and defend against, environmental stresses. Depending on the extent and severity of stress, cells try to alter their metabolism and adapt to a new state. Changes in alternative splicing of pre-mRNA are a crucial regulation mechanism through [...] Read more.
All living organisms must respond to, and defend against, environmental stresses. Depending on the extent and severity of stress, cells try to alter their metabolism and adapt to a new state. Changes in alternative splicing of pre-mRNA are a crucial regulation mechanism through which cells are able to respond to a decrease in oxygen tension in the cellular environment. Currently, only limited data are available in the literature on how short-term hypoxia influences mRNA isoform formation. In this work, we discovered that expressions of the same genes that are activated during cellular stress are also activated in cells under short-term hypoxic conditions. Our results demonstrate that short-term hypoxia influences the splicing of genes associated with cell stress and apoptosis; however, the mRNA isoform formation patterns from the same pre-mRNAs in cells under short-term hypoxic conditions and prolonged hypoxia are different. Obtained data also show that short-term cellular hypoxia increases protein phosphatase but not protein kinase expression. Enhanced levels of protein phosphatase expression in cells are clearly important for changing mRNA isoform formation. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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16 pages, 3004 KiB  
Article
An Alternatively Spliced Variant of METTL3 Mediates Tumor Suppression in Hepatocellular Carcinoma
by Rui-Yao Xu, Zhan Ding, Qing Zhao, Tiao-Ying Ke, Shu Chen, Xing-Yu Wang, Yao-Yun Wang, Meng-Fei Sheng, Wei Wang, Ni Long, Yu-Xian Shen, Yong-Zhen Xu and Wei Shao
Genes 2022, 13(4), 669; https://doi.org/10.3390/genes13040669 - 11 Apr 2022
Cited by 10 | Viewed by 4039
Abstract
Many post-transcriptional mRNA processing steps play crucial roles in tumorigenesis and the progression of cancers, such as N6-methyladenosine (m6A) modification and alternative splicing. Upregulation of methyltransferase-like 3 (METTL3), the catalytic core of the m6A methyltransferase complex, increases m6 [...] Read more.
Many post-transcriptional mRNA processing steps play crucial roles in tumorigenesis and the progression of cancers, such as N6-methyladenosine (m6A) modification and alternative splicing. Upregulation of methyltransferase-like 3 (METTL3), the catalytic core of the m6A methyltransferase complex, increases m6A levels and results in significant effects on the progression of hepatocellular carcinoma (HCC). However, alternative splicing of METTL3 has not been fully investigated, and the functions of its splice variants remain unclear. Here, we analyzed both our and online transcriptomic data, obtaining 13 splice variants of METTL3 in addition to canonical full-length METTL3-A in HCC cell lines and tissues. Validated by RT–qPCR and Western blotting, we found that METTL3-D, one of the splice variants expressing a truncated METTL3 protein, exhibits higher levels than METTL3-A in normal human livers but lower levels than METTL3-A in HCC tumor tissues and cell lines. Further functional assays demonstrated that METTL3-D expression decreased cellular m6A modification, inhibited the proliferation, migration, and invasion of HCC cells, and was negatively associated with the malignancy of patient tumors, exhibiting functions opposite to those of full-length METTL3-A. This study demonstrates that the METTL3-D splice variant is a tumor suppressor that could potentially be used as a target for HCC therapy. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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Review

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21 pages, 6548 KiB  
Review
Therapeutic Targeting of RNA Splicing in Cancer
by Elizabeth A. Bonner and Stanley C. Lee
Genes 2023, 14(7), 1378; https://doi.org/10.3390/genes14071378 - 29 Jun 2023
Cited by 12 | Viewed by 6629
Abstract
RNA splicing is a key regulatory step in the proper control of gene expression. It is a highly dynamic process orchestrated by the spliceosome, a macro-molecular machinery that consists of protein and RNA components. The dysregulation of RNA splicing has been observed in [...] Read more.
RNA splicing is a key regulatory step in the proper control of gene expression. It is a highly dynamic process orchestrated by the spliceosome, a macro-molecular machinery that consists of protein and RNA components. The dysregulation of RNA splicing has been observed in many human pathologies ranging from neurodegenerative diseases to cancer. The recent identification of recurrent mutations in the core components of the spliceosome in hematologic malignancies has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. This review article will discuss our current understanding of how aberrant RNA splicing regulation drives tumor initiation and progression. We will also review current therapeutic modalities and highlight emerging technologies designed to target RNA splicing for cancer treatment. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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19 pages, 2999 KiB  
Review
Nonsense-Mediated mRNA Decay as a Mediator of Tumorigenesis
by Preeti Nagar, Md Rafikul Islam and Mohammad Alinoor Rahman
Genes 2023, 14(2), 357; https://doi.org/10.3390/genes14020357 - 30 Jan 2023
Cited by 15 | Viewed by 6451
Abstract
Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved and well-characterized biological mechanism that ensures the fidelity and regulation of gene expression. Initially, NMD was described as a cellular surveillance or quality control process to promote selective recognition and rapid degradation of erroneous transcripts [...] Read more.
Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved and well-characterized biological mechanism that ensures the fidelity and regulation of gene expression. Initially, NMD was described as a cellular surveillance or quality control process to promote selective recognition and rapid degradation of erroneous transcripts harboring a premature translation-termination codon (PTC). As estimated, one-third of mutated and disease-causing mRNAs were reported to be targeted and degraded by NMD, suggesting the significance of this intricate mechanism in maintaining cellular integrity. It was later revealed that NMD also elicits down-regulation of many endogenous mRNAs without mutations (~10% of the human transcriptome). Therefore, NMD modulates gene expression to evade the generation of aberrant truncated proteins with detrimental functions, compromised activities, or dominant-negative effects, as well as by controlling the abundance of endogenous mRNAs. By regulating gene expression, NMD promotes diverse biological functions during development and differentiation, and facilitates cellular responses to adaptation, physiological changes, stresses, environmental insults, etc. Mutations or alterations (such as abnormal expression, degradation, post-translational modification, etc.) that impair the function or expression of proteins associated with the NMD pathway can be deleterious to cells and may cause pathological consequences, as implicated in developmental and intellectual disabilities, genetic defects, and cancer. Growing evidence in past decades has highlighted NMD as a critical driver of tumorigenesis. Advances in sequencing technologies provided the opportunity to identify many NMD substrate mRNAs in tumor samples compared to matched normal tissues. Interestingly, many of these changes are tumor-specific and are often fine-tuned in a tumor-specific manner, suggesting the complex regulation of NMD in cancer. Tumor cells differentially exploit NMD for survival benefits. Some tumors promote NMD to degrade a subset of mRNAs, such as those encoding tumor suppressors, stress response proteins, signaling proteins, RNA binding proteins, splicing factors, and immunogenic neoantigens. In contrast, some tumors suppress NMD to facilitate the expression of oncoproteins or other proteins beneficial for tumor growth and progression. In this review, we discuss how NMD is regulated as a critical mediator of oncogenesis to promote the development and progression of tumor cells. Understanding how NMD affects tumorigenesis differentially will pave the way for the development of more effective and less toxic, targeted therapeutic opportunities in the era of personalized medicine. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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17 pages, 1909 KiB  
Review
SR Splicing Factors Promote Cancer via Multiple Regulatory Mechanisms
by Ledong Wan, Min Deng and Honghe Zhang
Genes 2022, 13(9), 1659; https://doi.org/10.3390/genes13091659 - 16 Sep 2022
Cited by 11 | Viewed by 4475
Abstract
Substantial emerging evidence supports that dysregulated RNA metabolism is associated with tumor initiation and development. Serine/Arginine-Rich proteins (SR) are a number of ultraconserved and structurally related proteins that contain a characteristic RS domain rich in arginine and serine residues. SR proteins perform a [...] Read more.
Substantial emerging evidence supports that dysregulated RNA metabolism is associated with tumor initiation and development. Serine/Arginine-Rich proteins (SR) are a number of ultraconserved and structurally related proteins that contain a characteristic RS domain rich in arginine and serine residues. SR proteins perform a critical role in spliceosome assembling and conformational transformation, contributing to precise alternative RNA splicing. Moreover, SR proteins have been reported to participate in multiple other RNA-processing-related mechanisms than RNA splicing, such as genome stability, RNA export, and translation. The dysregulation of SR proteins has been reported to contribute to tumorigenesis through multiple mechanisms. Here we reviewed the different biological roles of SR proteins and strategies for functional rectification of SR proteins that may serve as potential therapeutic approaches for cancer. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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Other

23 pages, 2047 KiB  
Perspective
Alternative Splicing, RNA Editing, and the Current Limits of Next Generation Sequencing
by Manuela Piazzi, Alberto Bavelloni, Sara Salucci, Irene Faenza and William L. Blalock
Genes 2023, 14(7), 1386; https://doi.org/10.3390/genes14071386 - 30 Jun 2023
Cited by 7 | Viewed by 3755
Abstract
The advent of next generation sequencing (NGS) has fostered a shift in basic analytic strategies of a gene expression analysis in diverse pathologies for the purposes of research, pharmacology, and personalized medicine. What was once highly focused research on individual signaling pathways or [...] Read more.
The advent of next generation sequencing (NGS) has fostered a shift in basic analytic strategies of a gene expression analysis in diverse pathologies for the purposes of research, pharmacology, and personalized medicine. What was once highly focused research on individual signaling pathways or pathway members has, from the time of gene expression arrays, become a global analysis of gene expression that has aided in identifying novel pathway interactions, the discovery of new therapeutic targets, and the establishment of disease-associated profiles for assessing progression, stratification, or a therapeutic response. But there are significant caveats to this analysis that do not allow for the construction of the full picture. The lack of timely updates to publicly available databases and the “hit and miss” deposition of scientific data to these databases relegate a large amount of potentially important data to “garbage”, begging the question, “how much are we really missing?” This brief perspective aims to highlight some of the limitations that RNA binding/modifying proteins and RNA processing impose on our current usage of NGS technologies as relating to cancer and how not fully appreciating the limitations of current NGS technology may negatively affect therapeutic strategies in the long run. Full article
(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)
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