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Targeting Dysregulated RNA Processing in Cancer

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 21415

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Special Issue Editor

Prof. Dr. Victor van Beusechem

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Guest Editor

Department Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands
Interests: cancer therapy development; therapeutic target discovery; functional genetic screening; oncolytic immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Emerging data show that co-transcriptional and post-transcriptional modifications of protein-encoding messenger RNAs are important determinants of oncogenesis, response to cancer treatment, and anticancer drug resistance. Aberrant RNA methylation, splicing, and editing affect mRNA transport and stability, as well as its translation into protein isoforms with distinct or even opposing functions. Alternative mRNA splicing products and loss of canonically spliced variants were shown to correlate with stage and progression in malignancy. Frequent somatic mutations in regulators of RNA modification and altered splicing patterns in key cancer-associated genes were found in cancer cells and have been proposed as a hallmark of cancer. A deeper understanding of the molecular mechanisms associated with dysregulated RNA modification and the study of altered RNA modification events in cancer cells can provide key insights into the pathophysiology of cancer and pave the way for biomarker discovery and identification of novel therapeutic vulnerabilities. In particular, small molecule inhibitors of alternative RNA splicing represent a potentially promising class of anti-cancer agents, currently progressing toward clinical development.

This Special Issue of IJMS will provide new research results to broaden our understanding of dysregulated RNA processing in cancer and its effects on disease progression and treatment efficacy, as well as the identification of new biomarkers, therapeutic targets and experimental medicines based on this knowledge. Novel insights that may contribute to more effective cancer treatment are of particular interest for this issue. Authors are invited to submit their original research and timely review articles.

Relevant topics include, but are not limited to the following:

Identification of cancer-associated patterns of dysregulated RNA processing
Detection of genetic alterations in cancer that affect RNA processing
RNA splicing isoforms as potential biomarkers and therapeutic targets
Structural and functional analysis of RNA modifying proteins
Discovery of drugs targeting RNA modifying proteins
Preclinical or clinical evaluation of spliceosome-targeting compounds
Strategies to modulate oncogenic RNA splicing events
Bioinformatic analysis methods to study dysregulated RNA processing
Identification of putative cancer neoantigens formed by aberrant RNA processing

Prof. Dr. Victor van Beusechem
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

RNA splicing
RNA editing
RNA methylation
(Supra)spliceosome
Antisense oligonucleotides
RNA interference
Small molecules
Cancer biomarkers
Cancer therapy

Published Papers (4 papers)

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Research

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13 pages, 2148 KiB

Open AccessArticle

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation

by Lushang Jiang, Min Ji Park, Charles J. Cho, Kihak Lee, Min Kyo Jung, Chan Gi Pack, Seung-Jae Myung and Suhwan Chang

Int. J. Mol. Sci. 2020, 21(17), 6195; https://doi.org/10.3390/ijms21176195 - 27 Aug 2020

Cited by 13 | Viewed by 3466

Abstract

ADAR (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to generate inosine, through its binding to double-stranded RNA (dsRNA), a phenomenon known as RNA editing. One of the functions of ADAR1 is suppressing the type I interferon (IFN) response, but its mechanism in gastric cancer is not clearly understood. We analyzed changes in RNA editing and IFN signaling in ADAR1-depleted gastric cancer cells, to clarify how ADAR1 regulates IFN signaling. Interestingly, we observed a dramatic increase in the protein level of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 9 (IRF9) upon ADAR1 knockdown, in the absence of type I or type II IFN treatment. However, there were no changes in protein expression or localization of the mitochondrial antiviral signaling protein (MAVS) and interferon alpha and beta-receptor subunit 2 (IFNAR2), the two known mediators of IFN production. Instead, we found that miR-302a-3p binds to the untranslated region (UTR) of IRF9 and regulate its expression. The treatment of ADAR1-depleted AGS cells with an miR-302a mimic successfully restored IRF9 as well as STAT1 protein level. Hence, our results suggest that ADAR1 regulates IFN signaling in gastric cancer through the suppression of STAT1 and IRF9 via miR-302a, which is independent from the RNA editing of known IFN production pathway. Full article

(This article belongs to the Special Issue Targeting Dysregulated RNA Processing in Cancer)

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13 pages, 1331 KiB

Open AccessArticle

Silencing Core Spliceosome Sm Gene Expression Induces a Cytotoxic Splicing Switch in the Proteasome Subunit Beta 3 mRNA in Non-Small Cell Lung Cancer Cells

by Maxime Blijlevens, Malgorzata A. Komor, Rocco Sciarrillo, Egbert F. Smit, Remond J. A. Fijneman and Victor W. van Beusechem

Int. J. Mol. Sci. 2020, 21(12), 4192; https://doi.org/10.3390/ijms21124192 - 12 Jun 2020

Cited by 12 | Viewed by 2585

Abstract

The core spliceosomal Sm proteins were recently proposed as cancer-selective lethal targets in non-small cell lung cancer (NSCLC). In contrast, the loss of the commonly mutated cancer target SF3B1 appeared to be toxic to non-malignant cells as well. In the current study, the transcriptomes of A549 NSCLC cells, in which SF3B1 or SNRPD3 was silenced, were compared using RNA sequencing. The skipping of exon 4 of the proteasomal subunit beta type-3 (PSMB3) mRNA, resulting in a shorter PSMB3-S variant, occurred only after silencing SNRPD3. This observation was extended to the other six Sm genes. Remarkably, the alternative splicing of PSMB3 mRNA upon Sm gene silencing was not observed in non-malignant IMR-90 lung fibroblasts. Furthermore, PSMB3 was found to be overexpressed in NSCLC clinical samples and PSMB3 expression correlated with Sm gene expression. Moreover, a high PSMB3 expression corresponds to worse survival in patients with lung adenocarcinomas. Finally, silencing the canonical full-length PSMB3-L, but not the shorter PSMB3-S variant, was cytotoxic and was accompanied by a decrease in proteasomal activity. Together, silencing Sm genes, but not SF3B1, causes a cytotoxic alternative splicing switch in the PSMB3 mRNA in NSCLC cells only. Full article

(This article belongs to the Special Issue Targeting Dysregulated RNA Processing in Cancer)

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Review

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63 pages, 3129 KiB

Open AccessReview

Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities

by Maxime Blijlevens, Jing Li and Victor W. van Beusechem

Int. J. Mol. Sci. 2021, 22(10), 5110; https://doi.org/10.3390/ijms22105110 - 12 May 2021

Cited by 18 | Viewed by 7998

Abstract

Dysregulation of messenger RNA (mRNA) processing—in particular mRNA splicing—is a hallmark of cancer. Compared to normal cells, cancer cells frequently present aberrant mRNA splicing, which promotes cancer progression and treatment resistance. This hallmark provides opportunities for developing new targeted cancer treatments. Splicing of precursor mRNA into mature mRNA is executed by a dynamic complex of proteins and small RNAs called the spliceosome. Spliceosomes are part of the supraspliceosome, a macromolecular structure where all co-transcriptional mRNA processing activities in the cell nucleus are coordinated. Here we review the biology of the mRNA splicing machinery in the context of other mRNA processing activities in the supraspliceosome and present current knowledge of its dysregulation in lung cancer. In addition, we review investigations to discover therapeutic targets in the spliceosome and give an overview of inhibitors and modulators of the mRNA splicing process identified so far. Together, this provides insight into the value of targeting the spliceosome as a possible new treatment for lung cancer. Full article

(This article belongs to the Special Issue Targeting Dysregulated RNA Processing in Cancer)

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24 pages, 1436 KiB

Open AccessReview

Alternative Splicing: Expanding the Landscape of Cancer Biomarkers and Therapeutics

by Cláudia Bessa, Paulo Matos, Peter Jordan and Vânia Gonçalves

Int. J. Mol. Sci. 2020, 21(23), 9032; https://doi.org/10.3390/ijms21239032 - 27 Nov 2020

Cited by 26 | Viewed by 6570

Abstract

Alternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity. In the past decade, genome-wide transcriptome sequencing has revealed that AS is tightly regulated in a tissue- and developmental stage-specific manner, and also frequently dysregulated in multiple human cancer types. It is currently recognized that splicing defects, including genetic alterations in the spliced gene, altered expression of both core components or regulators of the precursor messenger RNA (pre-mRNA) splicing machinery, or both, are major drivers of tumorigenesis. Hence, in this review we provide an overview of our current understanding of splicing alterations in cancer, and emphasize the need to further explore the cancer-specific splicing programs in order to obtain new insights in oncology. Furthermore, we also discuss the recent advances in the identification of dysregulated splicing signatures on a genome-wide scale and their potential use as biomarkers. Finally, we highlight the therapeutic opportunities arising from dysregulated splicing and summarize the current approaches to therapeutically target AS in cancer. Full article

(This article belongs to the Special Issue Targeting Dysregulated RNA Processing in Cancer)

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