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Altered RNA Processing in Tumor Pathogenesis and Therapy

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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 (30 November 2022) | Viewed by 11648

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Special Issue Editor

Prof. Dr. Attila A. Seyhan

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Guest Editor

Department of Pathology and Laboratory Medicine, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Cancer Center at Brown University, Brown University, Providence, RI 02912, USA
Interests: translational research; epigenetic and genetic alterations; RNA processing; non-coding RNAs; therapeutic target and biomarker discovery; oncogenesis; cancer treatments; nucleic acid therapeutics; drug resistance

Special Issue Information

Dear Colleagues,

In recent years, large-scale genomic studies including single-cell RNA-seq have identified numerous modalities by which protein coding and noncoding RNA processing is altered in numerous cancers at the cellular level. These include mutations that drive cancer by perturbing cotranscriptional and post-transcriptional regulation of gene expressions such as alterations that affect each phase of RNA processing, including transcription, splicing, transport, editing, and decay of messenger and other RNAs. The discovery of these alterations in RNA transcription and processing and other mechanisms has revealed several novel therapeutic vulnerabilities in cancer, several of which have progressed to clinical development.

Consequently, targeting cells with these alterations or mutations is emerging as a novel therapeutic strategy. These include small molecule, antisense, RNA, and protein therapeutic modalities to modulate alternative RNA splicing or other RNA processing and modification mechanisms and some of these are currently progressing toward clinical development or are already in clinical trials.

Thereby, a better understanding of the molecular mechanisms associated with altered RNA processes and mechanisms and the biological impact of these alterations in RNA transcription and processing on tumorigenesis can provide insights into cancer pathophysiology, leading to the discovery of novel biomarkers and therapeutic vulnerabilities.

This Special Issue calls for original research, reviews and perspectives that address the progress and current knowledge on altered RNA processing and their impact on oncogenesis, response to cancer treatments and drug resistance, and their utility as biomarkers, therapeutic targets, and therapeutics.

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

epigenetic and genetic alterations in cancer that affect RNA processing;
cancer-associated patterns of dysregulated RNA processing including noncoding RNAs;
RNA splicing isoforms and modifying enzymes or proteins as potential biomarkers and therapeutic targets;
structural and functional analysis of RNA modifying proteins;
drugs targeting RNA, RNA-modifying enzymes and proteins;
preclinical or clinical investigation of RNA processing-targeting agents;
modulation of oncogenic RNA splicing events;
cancer neoantigens formed by aberrant RNA processing.

Prof. Dr. Attila A. Seyhan
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 transcription
RNA processing
RNA capping
RNA polyandenylation
RNA editing
RNA splicing and spliceosome
RNA methylation
RNA interference
Antisense oligonuclotides
CRISPR and other RNA editing platforms
Targeted cancer threapy
Cancer biomarkers

Published Papers (4 papers)

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Research

Jump to: Review

11 pages, 1069 KiB

Open AccessCommunication

MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Histone Proteomic Networks

by Sean Hacking, Charissa Chou, Yigit Baykara, Yihong Wang, Alper Uzun and Ece D. Gamsiz Uzun

Int. J. Mol. Sci. 2023, 24(6), 5327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065327 - 10 Mar 2023

Cited by 1 | Viewed by 1711

Abstract

Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes, including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR are largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare and only seen to occur in around 3% of BCs. In the present study, we analyzed TCGA data using a multi-sample protein–protein interaction (PPI) analysis tool, Proteinarium, and showed a distinct separation between specific MMR-deficient and -intact networks in a cohort of 994 BC patients. In the PPI networks specific to MMR deficiency, highly connected clusters of histone genes were identified. We also found the distribution of MMR-deficient BC to be more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. We recommend defining MMR-deficient BC by next-generation sequencing (NGS) when any somatic mutation is detected in one of the seven MMR genes. Full article

(This article belongs to the Special Issue Altered RNA Processing in Tumor Pathogenesis and Therapy)

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11 pages, 7531 KiB

Open AccessCommunication

Comprehensive Analysis of N6-Methyladenosine (m6A) Writers, Erasers, and Readers in Cervical Cancer

by Mateja Condic, Damian J. Ralser, Niklas Klümper, Jörg Ellinger, Maryam Qureischi, Eva K. Egger, Glen Kristiansen, Alexander Mustea and Thore Thiesler

Int. J. Mol. Sci. 2022, 23(13), 7165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137165 - 28 Jun 2022

Cited by 9 | Viewed by 2662

Abstract

There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ (METTL3, METTL4, METTL14, WTAP, KIAA1429), ‘erasers’ (FTO, ALKBH5), and ‘readers’ (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC. Full article

(This article belongs to the Special Issue Altered RNA Processing in Tumor Pathogenesis and Therapy)

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Review

Jump to: Research

34 pages, 4726 KiB

Open AccessReview

Insights and Strategies of Melanoma Immunotherapy: Predictive Biomarkers of Response and Resistance and Strategies to Improve Response Rates

by Attila A. Seyhan and Claudio Carini

Int. J. Mol. Sci. 2023, 24(1), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010041 - 20 Dec 2022

Cited by 6 | Viewed by 2896

Abstract

Despite the recent successes and durable responses with immune checkpoint inhibitors (ICI), many cancer patients, including those with melanoma, do not derive long-term benefits from ICI therapies. The lack of predictive biomarkers to stratify patients to targeted treatments has been the driver of primary treatment failure and represents an unmet medical need in melanoma and other cancers. Understanding genomic correlations with response and resistance to ICI will enhance cancer patients’ benefits. Building on insights into interplay with the complex tumor microenvironment (TME), the ultimate goal should be assessing how the tumor ’instructs’ the local immune system to create its privileged niche with a focus on genomic reprogramming within the TME. It is hypothesized that this genomic reprogramming determines the response to ICI. Furthermore, emerging genomic signatures of ICI response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways, are gaining momentum. In addition, emerging data suggest a role for checkpoint regulators, T cell functionality, chromatin modifiers, and copy-number alterations in mediating the selective response to ICI. As such, efforts to contextualize genomic correlations with response into a more insightful understanding of tumor immune biology will help the development of novel biomarkers and therapeutic strategies to overcome ICI resistance. Full article

(This article belongs to the Special Issue Altered RNA Processing in Tumor Pathogenesis and Therapy)

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21 pages, 1397 KiB

Open AccessReview

Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers

by Ilyas Sahin, Andrew George and Attila A. Seyhan

Int. J. Mol. Sci. 2021, 22(21), 11790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111790 - 30 Oct 2021

Cited by 13 | Viewed by 3709

Abstract

Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) processing, which includes the removal of introns by splicing, is frequently altered in tumors, producing multiple different isoforms and diversifying protein expression. These alterations in RNA processing result in numerous cancer-specific mRNAs and pathogenically spliced events that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumor suppressor genes. Abnormally spliced pre-mRNAs are also associated with resistance to cancer treatment, and certain cancers are highly sensitive to the pharmacological inhibition of splicing. The discovery of these alterations in RNA processing has not only provided new insights into cancer pathogenesis but identified novel therapeutic vulnerabilities and therapeutic opportunities in targeting these aberrations in various ways (e.g., small molecules, splice-switching oligonucleotides (SSOs), and protein therapies) to modulate alternative RNA splicing or other RNA processing and modification mechanisms. Some of these strategies are currently progressing toward clinical development or are already in clinical trials. Additionally, tumor-specific neoantigens produced from these pathogenically spliced events and other abnormal RNA processes provide a potentially extensive source of tumor-specific therapeutic antigens (TAs) for targeted cancer immunotherapy. Moreover, a better understanding of the molecular mechanisms associated with aberrant RNA processes and the biological impact they play might provide insights into cancer initiation, progression, and metastasis. Our goal is to highlight key alternative RNA splicing and processing mechanisms and their roles in cancer pathophysiology as well as emerging therapeutic alternative splicing targets in cancer, particularly in gastrointestinal (GI) malignancies. Full article

(This article belongs to the Special Issue Altered RNA Processing in Tumor Pathogenesis and Therapy)

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