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Cancers
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The Role of Alternative Splicing in Cancer
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The Role of Alternative Splicing in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 6932

Special Issue Editor

Prof. Dr. Luis Franco

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Guest Editor
1. Department of Biochemistry and Molecular Biology, Universitat de València, 46010 Valencia, Spain
2. Department of Oncology, Institute of Health Research INCLIVA, 46010 Valencia, Spain
Interests: alternative TSSs; alternative polyadenylation; mechanisms of RNA splicing; mRNA and protein isoforms; spliceosome; aberrant splicing; hRNPs; exon skipping; intron retention; spliceosomal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most eukaryotic structural genes contain several exons interspersed with introns. Among other mechanisms, the maturation of primary transcripts involves splicing, which most often results in the removal of introns to yield mature mRNA. Splicing of pre-mRNA is a very intricate mechanism that, in most cases, may be developed in several alternative ways. Some exons may be skipped and some introns may also be retained. In this way, alternative splicing may give rise to several mature mRNAs from a single structural gene, which may, in turn, be translated to yield several protein isoforms. The importance of alternative splicing transcends the academic interest because it is very common that the several mRNA or protein isoforms arising from a single gene possess different and even opposed functions. The use of alternative transcription start or termination sites further contributes to the multiplicity of isoforms.

Since the original discovery in 1994 that the canonical isoform of the FAS gene bound to the mitochondrial membrane is pro-apoptotic, while a soluble isoform is anti-apoptotic, many examples of alternative splicing have been found in which both oncogenic and suppressor isoforms may be produced from the same gene. Aberrant splicing may, therefore, result in oncogenicity in otherwise normal tissue. Due to these circumstances, a great interest in the relationships between alternative splicing and cancer has arisen in the last few years.

I am pleased to invite you to contribute to this Special Issue of Cancers, which tries to gather relevant papers supporting the increasing importance of those relationships. Both reviews and original manuscripts on mechanisms of alternative splicing, detection and analysis of isoforms, their value as diagnostic and/or prognostic factors, and splicing-related therapeutic approaches will be welcome. We hope that both basic and clinical oncologists will be interested in this exciting field of cancer research.

We are looking forward to receiving your contributions.

Prof. Dr. Luis Franco
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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • chromatin
  • histones
  • gene transcription
  • epigenetics
  • alternative splicing

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Published Papers (3 papers)

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Research

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24 pages, 3408 KiB  
Article
Molecular Insight into Drug Resistance Mechanism Conferred by Aberrant PIK3CD Splice Variant in African American Prostate Cancer
by Siyoung Ha and Bi-Dar Wang
Cancers 2023, 15(4), 1337; https://doi.org/10.3390/cancers15041337 - 20 Feb 2023
Cited by 5 | Viewed by 2229
Abstract
Targeting PI3Kδ has emerged as a promising therapy for hematologic and non-hematologic malignancies. Previously, we identified an oncogenic splice variant, PIK3CD-S, conferring Idelalisib resistance in African American (AA) prostate cancer (PCa). In the current study, we employed a comprehensive analysis combining molecular [...] Read more.
Targeting PI3Kδ has emerged as a promising therapy for hematologic and non-hematologic malignancies. Previously, we identified an oncogenic splice variant, PIK3CD-S, conferring Idelalisib resistance in African American (AA) prostate cancer (PCa). In the current study, we employed a comprehensive analysis combining molecular biology, biochemistry, histology, in silico simulation, and in vitro functional assays to investigate the PIK3CD-S expression profiles in PCa samples and to elucidate the drug resistance mechanism mediated by PI3Kδ-S (encoded by PIK3CD-S). The immunohistochemistry, RT-PCR, and Western blot assays first confirmed that PI3Kδ-S is highly expressed in AA PCa. Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Molecular docking, ATP-competitive assays, and PI3 kinase assays have further indicated a drastically reduced affinity of PI3Kδ inhibitors with PI3Kδ-S vs. PI3Kδ-L, attributed to the lack of core binding residues in the PI3Kδ-S catalytic domain. Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors. Full article
(This article belongs to the Special Issue The Role of Alternative Splicing in Cancer)
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Review

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30 pages, 3223 KiB  
Review
The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes
by Francisco Gimeno-Valiente, Gerardo López-Rodas, Josefa Castillo and Luis Franco
Cancers 2024, 16(11), 2123; https://doi.org/10.3390/cancers16112123 - 1 Jun 2024
Viewed by 1429
Abstract
Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing—which produces various mature mRNAs and, eventually, protein variants from a single gene—may also result in driving neoplastic transformation because of the [...] Read more.
Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing—which produces various mature mRNAs and, eventually, protein variants from a single gene—may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes. Full article
(This article belongs to the Special Issue The Role of Alternative Splicing in Cancer)
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23 pages, 1105 KiB  
Review
Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer
by Piedad Alba-Pavón, Lide Alaña, Itziar Astigarraga and Olatz Villate
Cancers 2022, 14(23), 5967; https://doi.org/10.3390/cancers14235967 - 2 Dec 2022
Cited by 2 | Viewed by 2566
Abstract
The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an [...] Read more.
The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing. Full article
(This article belongs to the Special Issue The Role of Alternative Splicing in Cancer)
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