The vast majority of human genes are alternatively spliced. Not surprisingly, aberrant alternative splicing is increasingly linked to cancer. Splice isoforms often encode proteins that have distinct ...and even antagonistic properties. The abnormal expression of splice factors and splice factor kinases in cancer changes the alternative splicing of critically important pre-mRNAs. Aberrant alternative splicing should be added to the growing list of cancer hallmarks.
Full text
Available for:
FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
•Catechins have effects based on preclinical and clinical trials studies.•Catechins exhibit both pro- and antioxidant activities.•Catechins multiple uses in cancer therapy.•Catechins are involved in ...alternative splicing.
Catechins and their gallate esters are a class of polyphenolic compounds. The catechin subclass known as flavan-3-ols have recently attracted much attention with regards to their beneficial effect on human health. Their biological actions are dependent on the structure of the compounds and vary according to cell type. They are best known as powerful antioxidants; however depending on the doses they also exhibit prooxidant effects. The anti- or prooxidant effects of green tea catechins have been implicated in the modulation of several cellular functions often associated with strong chemoprotective properties. This review summarises the benefit catechins to human health, the main molecular pathways modulated by catechins. The relationship between the structure and activity of the catechins needs to be studied further. In the future, the structure of catechins could be modified so as to synthesise novel compounds with more specific beneficial properties and higher bioavailability.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alternative splicing is a highly fine-tuned regulated process and one of the main drivers of proteomic diversity across eukaryotes. The vast majority of human multi-exon genes is alternatively ...spliced in a cell type- and tissue-specific manner, and defects in alternative splicing can dramatically alter RNA and protein functions and lead to disease. The eukaryotic genome is also intensively transcribed into long and short non-coding RNAs which account for up to 90% of the entire transcriptome. Over the years, lncRNAs have received considerable attention as important players in the regulation of cellular processes including alternative splicing. In this review, we focus on recent discoveries that show how lncRNAs contribute significantly to the regulation of alternative splicing and explore how they are able to shape the expression of a diverse set of splice isoforms through several mechanisms. With the increasing number of lncRNAs being discovered and characterized, the contribution of lncRNAs to the regulation of alternative splicing is likely to grow significantly.
The peer review process is a fundamental aspect of modern scientific paper publishing, underpinning essential quality control. First conceptualised in the 1700s, it is an iterative process that aims ...to elevate scientific literature to the highest standards whilst preventing publication of scientifically unsound, potentially misleading, and even plagiarised information. It is widely accepted that the peer review of scientific papers is an irreplaceable and fundamental aspect of the research process. However, the rapid growth of research and technology has led to a huge increase in the number of publications. This has led to increased pressure on the peer review system. There are several established peer review methodologies, ranging from single and double blind to open and transparent review, but their implementation across journals and research fields varies greatly. Some journals are testing entirely novel approaches (such as collaborative reviews), whilst others are piloting changes to established methods. Given the unprecedented growth in publication numbers, and the ensuing burden on journals, editors, and reviewers, it is imperative to improve the quality and efficiency of the peer review process. Herein we evaluate the peer review process, from its historical origins to current practice and future directions.
Editorial: The RNA revolution and cancer Dlamini, Zodwa; Ladomery, Michael R.; Kahraman, Abdullah
Frontiers in endocrinology (Lausanne),
05/2024, Volume:
15
Journal Article
Peer reviewed
Open access
RNA biology has revolutionized cancer understanding and treatment, especially in endocrine-related malignancies. This editorial highlights RNA's crucial role in cancer progression, emphasizing its ...influence on tumor heterogeneity and behavior. Processes like alternative splicing and noncoding RNA regulation shape cancer biology, with microRNAs, long noncoding RNAs, and circular RNAs orchestrating gene expression dynamics. Aberrant RNA signatures hold promise as diagnostic and prognostic biomarkers in endocrine-related cancers. Recent findings, such as aberrant PI3Kδ splice isoforms and epithelial-mesenchymal transition-related lncRNA signatures, unveil potential therapeutic targets for personalized treatments. Insights into m6A-associated lncRNA prognostic models and the function of lncRNA LINC00659 in gastric cancer represents ongoing research in this field. As understanding of RNA's role in cancer expands, personalized therapies offer transformative potential in managing endocrine-related malignancies. This signifies a significant stride towards precision oncology, fostering innovation for more effective cancer care.
Targeting Splicing in Prostate Cancer Antonopoulou, Effrosyni; Ladomery, Michael
International journal of molecular sciences,
04/2018, Volume:
19, Issue:
5
Journal Article
Peer reviewed
Open access
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
,
,
,
, and
. 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 text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•A complication post-cytokine storm is the development of de novo carcinogenesis.•Chemotherapy can induce cytokine storm, and a subsequent genotoxic bystander effect.•IL-6 appears to be a key ...cytokine in promoting mutagenesis during cytokine storm.•Inhibition/neutralisation of IL-6 may protect patients from de novo carcinogenesis.
Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT).
Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls.
Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
8.
Working with Hypoxia Bowler, Elizabeth; Ladomery, Michael R
Methods in molecular biology (Clifton, N.J.),
01/2019, Volume:
1990
Journal Article
A hypoxic environment can be defined as a region of the body or the whole body that is deprived of oxygen. Hypoxia is a feature of many diseases, such as cardiovascular disease, tissue trauma, ...stroke, and solid cancers. A loss of oxygen supply usually results in cell death; however, when cells gradually become hypoxic, they may survive and continue to thrive as described for conditions that promote metastatic growth. The role of hypoxia in these pathogenic pathways is therefore of great interest, and understanding the effect of hypoxia in regulating these mechanisms is fundamentally important. This chapter gives an extensive overview of these mechanisms. Moreover, given the challenges posed by tumor hypoxia we describe the current methods to simulate and detect hypoxic conditions followed by a discussion on current and experimental therapies that target hypoxic cells.
Angiogenesis is regulated by the balance of proangiogenic VEGF
165 and antiangiogenic VEGF
165b splice isoforms. Mutations in
WT1, the Wilms' tumor suppressor gene, suppress VEGF
165b and cause ...abnormal gonadogenesis, renal failure, and Wilms' tumors. In
WT1 mutant cells, reduced VEGF
165b was due to lack of WT1-mediated transcriptional repression of the splicing-factor kinase SRPK1. WT1 bound to the
SRPK1 promoter, and repressed expression through a specific WT1 binding site. In
WT1 mutant cells SRPK1-mediated hyperphosphorylation of the oncogenic RNA binding protein SRSF1 regulated splicing of VEGF and rendered
WT1 mutant cells proangiogenic. Altered VEGF splicing was reversed by wild-type WT1, knockdown of SRSF1, or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumor growth.
Display omitted
► SR protein kinase 1 is a target for the Wilms Tumor suppressor gene-1 ►
WT1 mutations lead to altered VEGF splicing by hyperphosphorylated SRSF1 ► SRPK1 overexpression regulates VEGF splicing and angiogenesis ► SRPK1 inhibition is antiangiogenic in tumors in vivo
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The class IV glycine‐rich RNA‐binding proteins are a distinct subgroup within the heterogenous superfamily of glycine‐rich proteins (GRPs). They are distinguished by the presence of an RNA‐binding ...domain in the N‐terminus; generally in the form of an RNA‐recognition motif (RRM) or a cold‐shock domain (CSD). These are followed by a C‐terminal glycine‐rich domain. Growing evidence suggests that these proteins play key roles in the adaptation of organisms to biotic and abiotic stresses including those resulting from pathogenesis, alterations in the osmotic, saline and oxidative environment and changes in temperature. Similar vertebrate proteins are also cold‐induced and involved in, e.g. hibernation, suggesting evolutionarily conserved functions. The class IV RNA‐binding GRPs are likely to operate as key molecular components of hormonally regulated development and to work by regulating gene expression at multiple levels by modifying alternative splicing, mRNA export, mRNA translation and mRNA degradation.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
