•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
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.
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
•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
Dysregulation of alternative splicing is a feature of cancer, both in aetiology and progression. It occurs because of mutations in splice sites or sites that regulate splicing, or because of the ...altered expression and activity of splice factors and of splice factor kinases that regulate splice factor activity. Recently the CDC2-like kinases (CLKs) have attracted attention due to their increasing involvement in cancer. We measured the effect of the CLK inhibitor, the benzothiazole TG003, on two prostate cancer cell lines. TG003 reduced cell proliferation and increased apoptosis in PC3 and DU145 cells. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 slowed scratch closure and reduced cell migration and invasion in a transwell assay. TG003 decisively inhibited the growth of a PC3 cell line xenograft in nude mice. We performed a transcriptomic analysis of cells treated with TG003. We report widespread and consistent changes in alternative splicing of cancer-associated genes including CENPE, ESCO2, CKAP2, MELK, ASPH and CD164 in both HeLa and PC3 cells. Together these findings suggest that targeting CLKs will provide novel therapeutic opportunities in prostate cancer.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Vascular endothelial growth factor A (VEGFA; hereafter referred to as VEGF) is a key regulator of physiological and pathological angiogenesis. Two families of VEGF isoforms are generated by alternate ...splice-site selection in the terminal exon. Proximal splice-site selection (PSS) in exon 8 results in pro-angiogenic VEGFxxx isoforms (xxx is the number of amino acids), whereas distal splice-site selection (DSS) results in anti-angiogenic VEGFxxxb isoforms. To investigate control of PSS and DSS, we investigated the regulation of isoform expression by extracellular growth factor administration and intracellular splicing factors. In primary epithelial cells VEGFxxxb formed the majority of VEGF isoforms (74%). IGF1, and TNFα treatment favoured PSS (increasing VEGFxxx) whereas TGFβ1 favoured DSS, increasing VEGFxxxb levels. TGFβ1 induced DSS selection was prevented by inhibition of p38 MAPK and the Clk/sty (CDC-like kinase, CLK1) splicing factor kinase family, but not ERK1/2. Clk phosphorylates SR protein splicing factors ASF/SF2, SRp40 and SRp55. To determine whether SR splicing factors alter VEGF splicing, they were overexpressed in epithelial cells, and VEGF isoform production assessed. ASF/SF2, and SRp40 both favoured PSS, whereas SRp55 upregulated VEGFxxxb (DSS) isoforms relative to VEGFxxx. SRp55 knockdown reduced expression of VEGF₁₆₅b. Moreover, SRp55 bound to a 35 nucleotide region of the 3'UTR immediately downstream of the stop codon in exon 8b. These results identify regulation of splicing by growth and splice factors as a key event in determining the relative pro-versus anti-angiogenic expression of VEGF isoforms, and suggest that p38 MAPK-Clk/sty kinases are responsible for the TGFβ1-induced DSS selection, and identify SRp55 as a key regulatory splice factor.
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 required for tumour growth and is induced principally by vascular endothelial growth factor A (VEGF-A). VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two ...families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer (PCa). In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by serine-arginine protein kinase 1 (SRPK1). Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared with benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in PCa may be under the control of SRPK1 activity. A switch in the expression of VEGF165 towards the anti-angiogenic splice isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knockdown (KD). PC-3 SRPK1-KD cells resulted in tumours that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1-KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Small-molecule inhibitors of SRPK1 switched splicing towards the anti-angiogenic isoform VEGF165b in PC-3 cells and decreased tumour growth when administered intraperitoneally in an orthotopic mouse model of PCa. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumour angiogenesis by regulation of VEGF splicing can alter prostate tumour growth and supports further studies for the use of SRPK1 inhibition as a potential anti-angiogenic therapy in PCa.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
AS (alternative splicing) and its role in disease, especially cancer, has come to forefront in research over the last few years. Alterations in the ratio of splice variants have been widely observed ...in cancer. Splice variants of cancer-associated genes have functions that can alter cellular phenotype, ultimately altering metastatic potential. As metastases are the cause of approximately 90% of all human cancer deaths, it is crucial to understand how AS is dysregulated in metastatic disease. We highlight some recent studies into the relationship between altered AS of key genes and the initiation of prostate cancer metastasis.
PDF
