| 1. |
- Aguilo, Francesca, PhD, et al.
(författare)
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Editorial : translational control in cancer
- 2024
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Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 6:3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Beneventi, Giulia, et al.
(författare)
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The small Cajal body-specific RNA 15 (SCARNA15) directs p53 and redox homeostasis via selective splicing in cancer cells
- 2021
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Ingår i: NAR Cancer. - : Oxford University Press (OUP). - 2632-8674. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Small Cajal body-specific RNAs (scaRNAs) guide post-transcriptional modification of spliceosomal RNA and, while commonly altered in cancer, have poorly defined roles in tumorigenesis. Here, we uncover that SCARNA15 directs alternative splicing (AS) and stress adaptation in cancer cells. Specifically, we find that SCARNA15 guides critical pseudouridylation (Ψ) of U2 spliceosomal RNA to fine-tune AS of distinct transcripts enriched for chromatin and transcriptional regulators in malignant cells. This critically impacts the expression and function of the key tumor suppressors ATRX and p53. Significantly, SCARNA15 loss impairs p53-mediated redox homeostasis and hampers cancer cell sur- vival, motility and anchorage-independent growth. In sum, these findings highlight an unanticipated role for SCARNA15 and Ψ in directing cancer-associated splicing programs.
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| 3. |
- Esteva-Socias, Margalida, et al.
(författare)
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METTL3 as a master regulator of translation in cancer : mechanisms and implications
- 2024
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Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m6A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m6A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m6A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m6A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.
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| 4. |
- Gabre, Jonatan L., 1988, et al.
(författare)
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Preclinical exploration of the DNA damage response pathway using the interactive neuroblastoma cell line explorer CLEAN
- 2024
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Ingår i: NAR Cancer. - 2632-8674. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma (NB) is the most common cancer in infancy with an urgent need for more efficient targeted therapies. The development of novel (combinatorial) treatment strategies relies on extensive explorations of signaling perturbations in neuroblastoma cell lines, using RNA-Seq or other high throughput technologies (e.g. phosphoproteomics). This typically requires dedicated bioinformatics support, which is not always available. Additionally, while data from published studies are highly valuable and raw data (e.g. fastq files) are nowadays released in public repositories, data processing is time-consuming and again difficult without bioinformatics support. To facilitate NB research, more user-friendly and immediately accessible platforms are needed to explore newly generated as well as existing high throughput data. To make this possible, we developed an interactive data centralization and visualization web application, called CLEAN (the Cell Line Explorer web Application of Neuroblastoma data; https://ccgg.ugent.be/shiny/clean/). By focusing on the regulation of the DNA damage response, a therapeutic target of major interest in neuroblastoma, we demonstrate how CLEAN can be used to gain novel mechanistic insights and identify putative drug targets in neuroblastoma.
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| 5. |
- Høye, Eirik, et al.
(författare)
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A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer
- 2022
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Ingår i: NAR Cancer. - : Oxford University Press (OUP). - 2632-8674. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as up-regulated at multiple metastatic sites Mir-210_3p, Mir-191_5p, Mir-8-P1b_3p [mir-141–3p], Mir-1307_5p and Mir-155_5p. Several have previously been implicated in metastasis through involvement in epithelial-to-mesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.
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| 6. |
- Kumari, Kanchan, et al.
(författare)
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Regulatory roles of RNA modifications in breast cancer
- 2021
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Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 3:3
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Forskningsöversikt (refereegranskat)abstract
- Collectively referred to as the epitranscriptome, RNA modifications play important roles in gene expression control regulating relevant cellular processes. In the last few decades, growing numbers of RNA modifications have been identified not only in abundant ribosomal (rRNA) and transfer RNA (tRNA) but also in messenger RNA (mRNA). In addition, many writers, erasers and readers that dynamically regulate the chemical marks have also been characterized. Correct deposition of RNA modifications is prerequisite for cellular homeostasis, and its alteration results in aberrant transcriptional programs that dictate human disease, including breast cancer, the most frequent female malignancy, and the leading cause of cancer-related death in women. In this review, we emphasize the major RNA modifications that are present in tRNA, rRNA and mRNA. We have categorized breast cancer-associated chemical marks and summarize their contribution to breast tumorigenesis. In addition, we describe less abundant tRNA modifications with related pathways implicated in breast cancer. Finally, we discuss current limitations and perspectives on epitranscriptomics for use in therapeutic strategies against breast and other cancers.
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| 7. |
- Sesink, Anouk, et al.
(författare)
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The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest
- 2024
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Ingår i: NAR Cancer. - 2632-8674. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.
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| 8. |
- Zivanovic, Andrej, et al.
(författare)
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Co-evolution of AR gene copy number and structural complexity in endocrine therapy resistant prostate cancer
- 2023
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Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. Resolving this is important for developing new therapies and predictive biomarkers. Here, we analyzed 41 CRPC tumors and 6 patient-derived xenografts (PDXs) using linked-read DNA-sequencing, and identified 7 tumors that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.
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