| Autor: |
Roberta Esposito, Andrés Lanzós, Tina Uroda, Sunandini Ramnarayanan, Isabel Büchi, Taisia Polidori, Hugo Guillen-Ramirez, Ante Mihaljevic, Bernard Mefi Merlin, Lia Mela, Eugenio Zoni, Lusine Hovhannisyan, Finn McCluggage, Matúš Medo, Giulia Basile, Dominik F. Meise, Sandra Zwyssig, Corina Wenger, Kyriakos Schwarz, Adrienne Vancura, Núria Bosch-Guiteras, Álvaro Andrades, Ai Ming Tham, Michaela Roemmele, Pedro P. Medina, Adrian F. Ochsenbein, Carsten Riether, Marianna Kruithof-de Julio, Yitzhak Zimmer, Michaela Medová, Deborah Stroka, Archa Fox, Rory Johnson |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-21 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-39160-7 |
| Popis: |
Abstract Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic “driver” mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink