RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas

Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these sarcomas. Despite genetic heterogeneity across samples, oncogenesis may be driven by commo...

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Published in:Cancers 2019-01, Vol.11 (1), p.81
Main Authors: Mauduit, Olivier, Brulard, Céline, Lesluyes, Tom, Delcroix, Vanessa, Pérot, Gaëlle, Choublier, Nina, Michaud, Mickael, Baud, Jessica, Lagarde, Pauline, Aurias, Alain, Coindre, Jean-Michel, Lartigue, Lydia, Blay, Jean-Yves, Chibon, Frédéric
Format: Article
Language:English
Subjects:
Apoptosis
Cell cycle
Cell proliferation
Chemotherapy
Drug resistance
Evolution
Genes
Genomics
Growth rate
Medical prognosis
Metastases
Metastasis
Mutation
Sarcoma
Therapeutic targets
Tumorigenesis
Tumors
Xenografts
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Summary:Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these sarcomas. Despite genetic heterogeneity across samples, oncogenesis may be driven by common pathway alterations. Therefore, genomic and transcriptomic profiles of 106 sarcomas with complex genomics were analyzed to identify common pathways with altered genes. This brought out a gene belonging to the "cell cycle" biological pathway, (RCC1 And BTB Domain Containing Protein 1), which is lost and downregulated in 62.5% of metastatic tumors against 34% of non-metastatic tumors. A retrospective study of three sarcoma cohorts revealed that low expression is prognostic for metastatic progression, specifically in patients that received chemotherapy. In vitro and in vivo, RCBTB1 overexpression in leiomyosarcoma cells specifically sensitized to docetaxel-induced apoptosis. This was associated with increased mitotic rate in vitro and higher growth rate of xenografts. By contrast, inhibition decreased cell proliferation and protected sarcoma cells from apoptosis induced by docetaxel. Collectively, these data evidenced that is frequently deleted in sarcomas with complex genomics and that its downregulation is associated with a higher risk of developing metastasis for patients receiving chemotherapy, likely due to their higher resistance to docetaxel.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11010081