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Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas

Soft-tissue sarcomas (STS) are rare tumors whose oncogenesis remains unknown and for which no common therapeutic target has yet been identified. Analysis of 318 STS by CGH array evidenced a frequent deletion affecting the DMD gene (encoding dystrophin isoforms) in 16.5% of STS, including sarcomas wi...

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Autores principales: Mauduit, Olivier, Delcroix, Vanessa, Lesluyes, Tom, Pérot, Gaëlle, Lagarde, Pauline, Lartigue, Lydia, Blay, Jean-Yves, Chibon, Frédéric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678178/
https://www.ncbi.nlm.nih.gov/pubmed/31266185
http://dx.doi.org/10.3390/cancers11070922
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author Mauduit, Olivier
Delcroix, Vanessa
Lesluyes, Tom
Pérot, Gaëlle
Lagarde, Pauline
Lartigue, Lydia
Blay, Jean-Yves
Chibon, Frédéric
author_facet Mauduit, Olivier
Delcroix, Vanessa
Lesluyes, Tom
Pérot, Gaëlle
Lagarde, Pauline
Lartigue, Lydia
Blay, Jean-Yves
Chibon, Frédéric
author_sort Mauduit, Olivier
collection PubMed
description Soft-tissue sarcomas (STS) are rare tumors whose oncogenesis remains unknown and for which no common therapeutic target has yet been identified. Analysis of 318 STS by CGH array evidenced a frequent deletion affecting the DMD gene (encoding dystrophin isoforms) in 16.5% of STS, including sarcomas with complex genomics, gastrointestinal tumors (GIST), and synovial sarcomas (SS). These deletions are significantly associated with metastatic progression, thus suggesting the role of DMD downregulation in the acquisition of aggressive phenotypes. We observed that targeted deletions of DMD were restricted to the 5’ region of the gene, which is responsible for the transcription of Dp427. Analysis of STS tumors and cell lines by RNA sequencing revealed that only the Dp71 isoform was widely expressed. Dp427 depletion had no effect on cell growth or migration. However, Dp71 inhibition by shRNA dramatically reduced the cell proliferation and clonogenicity of three STS cell lines, likely by altering the cell cycle progression through the G2/M-phase. Our work demonstrates that DMD deletions are not restricted to myogenic tumors and could be used as a biomarker for metastatic evolution in STS. Dp71 seems to play an essential role in tumor growth, thus providing a potential target for future STS treatments.
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spelling pubmed-66781782019-08-19 Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas Mauduit, Olivier Delcroix, Vanessa Lesluyes, Tom Pérot, Gaëlle Lagarde, Pauline Lartigue, Lydia Blay, Jean-Yves Chibon, Frédéric Cancers (Basel) Article Soft-tissue sarcomas (STS) are rare tumors whose oncogenesis remains unknown and for which no common therapeutic target has yet been identified. Analysis of 318 STS by CGH array evidenced a frequent deletion affecting the DMD gene (encoding dystrophin isoforms) in 16.5% of STS, including sarcomas with complex genomics, gastrointestinal tumors (GIST), and synovial sarcomas (SS). These deletions are significantly associated with metastatic progression, thus suggesting the role of DMD downregulation in the acquisition of aggressive phenotypes. We observed that targeted deletions of DMD were restricted to the 5’ region of the gene, which is responsible for the transcription of Dp427. Analysis of STS tumors and cell lines by RNA sequencing revealed that only the Dp71 isoform was widely expressed. Dp427 depletion had no effect on cell growth or migration. However, Dp71 inhibition by shRNA dramatically reduced the cell proliferation and clonogenicity of three STS cell lines, likely by altering the cell cycle progression through the G2/M-phase. Our work demonstrates that DMD deletions are not restricted to myogenic tumors and could be used as a biomarker for metastatic evolution in STS. Dp71 seems to play an essential role in tumor growth, thus providing a potential target for future STS treatments. MDPI 2019-07-01 /pmc/articles/PMC6678178/ /pubmed/31266185 http://dx.doi.org/10.3390/cancers11070922 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mauduit, Olivier
Delcroix, Vanessa
Lesluyes, Tom
Pérot, Gaëlle
Lagarde, Pauline
Lartigue, Lydia
Blay, Jean-Yves
Chibon, Frédéric
Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title_full Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title_fullStr Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title_full_unstemmed Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title_short Recurrent DMD Deletions Highlight Specific Role of Dp71 Isoform in Soft-Tissue Sarcomas
title_sort recurrent dmd deletions highlight specific role of dp71 isoform in soft-tissue sarcomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678178/
https://www.ncbi.nlm.nih.gov/pubmed/31266185
http://dx.doi.org/10.3390/cancers11070922
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