SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line
As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies...
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doaj-3ca3cf2ce39844f9a4dd52ae8b2cc02e2020-11-25T03:59:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-01217627762710.3390/ijms21207627SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell LineSabine Stöckl0Georg Lindner1Shushan Li2Philipp Schuster3Sebastian Haferkamp4Ferdinand Wagner5Peter M. Prodinger6Gabriele Multhoff7Melanie Boxberg8Axel Hillmann9Richard J. Bauer10Susanne Grässel11Department of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB/Biopark 1), University of Regensburg, 93053 Regensburg, GermanyInstitute of Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, GermanyDepartment of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB/Biopark 1), University of Regensburg, 93053 Regensburg, GermanyInstitute of Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, GermanyDepartment of Dermatology, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Pediatric Surgery, Dr. von Haunersche’s Children’s Hospital, LMU, 80337 Munich, GermanyDepartment of Orthopaedic Surgery, Klinikum Rechts der Isar, Technical University of Munich (TUM), 81675 Munich, GermanyCenter for Translational Cancer Research (TranslaTUM), Radiation Immuno Oncology Group, Klinikum Rechts der Isar, Technical University of Munich (TUM), 81675 Munich, GermanyDepartment of Pathology, Technical University of Munich (TMU), 80333 Munich, GermanyDepartment of Sarcomas and Musculoskeletal Tumors, Barmherzige Brüder Hospital, 93049 Regensburg, GermanyDepartment of Oral and Maxillofacial Surgery, Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, GermanyDepartment of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB/Biopark 1), University of Regensburg, 93053 Regensburg, GermanyAs most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options.https://www.mdpi.com/1422-0067/21/20/7627SOX9transcription factorchondrosarcomapolyploidyMMP13CRISPR/Cas9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sabine Stöckl Georg Lindner Shushan Li Philipp Schuster Sebastian Haferkamp Ferdinand Wagner Peter M. Prodinger Gabriele Multhoff Melanie Boxberg Axel Hillmann Richard J. Bauer Susanne Grässel |
spellingShingle |
Sabine Stöckl Georg Lindner Shushan Li Philipp Schuster Sebastian Haferkamp Ferdinand Wagner Peter M. Prodinger Gabriele Multhoff Melanie Boxberg Axel Hillmann Richard J. Bauer Susanne Grässel SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line International Journal of Molecular Sciences SOX9 transcription factor chondrosarcoma polyploidy MMP13 CRISPR/Cas9 |
author_facet |
Sabine Stöckl Georg Lindner Shushan Li Philipp Schuster Sebastian Haferkamp Ferdinand Wagner Peter M. Prodinger Gabriele Multhoff Melanie Boxberg Axel Hillmann Richard J. Bauer Susanne Grässel |
author_sort |
Sabine Stöckl |
title |
SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line |
title_short |
SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line |
title_full |
SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line |
title_fullStr |
SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line |
title_full_unstemmed |
SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line |
title_sort |
sox9 knockout induces polyploidy and changes sensitivity to tumor treatment strategies in a chondrosarcoma cell line |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-10-01 |
description |
As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options. |
topic |
SOX9 transcription factor chondrosarcoma polyploidy MMP13 CRISPR/Cas9 |
url |
https://www.mdpi.com/1422-0067/21/20/7627 |
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