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SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line
Sabine Stöckl1, Georg Lindner2, Shushan Li1
1Department of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB/Biopark 1), University of Regensburg, 93053 Regensburg, Germany.
Abstract:
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.
Insights
SOX9, a key factor in cartilage development, shows altered expression in chondrosarcoma. Its absence in dedifferentiated tumors impacts cell behavior and drug response, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chondrosarcoma exhibits resistance to conventional chemotherapy.
- SOX9 is a crucial transcription factor for chondrogenesis, essential for normal cartilage formation.
- Understanding SOX9's role in chondrosarcoma is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the expression pattern and functional significance of SOX9 in chondrosarcoma.
- To elucidate the molecular mechanisms underlying SOX9's role in chondrosarcoma progression and drug resistance.
- To identify potential therapeutic strategies targeting SOX9 in chondrosarcoma.
Main Methods:
- Analysis of SOX9 expression in chondrosarcoma tissues and cell lines.
- CRISPR/Cas9-mediated SOX9 knockout in a human chondrosarcoma cell line (HTB94).
- siRNA-mediated SOX9 knockdown.
- Assessment of cell proliferation, clonogenicity, migration, adhesion, apoptosis, and polyploidy formation.
- Evaluation of drug sensitivity (doxorubicin, oncolytic viruses) in SOX9-modified cells.
Main Results:
- SOX9 expression is elevated in chondrosarcoma but decreases in dedifferentiated chondrosarcoma (DDCS), particularly in non-chondroid areas.
- SOX9 knockout in HTB94 cells reduced proliferation, clonogenicity, and migration, while favoring adhesion, apoptosis, and polyploidy.
- SOX9 deletion impaired MMP13 activation and suggested involvement of BCL2 and survivin.
- SOX9 knockout cells showed increased sensitivity to doxorubicin but reduced sensitivity to oncolytic viruses.
Conclusions:
- SOX9 plays a complex role in chondrosarcoma, influencing key cancer-related processes.
- Altered SOX9 levels in DDCS are linked to dedifferentiation and altered cellular behavior.
- Targeting SOX9 or understanding its threshold may offer novel therapeutic avenues for chondrosarcoma, potentially overcoming drug resistance.
