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.
Highlights
Chondrosarcoma are known to be the second most frequent form of primary bone sarcoma and typically affect the long bones and pelvis [1]
Since SOX9 is associated with proliferation in various other cell types, we examined the effect of SOX9 inhibition on the growth rate of chondrosarcoma cells
The results indicated that SOX9 is essential for maintaining proliferation and the clonogenicity of chondrosarcoma cells
Summary
Chondrosarcoma are known to be the second most frequent form of primary bone sarcoma and typically affect the long bones and pelvis [1] They are generally thought to be relatively resistant to chemotherapy and radiation due to their high content of extracellular matrix, their small percentage of dividing cells and their low vascularity. A small proportion of conventional chondrosarcomas emerge from the bone surface In most cases, they develop as a result of a malignant transformation in the cartilage cap of an already existing osteochondroma and are termed secondary peripheral chondrosarcomas [4]. The objectives of our research study were to determine the expression pattern of SOX9 in chondrosarcoma biopsies from different grades and to understand the role of SOX9 during the process of chondrosarcoma development, progression and dedifferentiation. The analysis of chondrosarcoma cells after the knockdown and knockout of SOX9 was performed to determine the subsequent molecular impact on the carcinogenic properties, downstream targets of SOX9 and therapeutic resistance mechanisms
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