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Published on: July 9, 2019
Expression and Therapeutic Potential of SOX9 in Chordoma
Hua Chen1,2, Cassandra C Garbutt1, Dimitrios Spentzos1
1Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract:
Purpose: Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma.Experimental Design: SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescent assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound-healing assay and a Transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell-cycle arrest, as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by an MTT assay.Results: Tissue microarray and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell-cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells.Conclusions: Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma. Clin Cancer Res; 23(17); 5176-86. ©2017 AACR.
Insights
Targeting sex-determining region Y (SRY)-box 9 (SOX9) inhibits chordoma cell growth and motility. Combining SOX9 inhibition with chemotherapy enhances anti-cancer effects, offering a new therapeutic strategy for chordoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Chordoma is a rare bone tumor resistant to conventional chemotherapy.
- The role of sex-determining region Y (SRY)-box 9 (SOX9) in chordoma pathogenesis is not well understood.
Purpose of the Study:
- To investigate the functional significance and therapeutic potential of SOX9 in chordoma.
- To evaluate SOX9 as a therapeutic target for chordoma.
Main Methods:
- Immunohistochemistry (IHC) on 50 chordoma samples.
- Western blot and immunofluorescence assays for SOX9 expression.
- RNA interference (RNAi) using SOX9 siRNA to inhibit SOX9.
- Cell proliferation, cytotoxicity, motility, invasion, apoptosis, and cell-cycle assays.
- Combination therapy with SOX9 inhibition and chemotherapy (doxorubicin/cisplatin).
Main Results:
- SOX9 is broadly expressed in chordoma tissues, with higher levels correlating with poor prognosis.
- SOX9 knockdown inhibited chordoma cell proliferation, motility, and invasion.
- SOX9 inhibition induced apoptosis and cell-cycle arrest, decreasing cancer stem cell markers.
- Combined SOX9 inhibition and chemotherapy demonstrated enhanced anti-cancer effects.
Conclusions:
- SOX9 is a critical factor in chordoma development and progression.
- Targeting SOX9 represents a promising therapeutic strategy for chordoma.
- Combination therapy involving SOX9 inhibition may improve treatment outcomes for chordoma patients.
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