Expression and Therapeutic Potential of SOX9 in Chordoma

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 immunofluorescence 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 a MTT assay. Results Tissue microarray (TMA) 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.

Expression and correlation of MALAT1 and SOX9 in non‐small cell lung cancer

“…The physiological functions of SOX9 include cartilage formation, sex differentiation decision, nerve glial and heart development . In addition, it was found that the abnormal expression was related to many human disease and especially in tumours formation and development . SOX9 is over‐expressed in various cancers, such as colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, brain cancer, and melanoma …”

Upregulated SOX9 expression indicates worse prognosis in solid tumors: a systematic review and meta-analysis

“…Therefore, inhibited tumor growth and invasion by SOX9 knockdown shed light on regarding SOX9 as a therapeutic target for cancer. A plenty of studies investigated the correlation between SOX9 expression and prognosis in cancer patients, and demonstrated that upregulated expression of SOX9 in malignant tumors was correlated with poor prognosis in patients with different types of solid tumors such as chordoma [ 13 ], osteosarcoma [ 14 – 16 ], colorectal carcinoma [ 17 , 18 ], esophageal squamous cell carcinoma [ 10 , 19 ], breast cancer [ 20 – 23 ], hepatocellular carcinoma (HCC) [ 24 , 25 ], glioma [ 26 ], chondrosarcoma [ 27 ], gastric cancer [ 28 – 30 ], melanoma [ 31 ], pancreatic ductal adenocarcinoma (PDAC) [ 32 ], ovarian cancer (OC) [ 33 ], prostate cancer [ 34 , 35 ] and non-small cell lung cancer (NSCLC) [ 36 ]. However, some other studies revealed that overexpression of SOX9 was not significantly associated with prognosis of some patients with gastric cancer [ 9 ] and with breast cancer when looking at overall or 5-year survival [ 37 ].…”

SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line

“…Similar results were shown by Chen et al in chordoma cells, a rare type of sarcoma that occurs in the bones of the skull base and spine. They reported that a transient siRNA-based SOX9 knockdown in a chordoma cell line leads to enhanced apoptotic activity [ 30 ]. In line with their data, we observed, a reduction of survivin in the SOX9 knockout clones, but not in the SOX9 knockdown cells.…”