Transcription Factor SOX9 Promotes Osteosarcoma Cell Growth by Repressing Claudin-8 Expression [Retraction]

Abstract

Osteosarcoma is a malignant bone cancer that mainly affects children. SOX9 plays a key role in bone formation and osteosarcoma, and Claudin-8 (CLDN8), a tight junction protein, contributes to proliferation of osteosarcoma cells. The aim of this study was to investigate the relationship between SOX9 and CLDN8 in osteosarcoma. The expression levels of SOX9 and CLDN8 were determined in osteosarcoma specimens (n = 25) by qRT-PCR and Western blot analyses. The levels of SOX9 mRNA and protein were significantly higher in osteosarcoma tissues than those in adjacent non-tumor tissues, whereas the expression levels of CLDN8 mRNA and protein were significantly lower in osteosarcoma tissues. Immunohistochemical analysis showed the high expression of SOX9 in 56 out of 97 osteosarcoma tissues (57.7%). By contrast, the low expression of immunoreactive CLDN8 was observed in 62 of 97 osteosarcoma tissues (63.9%). There was the inverse correlation between the expression levels of SOX9 and CLDN8 proteins (R = −0.633, P < 0.001). The overall survival was poorer in the patients with high SOX9 expression. Subsequently, using two human osteosarcoma cell lines, we showed that knockdown of SOX9 inhibited cell proliferation and migration but promoted cell apoptosis. Importantly, knockdown of SOX9 increased the expression levels of CLDN8 protein. The transient luciferase-reporter assays suggest that SOX9 may inhibit the promoter activity of the CLDN8 gene in osteosarcoma cells. In conclusion, we provide the evidence demonstrating that SOX9 may promote cell growth by repressing the expression of CLDN8. Thus, SOX9 may be a therapeutic target for osteosarcoma.

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

“…The main characteristics of the 17 identified studies were presented in Table 1 . In total, 3307 patients from five regions (China, Korea, United States of America, Australia and Japan) with 11 distinct cancers, chordoma [ 13 ], osteosarcoma [ 14 , 16 ], esophageal cancer [ 9 , 19 ], hepatocellular carcinoma [ 24 , 38 ], intrahepatic cholangiocarcinoma [ 39 ], pancreatic ductal adenocarcinoma [ 32 ], prostate cancer [ 34 , 35 ], thyroid carcinoma [ 40 ], colorectal cancer [ 18 , 41 ], gastric cancers [ 10 , 42 ], non-small cell lung cancer [ 36 ] were included in these studies.…”

“…Aberrant SOX9 expression contributes to the development of gastric cancer by inactivation of GKN1 as an early event [ 10 ]. Conversely, knockdown of SOX9 suppresses chondrosarcoma growth and migration [ 11 ], and induces apoptosis, cell cycle arrest as well as decreased expression of cancer stem cell markers [ 12 – 14 ]. Therefore, inhibited tumor growth and invasion by SOX9 knockdown shed light on regarding SOX9 as a therapeutic target for cancer.…”

“…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 ].…”

SOX Genes and Cancer

“…However, CLDN8 expression was significantly lower in osteosarcoma tissues. Knockdown of SOX9 inhibited the proliferation and migration but promoted the apoptosis of human osteosarcoma cell lines by downregulating CLDN8 [47]. FOXK2 was overexpressed in colorectal cancer tissues and associated with poor prognosis.…”

“…SOX2 silencing significantly suppresses the tumorigenicity of glioblastoma tumor-initiating cells (TICs) [38]. Importantly, high levels of SOX2 have been associated with tumor aggressiveness and worse prognosis in glioblastoma, indicating targeting SOX2 might be an Glioblastoma ↑ Associated with tumor aggressiveness and worse prognosis [38,39] Gastric cancer↓ Promote tumor progression [40] SOX4 Oral cancer ↑ Promote tumor initiation and development [41,42] Prostate cancer↑ Associated with worse prognosis [43,44] Leukemia↑ Promote tumor progression [45] Primary gallbladder carcinoma↓ Associated with worse prognosis [46] SOX9 Papillary thyroid cancer↑ Promote tumor progression [47] Breast cancer ↑ Associated with chemoresistance [48] Gastric cancer ↑ Promote tumorigenesis [49] Cervical carcinoma↓ Promote tumor progression [50] SOX11 Breast cancer↑ Promote tumor progression [51] Mantle cell lymphoma↑ Promote tumor progression [52][53][54] Epithelial ovarian cancer↓ Associated with worse prognosis [55] Gastric cancer↓ Associated with worse prognosis Gene Expression and Regulation in Mammalian Cells -Transcription From General Aspects effective strategy for the treatment of glioblastoma [39]. SOX2 is also amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity.…”