TCF12 Transcriptionally Activates SPHK1 to Induce Osteosarcoma Angiogenesis by Promoting the S1P/S1PR4/STAT3 Axis

Abstract

Transcription factor 12 (TCF12) is a known oncogene in many cancers. However, whether TCF12 can regulate malignant phenotypes and angiogenesis in osteosarcoma is not elucidated. In this study, we demonstrated increased expression of TCF12 in osteosarcoma tissues and cell lines. High TCF12 expression was associated with metastasis and poor survival rate of osteosarcoma patients. Knockdown of TCF12 reduced the proliferation, migration, and invasion of osteosarcoma cells. TCF12 was found to bind to the promoter region of sphingosine kinase 1 (SPHK1) to induce transcriptional activation of SPHK1 expression and enhance the secretion of sphingosine-1-phosphate (S1P), which eventually resulted in the malignant phenotypes of osteosarcoma cells. In addition, S1P secreted by osteosarcoma cells promoted the angiogenesis of HUVECs by targeting S1PR4 on the cell membrane to activate the STAT3 signaling pathway. These findings suggest that TCF12 may induce transcriptional activation of SPHK1 to promote the synthesis and secretion of S1P. This process likely enhances the malignant phenotypes of osteosarcoma cells and induces angiogenesis via the S1PR4/STAT3 signaling pathway.

Graphical Abstract

Keywords:

• Osteosarcoma
• TCF12
• SPHK1
• S1P
• S1PR4/STAT3 signaling pathway
• angiogenesis

Authors’ contributions

Wo Li: conceived the ideas; provided critical materials; designed and performed the experiments; wrote the manuscript.

Jitong Liu: designed the experiments and performed the experiments; wrote the manuscript.

Ting Cai: performed the experiments.

Xia Hu: conceived the ideas; provided critical materials; analyzed the data; revised the manuscript; supervised the study.

All the authors have read and approved the final version for publication.

Availability of data and materials

The data including the uncropped images in Western blot that support the findings of this study are openly available in OSF at https://osf.io/sy346/ (doi: 10.17605/OSF.IO/SY346). The supplementary Figure 1 and its caption was included in Supplementary materials.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (82101316).