OTX1 promoting osteosarcoma malignancy by activating PTGS2 transcription

Osteosarcoma (OS) represents a highly aggressive bone malignancy characterized by limited therapeutic options, particularly in patients presenting with metastasis or recurrence. While the transcription factor Orthodenticle homeobox 1 (OTX1) has been implicated in various cancers, its functional role and underlying mechanism in OS remain largely unknown. In this study, the expression level of OTX1 was examined in OS tissues and cell lines. Aberrant upregulation of OTX1 was observed in OS, and this expression pattern was significantly correlated with unfavorable prognosis in patients. Functional assays revealed that OTX1 overexpression enhanced the proliferation, migration, and invasion abilities of OS cells. Mechanistic studies revealed that OTX1 acts as a transcriptional regulator, activating Prostaglandin-endoperoxide synthase 2 (PTGS2) expression. The upregulation of PTGS2 subsequently mediated anti-apoptotic and pro-invasive phenotypes. Moreover, intervention with the PTGS2 inhibitor celecoxib counteracted the tumor-promoting functions of OTX1 and demonstrated tumor-suppressive effects in in vivo OS models. Herein, results demonstrate that OTX1 drives OS malignant progression by transcriptionally activating PTGS2, which in turn modulates apoptosis- and invasion-related molecules. Targeting the OTX1/PTGS2 axis may represent a promising therapeutic strategy for OS, particularly in high-risk patients with aberrant OTX1 expression.