SHP2 promotes osteosarcoma via regulating STAT3/TET3/HOXB2 signaling.

To investigate the effect of SHP2 on the STAT3/TET3/HOXB2 signaling pathway in osteosarcoma, and its role in the proliferation, migration and invasion of osteosarcoma cells. First, bioinformatics analysis was used to identify relevant expressed genes. In vitro experiments, the expression levels of SHP2, p-STAT3, TET3, HOXB2, c-Myc, NANOG, NUSAP1 proteins in 143B cells and MG63 cells were detected by Western blot assay. The levels of TET3 and HOXB2 were detected by immunofluorescence double staining. Cell proliferation was detected by plate clone formation and CCK-8 assay. Cell migration was detected by scratch assay, and cell migration and invasion were detected by Transwell assay. Overexpression of SHP2 promotes osteosarcoma proliferation by upregulating STAT3, TET3 and HOXB2 proteins. VEGF activates RTK receptors and induces SHP2 autophosphorylation, which in turn activates STAT3 and enhances TET3 synthesis. TET3 then promotes HOXB2 transcription through demethylation. HOXB2 further upregulate the expression of c-Myc, NANOG and NUSAP1, ultimately driving the proliferation, migration and invasion of osteosarcoma and promoting tumor progression. This study confirmed that SHP2 promotes the proliferation, invasion and invasive ability of osteosarcoma cells by activating the STAT3/TET3/HOXB2 pathway, providing a new strategy for targeted treatment of osteosarcoma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-35493-7.