The P53N236S Mutation Plays a Regulatory Role in Osteosarcoma Metastasis Via the Cholesterol-Hedgehog Pathway.
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BACKGROUND/AIMS: Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Although many treatments for osteosarcoma have been explored, the overall survival rate for patients with metastatic osteosarcoma is only 20% due to the lack of understanding of the biological mechanisms by which osteosarcoma metastasis occurs. Therefore, it is important to uncover the molecular mechanism of metastasis in osteosarcoma. METHODS: We compared the migration ability of primary osteosarcoma cells from p53 knockout (p53null) and p53N236S knock-in (p53S) mice. Furthermore, via RNA-sequencing (RNA-seq) data from mouse embryonic fibroblast (MEF) cells, we explored the mechanism by which p53S regulates the cholesterol synthesis pathway and the Hedgehog signaling pathway in primary osteosarcoma cells. RESULTS: We found that the migration ability of primary tumor cells from p53S mice was increased both in vivo and in vitro . Further investigations revealed that the cholesterol content in p53S sarcoma tissue and primary cells was increased following the upregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). We subsequently observed that elevated cholesterol levels can regulate the Hedgehog (HH) pathway and lead to tumor metastasis. We subsequently treated p53S sarcoma cells with the cholesterol neutralizer methyl-β-cyclodextrin (MβCD) and an HH pathway inhibitor; consequently, we reported that total cholesterol levels reduced both Hedgehog pathway activity and cell migration, whereas HH pathway activity reduced only cell migration. CONCLUSION: In summary, we confirmed the enhanced metastatic ability of p53S sarcoma primary cells via in vivo and in vitro experiments and preliminarily confirmed the mechanism by which p53S promotes cholesterol synthesis and further activates the HH signaling pathway, thus leading to sarcoma metastasis. This study provides a theoretical basis for further revealing the function and mode of action of p53 mutations in the process of sarcoma metastasis, thereby providing a new potential target for the targeted diagnosis and treatment of sarcoma.