The Role of NR4A1 in the Pathophysiology of Osteosarcoma: A Comprehensive Bioinformatics Analysis of the Single-Cell RNA Sequencing Dataset.

Osteosarcoma is a kind of aggressive human malignancy, and the prognosis of the patients with osteosarcoma remains low. Studies have demonstrated that the tumor microenvironment plays a key role in regulating osteosarcoma progression. Recent studies have also shown that scRNA-seq plays an essential role in understanding the tumor heterogeneity and distinct subpopulations of tumors. In order to further understand the scRNA-seq data of osteosarcoma tissues, the present study further analyzed the scRNA-seq dataset (GSE152048) and explored the potential role of nuclear receptor-related genes in the pathophysiology of osteosarcoma. In our analysis, we identified 11 cell types in all the osteosarcoma tissues and nuclear receptors (NRs) were distributed in all types of cells. Further stratification analysis showed that NRs were mainly detected in "TIL" and "Osteoblastic" of the metastasis osteosarcoma, in "TIL", "Myoblast", "Endothelial", and "Myeloid" of the primary osteosarcoma, and in "Chondroblastic", "Osteoblast", and "Pericyte" of the recurrent osteosarcoma. The NRs were also differentially expressed in different cell types among the metastasis, primary, and recurrent osteosarcoma. Furthermore, several NRs such as NR4A2, NR4A1, and NR3C1 have been found to be differentially expressed in most types of DEGs among metastasis, primary, and recurrent osteosarcoma. A high expression of NR4A1 in the osteosarcoma tissues was significantly correlated with a shorter 5-year overall survival of patients with osteosarcoma. On the other hand, there was no significant association between NR4A2 expression and the 5-year overall survival of patients with osteosarcoma. The expression of NR4A1 was significantly higher in the metastasis osteosarcoma tissues than in the primary osteosarcoma tissues as validated from GSE32981 and GSE154540. The expression of NR4A1 was significantly higher in osteosarcoma tissues from patients with poor chemosensitivity than that from patients with good chemosensitivity as validated from GSE154540. Further analysis of the scRNA-seq data revealed that the percentage of osteoblasts with a high NR4A1 expression was higher in the recurrent osteosarcoma tissues than that with a low NR4A1 expression. In conclusion, the present study may suggest that NR4A1 may be an important prognostic biomarker for osteosarcoma progression. However, further validation studies should be performed to confirm our findings.