RESUMO
Background: The alterations in metabolic profile of tumors have been identified as one of the prognostic hallmarks of cancers, including osteosarcoma. These alterations are majorly controlled by groups of metabolically active genes. However, the regulation of metabolic gene signatures in tumor microenvironment of osteosarcoma has not been well explained. Objectives: Thus, we investigated the sets of previously published metabolic genes in osteosarcoma patients and normal samples. Methods: We applied computational techniques to identify metabolic genes involved in the immune function of tumor microenvironment (TME) and survival and prognosis of the osteosarcoma patients. Potential candidate gene PAICS (phosphoribosyl aminoimidazole carboxylase, phosphoribosyl aminoimidazole succino carboxamide synthetase) was chosen for further studies in osteosarcoma cell lines for its role in cell proliferation, migration and apoptosis. Results: Our analyses identified a list of metabolic genes differentially expressed in osteosarcoma tissues. Next, we scrutinized the list of genes correlated with survival and immune cells, followed by clustering osteosarcoma patients into three categories: C1, C2, and C3. These analyses led us to choose PAICS as potential candidate gene as its expression showed association with poor survival and negative correlation with the immune cells. Furthermore, we established that loss of PAICS induced apoptosis and inhibited proliferation, migration, and wound healing in HOS and MG-63 cell lines. Finally, the results were supported by constructing and validating a prediction model for prognosis of the osteosarcoma patients. Conclusion: Here, we conclude that metabolic genes specifically PAICS play an integral role in the immune cell infiltration in osteosarcoma TME, as well as cancer development and metastasis.
RESUMO
Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939, was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3ß/ß-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro. Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3ß/ß-catenin signaling.
