Abstract
Despite the development of diagnostic and treatment strategies, the survival outcome of patients with osteosarcoma remains poor. Nod-like receptor protein 3 (NLRP3) plays a crucial role in the inflammasome pathway, which is related to the progression of various tumors. However, the effect of NLRP3 on osteosarcoma has not yet been well explored. Our study aimed to investigate the role of NLRP3 in the malignant biological behavior of osteosarcoma as well as its therapeutic value. Immunohistochemistry was applied to investigate the NLRP3 expression in osteosarcoma and osteochondroma specimens. Cell Counting Kit-8, colony formation, wound healing, transwell, and flow cytometry assays were used to explore the contribution of NLRP3 to the proliferation, migration, invasion, apoptosis and cell cycle distribution of osteosarcoma cells in vitro. Western blot was performed to evaluate the expression of NLRP3 and the related proteins in osteosarcoma cell lines after the blockade of NLRP3 using CY-09 and lentivirus intervention. Furthermore, tumor formation assay was used to analyze the effect of NLRP3 on the growth of osteosarcoma in vivo. The results showed that the NLRP3 protein was overexpressed in osteosarcoma, which was independently correlated with the poor prognosis of patients. Moreover, NLRP3 suppression by the inhibitor of CY-09 or lentivirus-induced gene knockdown inhibited the cell proliferation, migration, invasion and promoted the cell apoptosis and G1 cell cycle arrest in osteosarcoma via targeting the inflammasome pathway. Our in vivo results confirmed that the inhibition of NLRP3 suppressed the tumor formation of osteosarcoma. In conclusion, NLRP3 may be regarded as an independent prognostic biomarker and a potential therapeutic target for osteosarcoma.
Highlights
Osteosarcoma is the most common primary aggressive bone tumor that usually occurs during childhood and adolescence (Chow et al, 2020)
The western blotting assay showed that Nod-like receptor protein 3 (NLRP3) protein was upregulated in MG63, MNNG/HOS, 143B, U2OS and Saos2 cells compared to the hFOB 1.19 cells, with 143B and U2OS cells exhibiting the highest level (Figure 1B)
The receiver operating characteristic (ROC) curve and Youden index revealed that the optimal cutoff value of NLRP3 protein expression for progressionfree survival (PFS) was 3.0, and overall survival (OS) was 3.0 (Figure 1D; Table 4)
Summary
Osteosarcoma is the most common primary aggressive bone tumor that usually occurs during childhood and adolescence (Chow et al, 2020). With the development of novel therapies, the five-year survival rate of patients with osteosarcoma has improved from 20 to 70%. Nearly 30% of osteosarcoma patients are prone to metastasis or recurrence, with an unfavorable prognosis, due to the limited efficacy of current treatment strategies (Dai et al, 2011). Exploring novel biomarkers and therapeutic targets for the treatment of osteosarcoma is critical. Nod-like receptor protein 3 (NLRP3) has been intensively investigated for its potential role in various human diseases (Yang et al, 2019; Lin et al, 2020). The prognostic and therapeutic values of NLRP3 protein have not been fully analyzed in osteosarcoma. Our study aimed to evaluate the expression of NLRP3 in osteosarcoma and its association with clinicopathological parameters of patients, and further explore the in vitro and in vivo effects of NLRP3 on the biological behaviors of osteosarcoma
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