NPR3 Inhibits EMT and Tumour Metastasis of Human Osteosarcoma by Activating AKT/mTOR-Mediated Autophagy

Abstract

BackgroundOsteosarcoma is an aggressive primary malignant cancer of bone mainly occurring in adolescence with a characteristic of high metastasis and relapse rate. In our previous study, we rst identi ed that NPR3 was signi cantly decreased in OS samples. Here, we purposed to investigate the effect and the possible mechanisms of NPR3 on the progression of human OS. MethodsThe expression of NPR3 in OS patients and cells was detected by qRT-PCR, and IHC analysis. The effect of the expression of NPR3 on tumour metastasis was examined in vitro and in vivo. The molecular mechanisms of the regulation of NPR3 were evaluated in vitro and in vivo. The clinical relevance of 5year overall survival with the expression of NPR3 was evaluated in 294 patients with OS. ResultsFirstly, we indicated that NPR3 was substantially downregulated expression in OS tissues and cells by qRT-PCR and IHC assay. And the patients with lower expression of NPR3 have a poor prognosis.Functional studies revealed that over-expression of NPR3 inhibited the proliferation and invasion of cells. Meanwhile, over-expression of NPR3 markedly inhibited tumorigenesis and weakened tumour metastasis in vivo. Interestingly, we found that over-expression of NPR3 could induce autophagy, promote apoptosis and inhibit EMT. Additionally, overexpression of NPR3 decreased the phosphorylation levels of AKT and mTOR. Loss-of-function experiments displayed that effects of NPR3 were weakened by treatment with the speci c autophagy inhibitor Baf-A1 and CQ. ConclusionsTaken together, these results demonstrated that down-regulation of NPR3 promote lung metastasis of human OS by promoting EMT in part through the AKT/mTOR mediated autophagy, suggesting that NPR3 has therapeutic potential for OS patients with metastasis.