Journal
CELLS
Volume 9, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/cells9010087
Keywords
osteosarcoma; ROS; HIF-1 alpha; FoxO1; microarray
Categories
Funding
- Chinese National Natural Science Foundation [81302342]
- Experimental Study on Predicting and Improving the Chemosensitivity of Osteosarcoma [2017MHZ76]
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Background: The present study was designed to explore the underlying role of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in reactive oxygen species (ROS) formation and apoptosis in osteosarcoma (OS) cells induced by hypoxia. Methods: In OS cells, ROS accumulated and apoptosis increased within 24 h after exposure to low HIF-1 alpha expression levels. A co-expression analysis showed that HIF was positively correlated with Forkhead box class O1 (FoxO1) expression and negatively correlated with CYP-related genes from the National Center for Biotechnology Information's Gene Expression Omnibus (NCBI GEO) datasets. Hypoxia also considerably increased HIF-1 alpha and FoxO1 expression. Moreover, the promoter region of FoxO1 was directly regulated by HIF-1 alpha. We inhibited HIF-1 alpha via siRNA and found that the ROS accumulation and apoptosis induced by hypoxia in OS cells decreased. In this study, a murine xenograft model of BALB-c nude mice was adopted to test tumour growth and measure the efficacy of 2-ME + As2O3 treatment. Results: Ad interim knockdown of HIF-1 alpha also inhibited manganese-dependent superoxide dismutase (MnSOD), catalase and sestrin 3 (Sesn3) expression in OS cells. Furthermore, hypoxia-induced ROS formation and apoptosis in OS cells were associated with CYP450 protein interference and were ablated by HIF-1 alpha silencing via siRNA. Conclusions: Our data reveal that HIF-1 alpha inhibits ROS accumulation by directly regulating FoxO1 in OS cells, which induces MnSOD, catalase and Sesn3 interference, thus resulting in anti-oxidation effects. The combination of an HIF-1 alpha inhibitor (2-mercaptoethanol,2-ME) and ROS inducer (arsenous oxide, As2O3) can prohibit proliferation and migration and promote apoptosis in MG63 cells in vitro while inhibiting tumour growth in vivo.
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