Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis.

In colon cancer, hypoxia promotes metastasis and angiogenesis, but little is known about the mediators of these effects. Here, we reported that expression of Orai1 is up-regulated in colon cancer cells in response to hypoxia, and the increase in Orai1 is mediated by Notch1 pathway. We also showed upregulation of Orai1 contributes to hypoxia-induced invasion and angiogenesis, and inhibition or downregulation of Orai1 reverses these effects. Mechanistic study revealed that upregulation of Orai1 by hypoxia potentiates store-operated Ca2+ entry (SOCE), and then causes activation of nuclear factor of activated T cells isoform c3 (NFATc3) in colon cancer cells. Furthermore, expression of Orai1 was correlated with tumor metastasis in patients. These results identify Orai1 as a novel target gene of hypoxia and reveal the role of Orai1 signaling in regulating hypoxia-induced invasiveness and angiogenesis under hypoxic conditions. Strategies to target this signaling might be developed to treat colon cancer metastasis and angiogenesis associated with hypoxia.