ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis Through PI3K/Akt Signaling and MAPK-dependent Focal Adhesion Disassembly

The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient which serves to maintain the morphological polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that Calcium Release-Activated Calcium Modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, is predominantly upregulated in the lymph node (LN) metastasis of gastric cancer (GC), supporting cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in GC tissues significantly correlated with poor differentiation, invasion, LN metastasis and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation and metastasis in both GC cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of GC cells by inducing FAK-mediated mitogen-activated protein kinase (MAPK)/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of GC.