<scp>ORAI3</scp> Modulates Oral Squamous Cell Carcinoma Metastasis Through the Ca ²⁺ /Calmodulin/Calcineurin/ <scp>ETV4</scp> Signaling Pathway

Oral squamous cell carcinoma (OSCC) significantly impairs a person's physical and psychological health despite active treatment efforts. Thus, it is important to investigate the pathogenesis of OSCC to discover new therapeutic targets for clinical treatments. ORAI3 is a store-operated calcium (Ca²⁺) channel that has been associated with several cancers, including breast, prostate, and pancreas. Although the ORAI3 channel is recognized for its oncogenic potential, its pathological functions in OSCC are not well understood, especially concerning its involvement in cancer progression. In this study, we found that ORAI3 was upregulated in OSCC clinical samples and cell lines. When the expression of ORAI3 was knocked down in vitro in OSCC cells, store-operated calcium entry-mediated Ca²⁺ influx into the cells was reduced. Importantly, the proliferation, migration, and invasive capabilities of these OSCC cells were also markedly decreased. Application of calmodulin or calcineurin inhibitors (W-7 or CsA, respectively) further suppressed these cell functions. Transcriptomic analysis revealed that ORAI3 knockdown led to downregulation of ETV4, a member of the ETS transcription factor family that is involved in cell differentiation, proliferation, and apoptosis and has been shown to be upregulated in some types of cancer. Here, overexpression of ETV4 rescued the suppressive effects on the proliferation, migration, and invasive capabilities of OSCC cells caused by ORAI3 knockdown. In addition, treatment with the calcineurin inhibitor CsA markedly reduced ETV4 expression levels in OSCC cells. Taken together, these results indicated that ORAI3 drives cancer progression by activating the Ca²⁺/calmodulin/calcineurin/ETV4 signaling pathway. Overall, these findings suggest that ORAI3/ETV4 may be a therapeutic target for the treatment of OSCC.