Depleting IFIT2 mediates atypical PKC signaling to enhance the migration and metastatic activity of oral squamous cell carcinoma cells.

Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is one of the most highly responsive interferon-stimulated genes, but its biological functions are poorly understood. In this study, we aimed to explore the underlying mechanisms by which depleting IFIT2 induces the migration of oral squamous cell carcinoma (OSCC) cells. Stable IFIT2-depleted cells underwent epithelial-mesenchymal transition (EMT) and exhibited enhanced cell motility and invasiveness compared with control cells. Furthermore, our results indicated that atypical protein kinase C (aPKC) was activated in IFIT2-depleted cells. Inhibition of aPKC using a specific myristoylated PKCζ pseudosubstrate or aPKC-targeting small interfering RNA (siRNA) abolished IFIT2 depletion-induced EMT, migration and invasion, indicating that the activation of aPKC has an essential role in regulating the cellular responses induced by IFIT2 depletion. Following tail-vein injection, IFIT2-depleted OSCC cells colonized not only the lungs but also the heart, head and neck, retroperitoneal, and peritoneal cavities; whereas control cells predominantly localized in the lungs. IFIT2 mRNA and protein expression was positively associated with E-cadherin expression in OSCC patient specimens. The loss of E-cadherin and IFIT2 expression was observed at the invasive front of OSCC tumors, suggesting that the loss of IFIT2 may induce EMT and lead to the metastasis of OSCCs. OSCC patients possessing reduced IFIT2-expression levels (IFIT2 <50%) exhibited greater rates of distant metastasis and poor prognoses compared with OSCC patients who expressed greater levels of IFIT2 (IFIT2 ≥50%). These results demonstrate that IFIT2 depletion activates the aPKC pathway and consequently induces EMT, cell migration and invasion. Most importantly, depleting IFIT2 may participate in OSCC tumor progression, particularly during metastasis. Taken together, our study demonstrates that IFIT2, a protein responsible for interferon stimulation, may prevent OSCC metastasis and serve as a valuable prognostic marker.