Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, ROC.
Oncogene. 2013 Aug 8;32(32):3686-97. doi: 10.1038/onc.2012.384. Epub 2012 Sep 17.
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.
干扰素诱导的四肽重复蛋白 2（IFIT2）是对干扰素刺激反应最强烈的基因之一，但它的生物学功能仍知之甚少。在这项研究中，我们旨在探索敲低 IFIT2 诱导口腔鳞状细胞癌（OSCC）细胞迁移的潜在机制。稳定敲低 IFIT2 的细胞经历上皮-间充质转化（EMT），与对照细胞相比，表现出增强的细胞迁移和侵袭能力。此外，我们的结果表明，IFIT2 敲低细胞中激活了非典型蛋白激酶 C（aPKC）。使用特异性豆蔻酰化 PKCζ 假底物或 aPKC 靶向小干扰 RNA（siRNA）抑制 aPKC 消除了 IFIT2 敲低诱导的 EMT、迁移和侵袭，表明 aPKC 的激活在调节 IFIT2 敲低诱导的细胞反应中起着至关重要的作用。尾静脉注射后，IFIT2 敲低的 OSCC 细胞不仅在肺部，而且在心、头颈部、腹膜后和腹腔中定植；而对照细胞主要局限于肺部。IFIT2 mRNA 和蛋白表达与 OSCC 患者标本中的 E-钙粘蛋白表达呈正相关。在 OSCC 肿瘤的侵袭前沿观察到 E-钙粘蛋白和 IFIT2 表达的丧失，表明 IFIT2 的丧失可能诱导 EMT 并导致 OSCC 的转移。与表达更高水平 IFIT2（IFIT2≥50%）的 OSCC 患者相比，表达水平较低（IFIT2＜50%）的 OSCC 患者具有更高的远处转移率和较差的预后。这些结果表明，IFIT2 敲低激活了 aPKC 通路，进而诱导 EMT、细胞迁移和侵袭。最重要的是，敲低 IFIT2 可能参与 OSCC 肿瘤的进展，特别是在转移过程中。总之，我们的研究表明，IFIT2，一种负责干扰素刺激的蛋白质，可能防止 OSCC 转移并作为有价值的预后标志物。
