Depleting IFIT2 mediates atypical PKC signaling to enhance the migration and metastatic activity of oral squamous cell carcinoma cells
Depleting IFIT2 mediates atypical PKC signaling to enhance the migration and metastatic activity of oral squamous cell carcinoma cells
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DOI：
10.1038/onc.2012.384
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发表时间：
2013-08-08
期刊：
影响因子：
8
通讯作者：
Lee, T. C.
中科院分区：
文献类型：
--
作者：
Lai, K. C.;Liu, C. J.;Lee, T. C.
干扰素诱导的三肽重复序列2（IFIT 2）是对干扰素刺激最敏感的基因之一，但其生物学功能尚不清楚。在这项研究中，我们的目的是探讨潜在的机制，其中消耗IFIT 2诱导口腔鳞状细胞癌（OSCC）细胞的迁移。与对照细胞相比，稳定的IFIT 2耗尽的细胞经历上皮-间充质转化（EMT）并表现出增强的细胞运动性和侵袭性。此外，我们的研究结果表明，非典型蛋白激酶C（aPKC）在IFIT 2缺失的细胞中被激活。使用特定肉豆蔻酰化PKC zeta假底物或aPKC靶向小干扰RNA（siRNA）抑制aPKC可消除IFIT 2耗竭诱导的EMT、迁移和侵袭，表明aPKC的激活在调节IFIT 2耗竭诱导的细胞应答中具有重要作用。尾静脉注射后，IFIT 2缺失的OSCC细胞不仅定植在肺中，而且还定植在心脏、头颈部、腹膜后和腹膜腔中;而对照细胞主要位于肺中。口腔鳞癌组织中IFIT 2 mRNA和蛋白表达与E-cadherin表达呈正相关。E-cadherin和IFIT 2在口腔鳞癌浸润前沿表达缺失，提示IFIT 2表达缺失可能导致EMT，进而导致口腔鳞癌的转移。OSCC患者具有降低的IFIT 2表达水平（IFIT 2 = 50%）。这些结果表明，IFIT 2耗竭激活aPKC途径，并因此诱导EMT、细胞迁移和侵袭。最重要的是，消耗IFIT 2可能参与OSCC肿瘤进展，特别是在转移期间。综上所述，我们的研究表明，IFIT 2，一种负责干扰素刺激的蛋白质，可以预防口腔鳞癌转移，并作为一个有价值的预后标志物。
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 PKC zeta 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%). 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.