Department of Otorhinolaryngology, The First Affiliated Hospital of China Medical University, Shenyang 110001, P.R. China.
Oncol Rep. 2014 Jun;31(6):2651-9. doi: 10.3892/or.2014.3120. Epub 2014 Apr 2.
SOX2 is a high mobility group box containing transcription factor that has been reported to be aberrantly overexpressed in various human malignancies, including laryngeal squamous cell carcinoma (LSCC). However, the potential role of SOX2 in LSCC migration and invasion remains to be elucidated. In the present study, we generated stable transformants of human LSCC cells constitutively overexpressing SOX2 and investigated the effects of SOX2 overexpression on migration and invasion in LSCC cells as well as the possible underlying mechanisms. We found that ectopic overexpression of SOX2 in LSCC cells enhanced their migratory and invasive ability in vitro, accompanied by increased expression and activity of matrix metalloproteinase (MMP)-2. Meanwhile, SOX2-induced cell migration and invasion were significantly abrogated by a neutralizing anti-MMP-2 antibody or small interfering RNA targeting MMP-2. Furthermore, overexpression of SOX2 induced phosphorylation of Akt and mammalian target of rapamycin (mTOR), which are downstream effectors of the PI3K pathway. Finally, LY294002, an inhibitor of PI3K, also markedly abolished SOX2-induced activation of the Akt/mTOR pathway and increased cell invasion and MMP-2 expression. Taken together, we conclude that SOX2 promotes migration and invasion of laryngeal cancer cells by inducing MMP-2 via the PI3K/Akt/mTOR pathway. Our findings suggest that SOX2 may serve as a potential therapeutic target for LSCC.
SOX2 是一种高迁移率族盒转录因子，已被报道在多种人类恶性肿瘤中异常过表达，包括喉鳞状细胞癌（LSCC）。然而，SOX2 在 LSCC 迁移和侵袭中的潜在作用仍有待阐明。在本研究中，我们构建了人 LSCC 细胞中 SOX2 稳定过表达的转化体，并研究了 SOX2 过表达对 LSCC 细胞迁移和侵袭的影响以及可能的潜在机制。我们发现，SOX2 在 LSCC 细胞中的异位过表达增强了它们在体外的迁移和侵袭能力，同时伴随着基质金属蛋白酶（MMP）-2 的表达和活性增加。同时，中和抗 MMP-2 抗体或靶向 MMP-2 的小干扰 RNA 显著抑制了 SOX2 诱导的细胞迁移和侵袭。此外，SOX2 的过表达诱导了 Akt 和雷帕霉素靶蛋白（mTOR）的磷酸化，这是 PI3K 通路的下游效应物。最后，PI3K 抑制剂 LY294002 也显著抑制了 SOX2 诱导的 Akt/mTOR 通路的激活以及增加的细胞侵袭和 MMP-2 表达。总之，我们得出结论，SOX2 通过 PI3K/Akt/mTOR 通路诱导 MMP-2 的表达促进了喉癌细胞的迁移和侵袭。我们的研究结果表明，SOX2 可能成为 LSCC 的潜在治疗靶点。
