Wang Xingqiang, Wang Shanshi, Li Xiaolong, Jin Shigang, Xiong Feng, Wang Xin
Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China.
Onco Targets Ther. 2017 May 31;10:2781-2789. doi: 10.2147/OTT.S138908. eCollection 2017.
To date, β-catenin has been reported to be implicated in mediating the epithelial-mesenchymal transition (EMT) in a variety of human cancers, which can be triggered by EGF. However, the mechanisms underlying EGF-β-catenin pathway-induced EMT of glioblastoma multiforme (GBM) have not been reported previously. In the present study, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blot were applied to investigate the effect of EGF-β-catenin pathway on EMT of GBM. Here, we identified that β-catenin mRNA and protein levels were up-regulated in GBM tissues and four kinds of glioblastoma cell lines, including T98G, A172, U87, and U251 cells, compared with normal brain tissue and astrocytes. In U87 cell line, inhibition of β-catenin by siRNA suppressed EGF-induced proliferation, migration, invasiveness, and the expression of EMT activators (Snail and Slug). In addition, the expression of epithelial markers (E-cadherin) was up-regulated and the expression of mesenchymal markers (N-cadherin and MMP9) was down-regulated. Finally, inhibitor of PI3K/Akt signaling pathways inactivated the EGF-β-catenin-induced EMT. In conclusion, β-catenin-EMT pathway induced by EGF is important for GBM progression by the PI3K/Akt pathways. Inhibition of β-catenin leads to suppression of EGF pathway-induced EMT, which provides a new way to treat GBM patients.
迄今为止，已有报道称β-连环蛋白参与介导多种人类癌症中的上皮-间质转化（EMT），而这一过程可由表皮生长因子（EGF）触发。然而，此前尚未有关于EGF-β-连环蛋白通路诱导多形性胶质母细胞瘤（GBM）发生EMT的潜在机制的报道。在本研究中，运用免疫组织化学、逆转录聚合酶链反应及蛋白质印迹法来探究EGF-β-连环蛋白通路对GBM发生EMT的影响。在此，我们发现与正常脑组织和星形胶质细胞相比，β-连环蛋白的mRNA和蛋白质水平在GBM组织以及四种胶质母细胞瘤细胞系（包括T98G、A172、U87和U251细胞）中均上调。在U87细胞系中，小干扰RNA（siRNA）抑制β-连环蛋白可抑制EGF诱导的增殖、迁移、侵袭以及EMT激活因子（Snail和Slug）的表达。此外，上皮标志物（E-钙黏蛋白）的表达上调，间充质标志物（N-钙黏蛋白和基质金属蛋白酶9）的表达下调。最后，PI3K/Akt信号通路抑制剂可使EGF-β-连环蛋白诱导的EMT失活。综上所述，EGF诱导的β-连环蛋白-EMT通路通过PI3K/Akt通路对GBM进展具有重要作用。抑制β-连环蛋白可导致EGF通路诱导的EMT受到抑制，这为治疗GBM患者提供了一种新方法。
