Liang Huaxin, Chen Guangyong, Li Jiayan, Yang Fuwei
Department of Neurosurgery, China-Japan Union Hospital of Jilin University Changchun 130033, Jilin, China.
Department of Neurosurgery, Zhuhai Hospital Affiliated with Jinan University Zhuhai 519000, Guangdong, China.
Am J Transl Res. 2019 Jul 15;11(7):4277-4289. eCollection 2019.
Glioblastoma (GBM) is one of most malignancy tumors worldwide. Temozolomide (TMZ) is an important chemotherapy drug in GBM therapy. However, acquired TMZ-resistance frequently happens in GBM therapy and leads to high percentage of GBM recurrence. In our study, we demonstrated that Snail is upregulated in recurrent GBM tumors, and promotes the GBM cells resistant to TMZ induced apoptosis. Enhanced expression of Snail compromises the apoptosis induced by TMZ, and increases the cell migration and invasion. Reversely, depletion of Snail by siRNA has the opposite effects. In addition, we confirmed that the expression of Snail is modulated by STAT3 activation, since phospho-STAT3 level is relatively higher in recurrent GBM tumors and TMZ resistant cells. Knockdown of STAT3 turns down the expression of Snail in protein and mRNA level, and thereby sensitized the resistant GBM cells to TMZ treatment. Interestingly, the activation of STAT3 in GBM resistant cells is modulated by IL-6 secretion. Suppression of IL-6 abandons the STAT3 activation, and reduces its binding with Snail promoter. Inhibition of IL-6 by its antibody enhanced the killing effects of TMZ both in vivo and in vitro. Overall, our results provided a rational to overcome the TMZ resistant in GBM treatment by targeting IL-6-STAT3-Snail pathway.
胶质母细胞瘤（GBM）是全球最具恶性的肿瘤之一。替莫唑胺（TMZ）是GBM治疗中的一种重要化疗药物。然而，在GBM治疗中经常会出现获得性TMZ耐药性，导致GBM复发率很高。在我们的研究中，我们证明Snail在复发性GBM肿瘤中上调，并促进GBM细胞对TMZ诱导的凋亡产生抗性。Snail表达增强会损害TMZ诱导的凋亡，并增加细胞迁移和侵袭。相反，通过siRNA敲低Snail则会产生相反的效果。此外，我们证实Snail的表达受STAT3激活的调节，因为在复发性GBM肿瘤和TMZ耐药细胞中磷酸化STAT3水平相对较高。敲低STAT3会降低Snail在蛋白质和mRNA水平的表达，从而使耐药GBM细胞对TMZ治疗敏感。有趣的是，GBM耐药细胞中STAT3的激活受IL-6分泌的调节。抑制IL-6会消除STAT3的激活，并减少其与Snail启动子的结合。用其抗体抑制IL-6可增强TMZ在体内和体外的杀伤作用。总体而言，我们的结果为通过靶向IL-6-STAT3-Snail通路克服GBM治疗中的TMZ耐药性提供了理论依据。
