Wang Shengwen, Chen Cheng, Li Junliang, Xu Xinke, Chen Wei, Li Fangcheng
Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, China.
J Neurol Sci. 2020 Jul 15;414:116837. doi: 10.1016/j.jns.2020.116837. Epub 2020 Apr 14.
Glioblastoma multiforme (GBM) is the most common primary malignancy in the adult central nervous, and is characterized by high aggressiveness and a high mortality rate. The high mortality rate is largely due to the development of drug resistance. Temozolomide (TMZ) resistance is considered to be one of the major reasons responsible for GBM therapy failure. CXCL12/CXCR4 has been demonstrated to be involved in cell proliferation, migration, invasion, angiogenesis, and radioresistance in GBM. However, its role in TMZ resistance in GBM is unknown. In this study, we aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. We found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. Our study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM.
多形性胶质母细胞瘤（GBM）是成人中枢神经系统中最常见的原发性恶性肿瘤，其特点是侵袭性高、死亡率高。高死亡率很大程度上归因于耐药性的产生。替莫唑胺（TMZ）耐药被认为是GBM治疗失败的主要原因之一。CXCL12/CXCR4已被证明参与GBM中的细胞增殖、迁移、侵袭、血管生成和放射抗性。然而，其在GBM的TMZ耐药中的作用尚不清楚。在本研究中，我们旨在评估CXCL12/CXCR4在介导GBM细胞对TMZ耐药中的作用，并探索其潜在机制。我们发现CXCL12/CXCR4轴增强了GBM细胞对TMZ的耐药性。进一步研究表明，CXCL12/CXCR4通过上调FOXM1赋予GBM细胞TMZ耐药性并促进其迁移和侵袭。抑制CXCL12/CXCR4和沉默FOXM1可部分逆转这种耐药性。我们的研究揭示了CXCL12/CXCR4在介导GBM细胞对TMZ耐药中的重要作用，并表明靶向CXCL12/CXCR4轴可能会减弱GBM对TMZ的耐药性。
