Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea.
Department of Radiation Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Korea.
Int J Mol Sci. 2021 Sep 11;22(18):9845. doi: 10.3390/ijms22189845.
GBM is a high-grade cancer that originates from glial cells and has a poor prognosis. Although a combination of surgery, radiotherapy, and chemotherapy is prescribed to patients, GBM is highly resistant to therapies, and surviving cells show increased aggressiveness. In this study, we investigated the molecular mechanism underlying GBM progression after radiotherapy by establishing a GBM orthotopic xenograft mouse model. Based on transcriptomic analysis, we found that the expression of BEX1 and BEX4 was upregulated in GBM cells surviving radiotherapy. We also found that upregulated expression of BEX1 and BEX4 was involved in the formation of the filamentous cytoskeleton and altered mechanotransduction, which resulted in the activation of the YAP/TAZ signaling pathway. BEX1- and BEX4-mediated YAP/TAZ activation enhanced the tumor formation, growth, and radioresistance of GBM cells. Additionally, latrunculin B inhibited GBM progression after radiotherapy by suppressing actin polymerization in an orthotopic xenograft mouse model. Taken together, we suggest the involvement of cytoskeleton formation in radiation-induced GBM progression and latrunculin B as a GBM radiosensitizer.
GBM 是一种起源于神经胶质细胞的高级癌症，预后较差。尽管为患者开了手术、放疗和化疗的组合，但 GBM 对治疗高度耐药，存活的细胞表现出更强的侵袭性。在这项研究中，我们通过建立 GBM 原位异种移植小鼠模型，研究了放疗后 GBM 进展的分子机制。基于转录组分析，我们发现 BEX1 和 BEX4 的表达在放疗后存活的 GBM 细胞中上调。我们还发现，BEX1 和 BEX4 的上调表达参与了丝状细胞骨架的形成和机械转导的改变，导致 YAP/TAZ 信号通路的激活。BEX1 和 BEX4 介导的 YAP/TAZ 激活增强了 GBM 细胞的肿瘤形成、生长和放射抗性。此外，在原位异种移植小鼠模型中，Latrunculin B 通过抑制肌动蛋白聚合来抑制 GBM 进展。总之，我们提出细胞骨架形成参与放射诱导的 GBM 进展，Latrunculin B 作为 GBM 放射增敏剂。
