Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, China.
School of Basic Medicine, Hebei University, Baoding, China.
Bioengineered. 2021 Dec;12(2):11768-11781. doi: 10.1080/21655979.2021.2009976.
Glioblastoma multiform (GBM) is the most frequent type of malignant brain tumor with a poor prognosis. After optimal surgery, radiotherapy plus temozolomide (TMZ) is the standard treatment for GBM patients. However, the development of TMZ resistance limits its efficacy in GBM management. Runt Related Transcription Factor 1 (RUNX1) and microRNAs have been implicated in drug resistance of TMZ in GBM. In this study, we revealed the underlying mechanism of TMZ resistance and identified miR-128-3p/RUNX1 axis as a novel target for TMZ resistance in GBM. RUNX1 expression was significantly upregulated in GBM tissues as compared to normal tissues, and its expression was even higher in recurrent GBM tissues and TMZ-resistant GBM cells. RUNX1 depletion inhibited the viability, proliferation, migration, invasion and TMZ resistance of GBM cells, which could be rescued by RUNX1 overexpression. We further identified miR-128-3p as a tumor-suppressor whose overexpression restored the sensitivity of TMZ in GBM cells. miR-128-3p negatively regulated RUNX1 and subsequently downregulated multidrug resistance-associated protein 1 (MRP1). Together, the present study indicates that RUNX1 confers TMZ resistance in GBM by upregulating MRP1, which is negatively regulated by miR-128-3p. Targeting miR-128-3p/RUNX1/MRP1 axis provides a potential strategy to overcome TMZ resistance in GBM.
多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤类型，预后不良。在进行最佳手术后，放疗联合替莫唑胺（TMZ）是 GBM 患者的标准治疗方法。然而，TMZ 耐药的发展限制了其在 GBM 管理中的疗效。 runt 相关转录因子 1（RUNX1）和 microRNAs 已被发现在 GBM 中与 TMZ 耐药有关。在这项研究中，我们揭示了 TMZ 耐药的潜在机制，并确定了 miR-128-3p/RUNX1 轴是 GBM 中 TMZ 耐药的新靶点。与正常组织相比，GBM 组织中 RUNX1 的表达明显上调，在复发性 GBM 组织和 TMZ 耐药的 GBM 细胞中表达更高。RUNX1 耗竭抑制了 GBM 细胞的活力、增殖、迁移、侵袭和 TMZ 耐药性，而过表达 RUNX1 可以挽救这种作用。我们进一步确定了 miR-128-3p 作为一种肿瘤抑制因子，其过表达可恢复 GBM 细胞对 TMZ 的敏感性。miR-128-3p 负调控 RUNX1，并随后下调多药耐药相关蛋白 1（MRP1）。总之，本研究表明，RUNX1 通过上调 MRP1 赋予 GBM 对 TMZ 的耐药性，而 miR-128-3p 则负调控 MRP1。靶向 miR-128-3p/RUNX1/MRP1 轴为克服 GBM 中的 TMZ 耐药提供了一种潜在策略。
