一种新型蛋白 SPECC1-415aa，由 N6-甲基腺苷修饰的 circSPECC1 编码，可调节胶质母细胞瘤对 TMZ 的敏感性。
A novel protein SPECC1-415aa encoded by N6-methyladenosine modified circSPECC1 regulates the sensitivity of glioblastoma to TMZ.
机构信息
Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, China.
出版信息
Cell Mol Biol Lett. 2024 Sep 27;29(1):127. doi: 10.1186/s11658-024-00644-z.
BACKGROUND
Circular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM.
METHODS
CircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity.
RESULTS
By analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The mA reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ.
CONCLUSIONS
CircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ.
背景
环状 RNA（circRNAs）可以影响多种生物功能，并在胶质母细胞瘤（GBM）的进展和复发中发挥重要作用。然而，在癌症中发现的编码 circRNAs 很少，其在 GBM 中的作用尚不清楚。本研究旨在鉴定编码 circRNAs，并探讨其在 GBM 进展和复发中的潜在作用。
方法
通过原发性和复发性 GBM 样本的 circRNAs 微阵列筛选 circSPECC1。为了确定 circSPECC1 的特征和编码能力，我们进行了一系列实验。之后，通过体内和体外实验，研究了 circSPECC1 及其编码的新型蛋白（SPECC1-415aa）在 GBM 中的生物学功能，以及它们对 TMZ 敏感性的影响。
结果
通过分析原发性和复发性 GBM 样本的 circRNAs 微阵列，发现与原发性 GBM 相比，circSPECC1 在复发性 GBM 中是一种下调的具有编码潜力的 circRNA。circSPECC1 通过编码一种新的蛋白质 SPECC1-415aa 来抑制 GBM 细胞的增殖、迁移、侵袭和集落形成能力。circSPECC1 通过编码新蛋白 SPECC1-415aa 恢复 TMZ 耐药 GBM 细胞对 TMZ 的敏感性。mA 读蛋白 IGF2BP1 可以与 circSPECC1 结合，促进其表达和稳定性。在机制上，SPECC1-415aa 可以与 ANXA2 结合，并竞争性抑制 ANXA2 与 EGFR 的结合，从而抑制 EGFR（Tyr845）及其下游途径蛋白 AKT（Ser473）的磷酸化。体内实验表明，circSPECC1 的过表达可以与 TMZ 联合治疗 TMZ 耐药 GBM，从而恢复 TMZ 耐药 GBM 对 TMZ 的敏感性。
结论
与原发性 GBM 相比，circSPECC1 在复发性 GBM 中下调。mA 读蛋白 IGF2BP1 可以促进 circSPECC1 的表达和稳定性。由 circSPECC1 编码的 SPECC1-415aa 序列可以通过竞争性结合 ANXA2 并抑制 EGFR 和 AKT 的磷酸化来抑制 ANXA2 与 EGFR 的结合，从而恢复 TMZ 耐药 GBM 细胞对 TMZ 的敏感性。
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