Yuan Shuai, Yan Qi, Zhao Zhi-Yong, Zhang Jing-Long, Zhang He, Yin Hang, Yuan Zhi
Department of Neurosurgery, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Gansu, 730030, Lanzhou, China.
Department of Neurology, Lanzhou University Second Hospital, 730030, Lanzhou, Gansu, China.
Cancer Cell Int. 2022 Aug 9;22(1):248. doi: 10.1186/s12935-022-02659-y.
A considerable number of glioblastoma (GBM) patients developed drug resistance to Temozolomide (TMZ) during chemotherapy, resulting in therapeutic failure and tumor recurrence. However, the exact mechanism of TMZ chemoresistance in GBM is still poorly clarified. As a novel identified lncRNA, LINC00520 was located on chromosome 14 and overexpressed in multiple human cancers. This study was designed and conducted to investigate the role and underlying mechanism of LINC00520 in GBM chemoresistance to TMZ. The qRT-PCR assay demonstrated that LINC00520 was significantly overexpressed in TMZ-sensitive and/or TMZ-resistant GBM cells (P < 0.001). The silencing of LINC00520 markedly reduced the cell viability, suppressed colony formation, induced cell apoptosis and G1/S phase arrest in TMZ-resistant cells (P < 0.001). In contrast, overexpression of LINC00520 conferred TMZ-resistant phenotype of GBM cells in vitro (P < 0.001). The orthotopic xenograft model was established and the results indicated that the volume of tumor xenografts in vivo was markedly inhibited by TMZ treatment after the silencing of LINC00520 (P < 0.001). Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay revealed a strong affinity of transcription factor STAT3 to the promoter regions of LINC00520, suggesting that STAT3 mediated the aberrant expression of LINC00520 in GBM. Further experiments demonstrated that LINC00520 could interact with RNA-binding protein LIN28B to inhibit autophagy and reduce DNA damage, thereby contributing to TMZ chemoresistance in GBM. These findings suggested that STAT3/LINC00520/LIN28B axis might be a promising target to improve TMZ chemoresistance of GBM.
相当数量的胶质母细胞瘤（GBM）患者在化疗期间对替莫唑胺（TMZ）产生耐药性，导致治疗失败和肿瘤复发。然而，GBM中TMZ耐药的确切机制仍不清楚。作为一种新发现的lncRNA，LINC00520位于14号染色体上，在多种人类癌症中过表达。本研究旨在探讨LINC00520在GBM对TMZ耐药中的作用及潜在机制。qRT-PCR检测表明，LINC00520在TMZ敏感和/或TMZ耐药的GBM细胞中显著过表达（P<0.001）。沉默LINC00520显著降低了TMZ耐药细胞的活力，抑制了集落形成，诱导了细胞凋亡和G1/S期阻滞（P<0.001）。相反，LINC00520的过表达赋予了GBM细胞体外TMZ耐药表型（P<0.001）。建立了原位异种移植模型，结果表明，沉默LINC00520后，TMZ治疗显著抑制了体内肿瘤异种移植的体积（P<0.001）。荧光素酶报告基因检测和染色质免疫沉淀（ChIP）检测显示转录因子STAT3与LINC00520的启动子区域有很强的亲和力，提示STAT3介导了GBM中LINC00520的异常表达。进一步实验表明，LINC00520可与RNA结合蛋白LIN28B相互作用，抑制自噬并减少DNA损伤，从而导致GBM对TMZ耐药。这些发现表明，STAT3/LINC00520/LIN28B轴可能是改善GBM对TMZ耐药性的一个有前景的靶点。
