The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma.
The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma.
复制标题
DOI：
10.18632/oncotarget.14244
复制
发表时间：
2017-01-24
期刊：
影响因子：
--
通讯作者：
Westmoreland TJ
中科院分区：
文献类型：
--
作者：
Mazar J;Rosado A;Shelley J;Marchica J;Westmoreland TJ
已显示长非编码RNA GAS 5在许多人类癌症系统中调节癌症增殖，并且与成功的患者结果相关。我们对神经母细胞瘤中GAS 5的检测显示，在MYCN扩增和非扩增细胞系中均有强表达。GAS5在体外的敲低导致细胞增殖、凋亡和诱导的细胞周期停滞的缺陷。GAS5克隆的进一步分析揭示了多个新的剪接变体，其中两个与MYCN状态呈负相关。GAS 5敲低后变体的互补研究表明了替代表型，其中一种变体（FL）通过挽救细胞周期停滞而显著增强细胞增殖，另一种变体（C2）驱动细胞凋亡，这表明每种变体在神经母细胞瘤癌症生理学中具有独特的作用。全局测序和ELISA阵列显示，GAS5的缺失诱导了p53、BRCA1和GADD 45 A，它们似乎共同调节细胞周期停滞。仅与FL GAS 5克隆互补可以挽救细胞周期停滞，稳定HDM2，并导致p53的丢失。总之，这些数据以lncRNA剪接变体的形式提供了新的治疗靶点，用于对抗癌症生长和细胞死亡的单独挑战。
The long non-coding RNA GAS5 has been shown to modulate cancer proliferation in numerous human cancer systems and has been correlated with successful patient outcome. Our examination of GAS5 in neuroblastoma has revealed robust expression in both MYCN-amplified and non-amplified cell lines. Knockdown of GAS5 In vitro resulted in defects in cell proliferation, apoptosis, and induced cell cycle arrest. Further analysis of GAS5 clones revealed multiple novel splice variants, two of which inversely modulated with MYCN status. Complementation studies of the variants post-knockdown of GAS5 indicated alternate phenotypes, with one variant (FL) considerably enhancing cell proliferation by rescuing cell cycle arrest and the other (C2) driving apoptosis, suggesting a unique role for each in neuroblastoma cancer physiology. Global sequencing and ELISA arrays revealed that the loss of GAS5 induced p53, BRCA1, and GADD45A, which appeared to modulate cell cycle arrest in concert. Complementation with only the FL GAS5 clone could rescue cell cycle arrest, stabilizing HDM2, and leading to the loss of p53. Together, these data offer novel therapeutic targets in the form of lncRNA splice variants for separate challenges against cancer growth and cell death.