Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China.
Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China.
Mol Ther. 2018 Mar 7;26(3):755-773. doi: 10.1016/j.ymthe.2017.12.017. Epub 2017 Dec 22.
Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk-associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor-suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor-suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation.
神经母细胞瘤（NB）是儿童期最常见的颅外肿瘤。最近的研究表明，长非编码 RNA（lncRNA）在肿瘤发生和侵袭性中具有新的作用。然而，风险相关 lncRNA 在 NB 进展中的功能和靶标仍有待确定。在此，通过挖掘公共微阵列数据集，我们确定叉头框 D3 反义 RNA 1（FOXD3-AS1）是 NB 患者预后良好的独立预后标志物。FOXD3-AS1 在 NB 组织和细胞系中下调，FOXD3-AS1 的异位表达诱导 NB 细胞的神经元分化，并降低其在体外和体内的侵袭性。在机制上，作为一种核 lncRNA，FOXD3-AS1 与聚（ADP-核糖）聚合酶 1（PARP1）相互作用，抑制 CTCF 的多聚（ADP-核糖基）化和激活，导致下游肿瘤抑制基因的表达被解除抑制。挽救实验表明，FOXD3-AS1 通过抑制 PARP1 或 CTCF 的致癌作用而具有肿瘤抑制特性，并在全反式视黄酸对 NB 的治疗效果中发挥关键作用。FOXD3-AS1 构建体或针对 PARP1 或 CTCF 的 siRNAs 的给药减少了裸鼠的肿瘤生长并延长了其存活时间。这些发现表明，作为一种风险相关的 lncRNA，FOXD3-AS1 通过抑制 PARP1 介导的 CTCF 激活来抑制 NB 的进展。
