State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing China.
Mol Ther. 2019 Sep 4;27(9):1621-1637. doi: 10.1016/j.ymthe.2019.05.023. Epub 2019 Jun 5.
Glioma, the most common primary malignancy in the brain, has high recurrence and lethality rates, and thus, elucidation of the molecular mechanisms of this incurable disease is urgently needed. Poly-pyrimidine tract binding protein (PTBP1, also known as hnRNP I), an RNA-binding protein, has various mechanisms to promote gliomagenesis. However, the mechanisms regulating PTBP1 expression are unclear. Herein, we report a novel natural antisense noncoding RNA, PTB-AS, whose expression correlated positively with PTBP1 mRNA. We found that PTB-AS significantly promoted the proliferation and migration in vivo and in vitro of glioma cells. PTB-AS substantially increased the PTBP1 level by directly binding to its 3' UTR and stabilizing the mRNA. Furthermore, staphylococcal nuclease domain-containing 1 (SND1) dramatically increased the binding capacity between PTB-AS and PTBP1 mRNA. Mechanistically, PTB-AS could mask the binding site of miR-9 in the PTBP1-3' UTR; miR-9 negatively regulates PTBP1. To summarize, we revealed that PTB-AS, which maintains the PTBP1 level through extended base pairing to the PTBP1 3' UTR with the assistance of SND1, could significantly promote gliomagenesis.
神经胶质瘤是最常见的原发性脑恶性肿瘤，具有高复发率和致死率，因此迫切需要阐明这种无法治愈疾病的分子机制。多嘧啶 tract 结合蛋白（PTBP1，也称为 hnRNP I）是一种 RNA 结合蛋白，具有多种促进神经胶质瘤发生的机制。然而，调节 PTBP1 表达的机制尚不清楚。在此，我们报道了一种新型的天然反义非编码 RNA，PTB-AS，其表达与 PTBP1 mRNA 呈正相关。我们发现 PTB-AS 可显著促进体内和体外神经胶质瘤细胞的增殖和迁移。PTB-AS 通过直接结合其 3' UTR 并稳定 mRNA，显著增加了 PTBP1 水平。此外，葡萄球菌核酸酶结构域蛋白 1（SND1）显著增加了 PTB-AS 与 PTBP1 mRNA 之间的结合能力。在机制上，PTB-AS 可以掩盖 miR-9 在 PTBP1 3' UTR 中的结合位点；miR-9 负调控 PTBP1。总之，我们揭示了 PTB-AS 通过与 SND1 辅助的 PTBP1 3' UTR 进行扩展碱基配对来维持 PTBP1 水平，可显著促进神经胶质瘤发生。
