Xu Huanyu, Guo Sen, Li Wei, Yu Ping
Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Zhejiang Provincial Key Laboratory of Medical Genetics; School of Laboratory Medicine &Life Sciences, Wenzhou Medical University, Zhejiang, China.
Sci Rep. 2015 Jul 27;5:12453. doi: 10.1038/srep12453.
Among the identified thousands of circular RNAs (circRNA) in humans and animals, Cdr1as (also known as CiRS-7) was recently demonstrated to act as a powerful miR-7 sponge/inhibitor in developing midbrain of zebrafish, suggesting a novel mechanism for regulating microRNA functions. MiR-7 is abundantly expressed in islet cells, but overexpressing miR-7 in transgenic mouse β cells causes diabetes. Therefore, we infer that Cdr1as expression may inhibit miR-7 function in islet cells, which in turn improves insulin secretion. Here, we show the first characterization of Cdr1as expression in islet cells, which was upregulated by long-term forskolin and PMA stimulation, but not high glucose, indicating the involvement of cAMP and PKC pathways. Remarkably, both insulin content and secretion were significantly increased by overexpression of Cdr1as in islet cells. We further identified a new target Myrip in the Cdr1as/miR-7 pathway that regulates insulin granule secretion, and also another target Pax6 that enhances insulin transcription. Taken together, our findings revealed the effects of the strongly interacting pair of Cdr1as/miR-7 on insulin secretion, which may become a new target for improving β cell function in diabetes.
在人和动物中已鉴定出的数千种环状RNA（circRNA）中，Cdr1as（也称为CiRS-7）最近被证明在斑马鱼发育中的中脑中作为一种强大的miR-7海绵/抑制剂发挥作用，这提示了一种调节 microRNA 功能的新机制。MiR-7在胰岛细胞中大量表达，但在转基因小鼠β细胞中过表达miR-7会导致糖尿病。因此，我们推断Cdr1as的表达可能会抑制胰岛细胞中miR-7的功能，进而改善胰岛素分泌。在这里，我们首次描述了Cdr1as在胰岛细胞中的表达特征，其表达受长期福斯高林和佛波酯刺激上调，但不受高糖刺激，表明cAMP和PKC信号通路参与其中。值得注意的是，在胰岛细胞中过表达Cdr1as可显著增加胰岛素含量和分泌。我们进一步在Cdr1as/miR-7通路中鉴定出一个调节胰岛素颗粒分泌的新靶点Myrip，以及另一个增强胰岛素转录的靶点Pax6。综上所述，我们的研究结果揭示了Cdr1as/miR-7这一强相互作用对胰岛素分泌的影响，这可能成为改善糖尿病β细胞功能的新靶点。
