The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells

TLDR

Cdr1as is a circular RNA that acts as a potent miR‑7 sponge, and miR‑7 is highly expressed in pancreatic β‑cells where its overexpression induces diabetes. The study aimed to determine whether Cdr1as can inhibit miR‑7 in β‑cells and thereby enhance insulin secretion. Cdr1as is expressed in islet cells, is induced by cAMP/PKC signaling, and its overexpression boosts insulin content and secretion by modulating miR‑7 targets Myrip and Pax6, indicating that the Cdr1as/miR‑7 axis could be exploited to improve β‑cell function in diabetes.

Abstract

Abstract 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.