MicroRNA-223 is essential for maintaining functional β-cell mass during diabetes through inhibiting both FOXO1 and SOX6 pathways

Abstract

The initiation and development of diabetes are mainly ascribed to the loss of functional ␤-cells. Therapies designed to regenerate ␤-cells provide great potential for controlling glucose levels and thereby preventing the devastating complications associated with diabetes. This requires detailed knowledge of the molecular events and underlying mechanisms in this disorder. Here, we report that expression of microRNA-223 (miR-223) is up-regulated in islets from diabetic mice and humans, as well as in murine Min6 ␤-cells exposed to tumor necrosis factor ␣ (TNF␣) or high glucose. Interestingly, miR-223 knockout (KO) mice exhibit impaired glucose tolerance and insulin resistance. Further analysis reveals that miR-223 deficiency dramatically suppresses ␤-cell proliferation and insulin secretion. Mechanistically, using luciferase reporter gene assays, histological analysis, and immunoblotting, we demonstrate that miR-223 inhibits both forkhead box O1 (FOXO1) and SRY-box 6 (SOX6) signaling, a unique bipartite mechanism that modulates expression of several ␤-cell markers (pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), and urocortin 3 (UCN3)) and cell cycle-related genes (cyclin D1, cyclin E1, and cyclin-dependent kinase inhibitor P27 (P27)). Importantly, miR-223 overexpression in ␤-cells could promote ␤-cell proliferation and improve ␤-cell function. Taken together, our results suggest that miR-223 is a critical factor for maintaining functional ␤-cell mass and adaptation during metabolic stress.

Ultraconserved element uc.333 increases insulin sensitivity by binding to miR-223

“…Previous studies have shown that miR-223 could be involved in a variety of biological activities such as tumor suppression or metabolic disease [22][23][24][25][26][27]. Furthermore, it is reported that miR-223 knockout mice exhibit impaired glucose tolerance and IR [20]. Here, in vitro studies validated that uc.333 can suppress the level of miR-223 in HepG2 cells.…”

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

“…He et al (38) demonstrated that in human osteosarcoma, mir-374a enhanced cell growth by inhibiting downstream FOXO1 signaling, which is consistent with the results of the current study in human ovarian cancer cells. Furthermore, p27 is a CDK inhibitor that has a negative regulatory effect on proliferation and is a downstream target of FOXO1; consequently, FOXO1 inhibits cell proliferation by upregulating p27 (39)(40)(41)(42). The Bim protein belongs to the Bcl-2 protein family and exerts a pro-apoptotic effect on cells (43,44); previous studies have confirmed that FOXO1 regulates cell apoptosis through its downstream targets, including Bim (45,46).…”

Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer

“…In accordance with these findings, miR-223 was discovered to be downregulated in peripheral blood. Interestingly, it was found to be upregulated in the pancreatic islets of T2DM patients, which can likely be explained by a feedback mechanism caused by high blood glucose [82]. Also, miR-223 increases the expression of GLUT4 protein to improve glucose intake, so that insulin resistance is mitigated [83].…”