MALAT1: A Pivotal lncRNA in the Phenotypic Switch of Gastric Smooth Muscle Cells via the Targeting of the miR-449a/DLL1 Axis in Diabetic Gastroparesis

Abstract

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus (DM). Our previous study suggested that the expression of the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is closely related to DGP. However, the role of MALAT1 in DGP pathogenesis remains unclear. Here, we aim to characterize the role of MALAT1 in DGP. First, we analyzed the lncRNA expression profiles through lncRNA sequencing. Next, we detected MALAT1 expression in the stomach tissues of DGP model mice and diabetic patients. Then, we investigated the role and mechanisms of MALAT1 in the proliferation, migration, phenotypic switch, and carbachol-induced intracellular Ca2+ changes in human gastric smooth muscle cells (HGSMCs) under high glucose (HG) conditions, using short hairpin RNA technology, RNA immunoprecipitation, and dual-luciferase reporter assays. We show that MALAT1 expression was upregulated in the gastric tissues of DGP model mice, the adjacent healthy tissues collected from diabetic gastric cancer patients with DGP symptoms, and in HGSMCs cultured under HG conditions. Functionally, MALAT1 knockdown in vitro impacted the viability, proliferation, migration and promoted the phenotypic switch of HGSMCs under HG conditions. Additionally, we show that MALAT1 sponged miR-449a, regulating Delta-like ligand 1 (DLL1) expression in HGSMCs; any disturbance of the MALAT1/miR-449a/DLL1 pathway affects the proliferation, migration, phenotypic switch, and carbachol-induced Ca2+ transient signals in HGSMCs under HG conditions. Collectively, our data highlight a novel regulatory signaling pathway, the MALAT1/miR-449a/DLL1 axis, in the context of DGP.

Low‐intensity pulsed ultrasound combined with ST36 modulate gastric smooth muscle contractile marker expression via RhoA/Rock and MALAT1/miR‐449a/DLL1 signaling in diabetic rats

“…MALAT1 can precisely control the levels of miR‐449a by acting as a sponge. Delta‐like ligand 1 (DLL1) is a direct target of miR‐449a, the downregulation of miR‐449a promoted the expression of DLL1 19 . The DLL family plays a pivotal role in controlling the differentiation and phenotypic switching of vascular smooth muscle cells, 20 but it has not been confirmed in GSMCs of diabetic mice.…”

“…The DLL family plays a pivotal role in controlling the differentiation and phenotypic switching of vascular smooth muscle cells, 20 but it has not been confirmed in GSMCs of diabetic mice. Up‐regulation of MALAT1/miR‐449a/DLL1 signaling may be responsible for delayed gastric emptying in diabetic mice 19 . However, there are no studies on the effect of ST36 on MALAT1 signaling.…”

“…Delta-like ligand 1 (DLL1) is a direct target of miR-449a, the downregulation of miR-449a promoted the expression of DLL1. 19 The DLL family plays a pivotal role in controlling the differentiation and phenotypic switching of vascular smooth muscle cells, 20 but it has not been confirmed in GSMCs of diabetic mice. Up-regulation of MALAT1/miR-449a/DLL1 signaling may be responsible for delayed gastric emptying in diabetic mice.…”

“…Up-regulation of MALAT1/miR-449a/DLL1 signaling may be responsible for delayed gastric emptying in diabetic mice. 19 However, there are no studies on the effect of ST36 on MALAT1 signaling. Therefore, we need to explore the signaling changes of MALAT1 in the stomach of diabetic rats and to further investigate whether they are regulated by LIPUS in the stomach of diabetic rats.…”

“…Recent years, it has been reported that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP 10,19. The up-regulation of MALAT1 promotes the phenotype switching of GSMCs under high-glucose conditions via the miR-449a/DLL1 axis 19. DLL1 may then regulate the phenotypic switching via the activation of the Notch signaling pathway 20.…”