CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells

Abstract

Background: Circular RNAs (circRNAs) are a new group of non-coding RNAs that play vital roles in cancer occurrence, including gastric cancer (GC). Nevertheless, the role and underlying regulatory mechanisms of circHIPK3 in GC remain unclear. Methods: The expression levels of circHIPK3, miR-876-5p, and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were estimated by real-time quantitative polymerase chain reaction (RT-qPCR) assay. The proliferation, migration, and invasion of GC cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and transwell assay. Glutaminolysis of GC cells was assessed by measuring glutamine, glutamate, and α-ketoglutarate levels. The western blot was employed to examine the related-protein expression. The association between miR-876-5p and circHIPK3 or PIK3R1 was predicted and affirmed by bioinformatics database starBase v2.0 and dual-luciferase reporter assay, respectively. Eventually, the xenograft experiment was used to assess the role of circHIPK3 silencing in vivo. Results: CircHIPK3 was upregulated in GC tissues and cells compared with controls, and circHIPK3 was more resistance to RNase R than linear homeodomain interacting protein kinase 3 (HIPK3) mRNA. Silencing of circHIPK3 inhibited GC cells proliferation, migration, invasion, and glutaminolysis as well as tumor tumorigenic ability. Moreover, we also found that miR-876-5p, interacted with PIK3R1, was a target gene of circHIPK3. CircHIPK3 silencing induced effects on GC cells were abolished by silencing of miR-876-5p. In addition, upregulation of PIK3R1 inversed miR-876-5p overexpression-induced effects on GC cells. Conclusion: The circHIPK3 mediated the proliferation, migration, invasion, and glutaminolysis of GC cells partly through regulation of miR-876-5p/PIK3R1 axis by the mechanism of competing endogenous RNAs (ceRNA), indicating circHIPK3 was a GC-associated circRNA that promoted GC development.