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.