CircGSK3B promotes RORA expression and suppresses gastric cancer progression through the prevention of EZH2 trans-inhibition

Abstract

Background Circular RNAs (circRNAs) are a class of non-coding RNA that play critical roles in the development and pathogenesis of various cancers. The circRNA circGSK3B (hsa_circ_0003763) has been shown to enhance cell proliferation, migration, and invasion in hepatocellular carcinoma. However, the specific functions and underlying mechanistic involvement of circGSK3B in gastric cancer (GC) have not yet been explored. Our study aimed to investigate the effect of circGSK3B on the progression of GC and to identify any potential mechanisms underlying this process. Methods CircRNA datasets associated with GC were obtained from the PubMed, GEO, and ArrayExpress databases, and circRNAs were validated via RT-qPCR and Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, and in vitro binding assays were employed to determine proteins demonstrating interactions with circGSK3B. Gene expression regulation was assessed through RT-qPCR, chromatin immunoprecipitation, and western blot assays. Gain- and loss-of-function assays were used to analyze any effects of circGSK3B and its partner regulatory molecule (EZH2) on the proliferation, invasion, and migration abilities of GC cells both in vitro and in vivo. Results CircGSK3B was mainly identified in the nucleus. This circRNA was present at a reduced concentration in GC tissues and cell lines. Overexpression of circGSK3B was shown to inhibit the growth, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circGSK3B directly interacted with EZH2, acting to suppress the binding of EZH2 and H3K27me3 to the RORA promoter, and leading to an elevation in RORA expression and ultimately the suppression of GC progression. Conclusions CircGSK3B acts as a tumor suppressor, reducing EZH2 trans-inhibition and GC progression. This demonstrates the potential use of this RNA as a therapeutic target for GC.

circ_0006089 promotes gastric cancer growth, metastasis, glycolysis, and angiogenesis by regulating miR‐361‐3p/TGFB1

“…Of course, different circRNAs have also been shown to have different effects. Some circRNAs mediate the progression of GC as tumor‐promoting factors, such as circ‐0002570 21 and circC6orf132, 22 and some mediate GC development as tumor‐inhibiting factors, such as circ‐TNPO3 23 and circGSK3B 24 . In this, the role of highly expressed circ_0006089 in GC progression was verified.…”

“…Some circRNAs mediate the progression of GC as tumor‐promoting factors, such as circ‐0002570 21 and circC6orf132, 22 and some mediate GC development as tumor‐inhibiting factors, such as circ‐TNPO3 23 and circGSK3B. 24 In this, the role of highly expressed circ_0006089 in GC progression was verified. We discovered that circ_0006089 interference restrained GC cell growth, metastasis, glycolysis, and angiogenesis, as well as reduced tumor growth.…”

CircARID1A binds to IGF2BP3 in gastric cancer and promotes cancer proliferation by forming a circARID1A-IGF2BP3-SLC7A5 RNA–protein ternary complex

“…CircRNAs can act as miRNAs sponge, protein scaffolds, transporters, or decoys, translational template, and transcriptional regulators [21]. Interestingly, there is aberrant circRNA expression in GC and these molecules are linked to GC progression through interactions with miRNAs and proteins [22][23][24]. Whether circRNAs and IGF2BP3 interact in cancer or even under homeostatic conditions is largely unknown.…”

Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer

“…4B). The retinoic acid receptor-related orphan receptor alpha (RORa) the protein product of RORA is involved in tumor suppression, and plays pro-and anti-inflammatory roles, which are context-dependent [30][31][32]. RORA in tumors treated with losartan+FFX+CRT correlated strongly with NFATC4 (Spearman R=0.918) a gene also upregulated by losartan+FFX+CRT (Supplementary Fig.…”