Circ_SMAD4 promotes gastric carcinogenesis by activating wnt/β-catenin pathway.

Objectives: Circular RNAs (circRNAs) are essential participants in tumour progression. This study focused on investigating the mechanism of a novel functional circRNA in gastric cancer (GC).

Methods: Gene expression was detected by qRT-PCR or Western blot. Survival curves were generated via Kaplan-Meier method. In vitro and in vivo assays were used to investigate the impact of circ_SMAD4 on GC cell growth and tumorigenesis. Agarose gel electrophoresis assay, RNase R treatment and Sanger sequencing were utilized for confirming the circular structure of circ_SMAD4. Relationship between molecules was monitored by a series of mechanical experiments, as needed.

Results: Circ_SMAD4 expression was potentiated in GC. Circ_SMAD4 depletion impeded GC cell growth in vitro and restrained tumorigenesis in vivo. Mechanically, nuclear circ_SMAD4 recruited TCF4 to facilitate CTNNB1 transcription, while cytoplasmic circ_SMAD4 sequestered miR-1276 to prevent the silence of CTNNB1 mRNA, leading to activation of Wnt/β-catenin pathway. Rescue experiments validated that circ_SMAD4 depended on miR-1276/TCF4-regulated CTNNB1 to elicit accelerating effects on GC cell growth.

Conclusion: Circ_SMAD4 facilitated GC tumorigenesis by activating CTNNB1-dependent Wnt/β-catenin pathway. Hopefully, the findings could provide new clues for improving GC prognosis and treatment.