ATF4-mediated circTDRD3 promotes gastric cancer cell proliferation and metastasis by regulating the miR-891b/ITGA2 axis and AKT signaling pathway.

Background: Gastric cancer (GC) is a cancer of the gastrointestinal tract that is highly malignant and has poor prognosis. Circular RNAs are a class of nonclassical RNA molecules that have been determined to be involved in GC malignancy in various ways. However, the underlying function and mechanism of circTDRD3 in gastric cancer remain largely unknown.

Methods: We analyzed circTDRD3 expression in databases and verified the findings in GC cell lines and tissue specimens. A series of functional gene overexpression and knockdown assays in vivo and in vitro were carried out to investigate the role of circTDRD3 in proliferation and metastasis. Here, we revealed the role of the miR-891b/ITGA2 axis by analyzing bioinformatics datasets. Furthermore, we performed dual-luciferase, fluorescence in situ hybridization, RNA pull-down, and functional rescue experiments to examine the relationships between circTDRD3 and its interacting molecules. Western blot confirmed the positive regulatory role of circTDRD3 in the AKT signaling pathway. A promoting effect of ATF4 on circTDRD3 was determined through chromatin immunoprecipitation.

Results: CircTDRD3 was significantly overexpressed in GC tissues compared with adjacent benign tissue, and its expression level was positively correlated with tumor volume and lymph node metastasis. CircTDRD3 promoted GC cell proliferation and migration in vitro and in vivo. Mechanistically, circTDRD3 exerted a tumor-promoting effect by regulating the miR-891b/ITGA2 axis and AKT signaling pathway in a positive feedback manner mediated by the transcription factor ATF4.

Conclusions: ATF4-mediated circTDRD3 overexpression modulates the proliferation and metastasis of GC cells through the miR-891b/ITGA2 axis in a positive feedback manner.