circCNN2 drives endometrial cancer progression through ALKBH5/YTHDF2-mediated m6A regulation and miR-615-5p sponging
To investigate the role and regulatory mechanisms of circCNN2 in endometrial cancer progression, focusing on its epitranscriptomic regulation and interaction with the miR-615-5p/MYH14 axis. CircCNN2 expression was analyzed in endometrial cancer tissues (n = 15) and cell lines using qRT-PCR. N6-methyladenosine (m6A) modification was assessed by methylated RNA immunoprecipitation. CircCNN2-miR-615-5p-MYH14 interactions were validated through RNA pull-down, dual-luciferase reporter assays, and rescue experiments. Functional studies included proliferation, migration, invasion, and apoptosis assays. Subcutaneous xenograft models evaluated in vivo tumorigenicity and metastasis. CircCNN2 was significantly overexpressed in endometrial cancer tissues and cell lines. ALKBH5-mediated demethylation stabilized circCNN2, while YTHDF2 promoted its degradation through m6A recognition. CircCNN2 functioned as a molecular sponge for miR-615-5p, preventing MYH14 downregulation. CircCNN2 knockdown inhibited cell proliferation, colony formation, migration, and invasion while inducing apoptosis. MYH14 overexpression reversed these tumor-suppressive effects, confirming its role as the key downstream effector. In vivo, circCNN2 depletion significantly reduced tumor growth and lung metastasis, accompanied by decreased Ki67 and N-cadherin expression and increased E-cadherin levels. This study identifies circCNN2 as a novel oncogenic driver in endometrial cancer, operating through an m6A-regulated circRNA-miRNA-mRNA axis. The circCNN2/miR-615-5p/MYH14 pathway represents a promising therapeutic target for endometrial cancer treatment, particularly for patients with limited conventional therapy options. Our findings advance understanding of epitranscriptomic regulation in circular RNA biology and provide potential biomarkers for diagnosis and prognosis.