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circCNN2 drives endometrial cancer progression through ALKBH5/YTHDF2-mediated m6A regulation and miR-615-5p sponging

Chunyan Cai1, Xing Peng1, Yaqing Han1

  • 1Department of Gynecology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, Jiangsu, China.

Life Sciences
|November 28, 2025
PubMed
Abstract

Insights

Circular RNA circCNN2 drives endometrial cancer by regulating the miR-615-5p/MYH14 axis. Targeting this pathway offers a new therapeutic strategy for endometrial cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epitranscriptomics

Background:

  • Endometrial cancer (EC) is a prevalent gynecological malignancy.
  • Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer, but their functions and regulation in EC remain incompletely understood.
  • Epitranscriptomic modifications, such as N6-methyladenosine (m6A), are crucial regulators of RNA metabolism and function.

Purpose of the Study:

  • To elucidate the role of circCNN2 in endometrial cancer progression.
  • To investigate the epitranscriptomic regulation of circCNN2.
  • To explore the interaction between circCNN2, miR-615-5p, and MYH14 in EC.

Main Methods:

  • Quantitative real-time PCR (qRT-PCR) for circCNN2 expression analysis in EC tissues and cell lines.
  • Methylated RNA immunoprecipitation (MeRIP) to assess m6A modification.
  • RNA pull-down, dual-luciferase reporter assays, and rescue experiments to validate molecular interactions.
  • In vitro functional assays (proliferation, migration, invasion, apoptosis) and in vivo xenograft models.

Main Results:

  • CircCNN2 is significantly overexpressed in EC tissues and cell lines.
  • ALKBH5-mediated demethylation stabilizes circCNN2, while YTHDF2 promotes its degradation via m6A.
  • CircCNN2 acts as a molecular sponge for miR-615-5p, thereby inhibiting MYH14 downregulation.
  • Knockdown of circCNN2 suppressed tumor growth, proliferation, migration, and invasion, and induced apoptosis, effects reversed by MYH14 overexpression.
  • In vivo studies showed circCNN2 depletion reduced tumor growth and metastasis.

Conclusions:

  • CircCNN2 acts as an oncogenic driver in endometrial cancer through an m6A-regulated circRNA-miRNA-mRNA axis (circCNN2/miR-615-5p/MYH14).
  • This pathway presents a potential therapeutic target for endometrial cancer.
  • Findings contribute to understanding circRNA epitranscriptomic regulation and offer potential diagnostic/prognostic biomarkers.
Keywords:
Circular RNACompeting endogenous RNAEndometrial carcinomaEpitranscriptomicsN6-methyladenosine

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