Circular RNA circEZH2 Promotes Lung Adenocarcinoma Progression by Regulating microRNA-495-3p/Tumor Protein D52 Axis and Activating Nuclear Factor-Kappa B Pathway

Liping Chen; Tongwei Xiang; Jing Xing; Xinan Lu; Shan Wei; Huaying Wang; Jipeng Li; Wanjun Yu

doi:10.2147/IJGM.S473202

Circular RNA circEZH2 Promotes Lung Adenocarcinoma Progression by Regulating microRNA-495-3p/Tumor Protein D52 Axis and Activating Nuclear Factor-Kappa B Pathway

Int J Gen Med. 2024 Sep 28:17:4419-4433. doi: 10.2147/IJGM.S473202. eCollection 2024.

Authors

Liping Chen¹, Tongwei Xiang², Jing Xing², Xinan Lu², Shan Wei², Huaying Wang², Jipeng Li¹, Wanjun Yu²

Affiliations

¹ Department of Central Laboratory, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China.
² Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China.

Abstract

Background: It has been increasingly recognized that circular RNAs (circRNAs) act as a pivotal factor in the onset and progression of human malignancies. Yet, the specific activities and mechanistic roles of these RNAs in the context of lung adenocarcinoma (LUAD) are not fully understood.

Methods: Microarray analysis identified a novel LUAD-associated circular RNA, termed hsa_circ_0006357 (also referred to as circEZH2). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized for the analysis of circEZH2 expression in tissues and cell lines. The characteristics of circEZH2 were verified by RNase R treatment and fluorescence in situ hybridization (FISH) assays. The functions of circEZH2 were detected by Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays. The molecular mechanism of circEZH2 was clarified through bioinformatics analysis as well as RNA pulldown, dual-luciferase reporter, RT-qPCR, and immunoblotting assays. The role of circEZH2 in vivo was investigated using a xenograft model.

Results: This investigation revealed that circEZH2 expression was elevated in LUAD cell lines and tumor samples. This elevation was associated with enhanced cell proliferation, migratory capacity, epithelial-mesenchymal transition (EMT), and invasion in vitro. Conversely, silencing of circEZH2 in vivo resulted in a notable decrease in LUAD tumorigenesis, whereas its overexpression led to the opposite effects. Mechanistically, circEZH2 appeared to act as a sponge for miR-495-3p, facilitating the upregulation of tumor protein D52 (TPD52) and triggering the nuclear factor kappa B (NF-κB) signaling pathway, thus contributing to the progression of LUAD.

Conclusion: These findings indicate that circEZH2 may function as a competitive endogenous RNA (ceRNA), driving the progression of LUAD by manipulating the miR-495-3p/TPD52 axis and activating the NF-κB pathway.

Keywords: circular RNA; lung adenocarcinoma; miR-495-3p; nuclear factor kappa B; tumor protein D52.

Grants and funding

This work was supported by the Natural Science Foundation of Ningbo (Grant numbers: 2022J032 and 2023J387), a Medical Science and Technology Project of Zhejiang Province (Grant number: 2024KY370), a Ningbo Leading Medical & Health Discipline grant (Grant number: 2022-B19), and the National Natural Science Foundation of China (Grant number: 81872433).