LncRNA ZNF582-AS1 Acts as a Tumor Suppressor in Endometrial Cancer via the miR-21-5p/miR-516a-3p/CREBRF Axis.
TL;DR
The ZNF582-AS1/miR-21-5p/miR-516a-3p/CREBRF regulatory axis provides mechanistic insights into EC tumorigenesis and emphasizes the tumor suppressive effect of ZNF582-AS1.
Abstract
INTRODUCTION Endometrial Carcinoma (EC) is a prevalent gynecological malignant tumor with a rising incidence rate. Long non-coding RNAs (lncRNAs) are key regulatory factors in tumorigenesis. Although ZNF582-AS1 is an lncRNA that has been linked to other cancers, its role and mechanism in EC have not yet been explored.
Methods
ZNF582-AS1 expression was examined in the GEPIA database and confirmed in 45 pairs of EC/normal tissues and cell lines. Functional assays (including MTT and flow cytometry) were performed after ZNF582-AS1 overexpression. Potential miRNA targets were predicted using bioinformatics and validated using luciferase reporter and RNA Immunoprecipitation (RIP) detection. Downstream targets of miRNA were identified and detected using qPCR and Western blotting. Rescue experiments were conducted to confirm the functional interactions. A xenograft mouse model was used for in vivo validation.
Results
ZNF582-AS1 exhibits marked downregulation in EC tissues and cell lines. Low ZNF582-AS1 expression is linked to unfavorable prognosis. ZNF582-AS1 overexpression suppresses EC cell proliferation, triggers cell cycle arrest, and decreases miR-21-5p and miR-516a3p mRNA levels. Additionally, miR-21-5p/miR-516a-3p suppresses CREBRF expression by binding directly to the 3'-UTR of CREBRF, and ZNF582-AS1 overexpression attenuates this CREBRF suppression. In the in vivo studies, ZNF582-AS1 overexpression effectively inhibited tumor growth in nude mice.
Discussion
These findings support a competitive endogenous RNA mechanism, in which ZNF582-AS1 acts as a molecular sponge for miR-21-5p and miR-516a-3p, thereby alleviating their inhibitory effect on CREBRF expression. The recovery of CREBRF subsequently inhibits EC cell proliferation and promotes G0/G1 phase arrest, possibly by downregulating the CDK4/Cyclin D1 signaling pathway. The in vivo anti-tumor effect of ZNF582-AS1 further supports its biological relevance in EC progression. Overall, the ZNF582-AS1/miR-21-5p/miR516a-3p/CREBRF regulatory axis provides mechanistic insights into EC tumorigenesis and emphasizes the tumor suppressive effect of ZNF582-AS1.
Conclusion
LncRNA ZNF582-AS1 inhibits cell proliferation in EC by regulating the miR-21- 5p/miR-516a-3p/CREBRF axis. ZNF582-AS1 represents a potential treatment target and prognostic marker for EC.