Circ‐PGAM1 promotes malignant progression of epithelial ovarian cancer through regulation of the miR‐542‐3p/CDC5L/PEAK1 pathway

• Published in: Cancer medicine (Malden, MA) Vol. 9; no. 10; pp. 3500 - 3521
• Main Authors: Zhang, Chunmei, Li, Yang, Zhao, Wancheng, Liu, Guipeng, Yang, Qing
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2020; John Wiley and Sons Inc; Wiley
• Subjects: Apoptosis; Binding sites; Bioinformatics; Cancer Biology; Cancer therapies; CDC5L; Cell adhesion & migration; Cell division; Cell growth; Cell proliferation; Chemotherapy; Cholecystokinin; Chromatin; Circular RNA; circ‐PGAM1; Colorectal cancer; EOC; Extracellular signal-regulated kinase; Flow cytometry; Gene expression; Hybridization; Immunohistochemistry; Immunoprecipitation; Janus kinase 2; Kinases; Localization; Lung cancer; Mammals; Metabolism; MicroRNAs; miR‐485‐5p; Mortality; Original Research; Ovarian cancer; PEAK1; Phosphoglycerate mutase; Proteins; Ribonucleic acid; RNA; Therapeutic applications; Transcription; Tumors; China; EOC; circ-PGAM1; CDC5L; PEAK1; miR-485-5p
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2929

Background Epithelial ovarian cancer (EOC) is the most common ovarian malignant cancer. Circular RNA is a type of endogenous noncoding RNA and is considered as a novel regulatory molecule in the development and progression of tumors. This study investigated the expression and functions of a circular RNA, circular‐phosphoglycerate mutase 1 (circ‐PGAM1), in EOC tissues and cells. Methods The expression of circ‐PGAM1 and miR‐542‐3p in EOC was analyzed using quantitative RT‐PCR. Immunohistochemistry and western blot were performed to confirm the localization and expression of cell division cycle 5‐like (CDC5L) and pseudopodium enriched atypical kinase 1 (PEAK1) in EOC tissues. Cell lines (CAOV3 and OVCAR3) overexpressing or silencingcirc‐PGAM1 and miR‐542‐3p were established to explore the functions of circ‐PGAM1 and miR‐542‐3p in ovarian cancer cells. Furthermore, dual‐luciferase reporter assay was performed to study the interactions between circ‐PGAM1 and miR‐542‐3p and between miR‐542‐3p and CDC5L. CCK‐8, transwell, and flow cytometry were used to study the effect of circ‐PGAM1 and miR‐542‐3p on cell biological behaviors including proliferation, migration, invasion, and apoptosis. The interaction between CDC5L and the PEAK1 gene promoter was confirmed using chromatin immunoprecipitation (ChIP). Results Circ‐PGAM1 was upregulated in EOC tissues, whereas linear PGAM1 was not deregulated in EOC tissues. Silencing of circ‐PAGM1 inhibited proliferation, migration, and invasion of ovarian cancer cells and promoted cell apoptosis. MiR‐542‐3p was downregulated in EOC tissues, and miR‐542‐3p overexpression inhibited malignant progression of ovarian cancer cells. Circ‐PGAM1 directly interacted with miR‐542‐3p, with mutual negative feedback between them. CDC5L was a direct target of miR‐542‐3p and played an oncogenic role in ovarian cancer cells. Furthermore, the CDC5L protein binds directly to the PEAK1 promoter to promote its transcription. PEAK1 overexpression activated ERK1/2 and JAK2 signaling pathways and promoted malignant biological behaviors of ovarian cancer cells. Circ‐PAGM1 silencing combined with miR‐542‐3p overexpression played the greatest anticancer role in vivo. Conclusion The circ‐PGAM1/miR‐542‐3p/CDC5L/PEAK1 pathway played an important role in the progression of ovarian cancer and might be a novel therapeutic target for ovarian cancer. Our study confirmed that circ‐PGAM1 promoted proliferation, migration, and invasion and inhibited apoptosis of ovarian cancer cells through down‐regulation of miR‐542‐3p. MiR‐542‐3p played a tumor‐suppressing role through down‐regulation of CDC5L. CDC5L was a downstream target of miR‐542‐3p, and PEAK1 is a downstream target of CDC5L.