CircHIPK2 Contributes to DDP Resistance and Malignant Behaviors of DDP-Resistant Ovarian Cancer Cells Both in vitro and in vivo Through circHIPK2/miR-338-3p/CHTOP ceRNA Pathway.

backgroundCisplatin (DDP) is standard-of-care and first-line management for ovarian cancer (OvCa). Circular RNA HIPK2 (circHIPK2) is abnormally upregulated in serum of OvCa patients. However, its role in DDP resistance remains unclear.

methodsExpression of cirHIPK2, microRNA (miR)-338-3p and chromatin target of protein arginine methyltransferase (CHTOP) was detected by quantitative reverse transcription PCR and Western blotting. Functional experiments were performed using cell counting kit-8 assay, flow cytometry, transwell assays, Western blotting, and xenograft experiment. The interaction among cirHIPK2, miR-338-3p and CHTOP was confirmed by dual-luciferase reporter assay and RNA pull-down assay.

resultsExpression of circHIPK2 and CHTOP was upregulated, and miR-338-3p was downregulated in human DDP-resistant OvCa tumors and cells. Blocking circHIPK2 could promote apoptosis and suppress the 50% inhibitory concentration (IC50) of DDP, cell proliferation, cell cycle entrance, migration and invasion in SKOV3/DDP and A2780/DDP cells. Allied with that was decreased B cell lymphoma (Bcl)-2, matrix metalloproteinase 2 (MMP2) and MMP9 levels, and increased Bcl-2-associated X protein (Bax) level. Similarly, overexpression of miR-338-3p functioned suppressive role in SKOV3/DDP and A2780/DDP cells. MiR-338-3p was a target for circHIPK2, and CHTOP was targeted by miR-338-3p, whereas silencing miR-338-3p counteracted the role of circHIPK2 knockdown, and restoring CHTOP either cancelled miR-338-3p role. The growth of A2780/DDP cells in nude mice was restrained by silencing circHIPK2 under DDP treatment or not.

conclusionCircHIPK2 might be a tumor promoter in OvCa and was associated with DDP resistance. Silencing circHIPK2 might suppress DDP-resistant OvCa through regulating miR-338-3p/CHTOP axis.