OncoTargets and Therapy (May 2021)
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
Abstract
Yang Cao,1 Xin Xie,2 Mingzhu Li,3 Yuhua Gao1 1Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang City, Liaoning Province, People’s Republic of China; 2Department of Teaching and Research Center, Liaoning University of Traditional Chinese Medicine, Shenyang City, Liaoning Province, People’s Republic of China; 3Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang City, Liaoning Province, People’s Republic of ChinaCorrespondence: Yuhua GaoDepartment of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Shenyang, 110042, Liaoning Province, People’s Republic of ChinaTel/Fax +86 024-31916913Email [email protected]: Cisplatin (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.Methods: Expression 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.Results: Expression 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.Conclusion: CircHIPK2 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.Keywords: circHIPK2, miR-338-3p, ovarian cancer, DDP resistance, CHTOP
