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

Background: 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.

Hsa‐miR‐503‐5p regulates CTDSPL to accelerate cisplatin resistance and angiogenesis of lung adenocarcinoma cells

“…Chemotherapy drugs like cisplatin and other platinum agents have wide application in solid tumors, such as LUAD, as main anticancer agents. Nevertheless, efficacy decreased due to the emergence of drug resistance (Cao et al, 2021;He et al, 2022). More and more studies add up to the statement that miRNAs feature in cancer development and drug resistance (Hussen et al, 2023).…”

CircRNA_0008194 functions as a ceRNA to promote invasion of hepatocellular carcinoma via inhibiting miR‐190a/AHNAK signaling pathway

“…For the ceRNA mechanism, multiple circRNAs have been proved to interacting with miRNA and protein‐coding RNA in human cancers. For example, suppression of CirchipK2 was reported to inhibit the DDP resistance in ovarian cancer (OVC) through regulating CHTOP as a ceRNA approach 24 . In addition, circ_0032822 could promote the prognosis of laryngeal cancer through the miR‐141/E2F3 axis 25 .…”

“…For example, suppression of CirchipK2 was reported to inhibit the DDP resistance in ovarian cancer (OVC) through regulating CHTOP as a ceRNA approach. 24 In addition, circ_0032822 could promote the prognosis of laryngeal cancer through the miR‐141/E2F3 axis. 25 Previously, research also showed that increased miR‐190a could suppress the expression of PAR1 and induced the inhibition of cell migration and invasion in breast cancer.…”

Advances in the Study of CircRNAs in Tumor Drug Resistance

“…The coincidence targets in these different pathways provide some support for us to analyze the generation of drug resistance of tumor cells as a whole. For example, miR-338-3p can play a role in promoting drug resistance in a variety of tumors according to current reports ( 99 , 106 ), but the mechanisms of action are different. It is worth thinking whether the regulatory mechanisms of the same miRNAs in different tumor lines overlap, and if not, what determines the target of miRNAs to exert regulatory effects in tumor cells, and if so, whether it is of limited significance to focus on individual pathways according to most of the current literature.…”

“…For example, also in non-small cell lung cancer, circRNAPRMT5 can target miR-381-3p ( 24 ) and miR-4458 ( 26 ) to regulate the expression of different downstream proteins to promote tumor, and the same circ_007630 can also target miR-296-5p ( 31 ) and miR-186-5p ( 51 ) respectively. Interestingly, the same miRNA targets different genes in different tumors and regulates downstream pathways, such as miR-338-3p, which promotes the progressive drug resistance of oral squamous cell carcinoma ( 99 ) and ovarian cancer ( 106 ) at the same time. As we all know, the effect of circRNA on tumor drug resistance is often the result of a variety of mechanisms, so we need to pay attention to the interaction between various mechanisms and pathways, and pay attention to the integration and analysis of various mechanism information.…”