Circular RNA Eps15-homology domain-containing protein 2 induce resistance of renal cell carcinoma to sunitinib via microRNA-4731-5p/ABCF2 axis

Abstract

Circular RNAs (circRNAs) are linked with the occurrence and progression of renal cell carcinoma (RCC). However, circRNAs’ mechanism in developing resistance to RCC has not been clarified. This research assessed the role and mechanism of circular RNA circ Eps15-homology domain-containing protein 2 (EHD2) in the resistance of sunitinib (SU) to RCC. ACHN, 786-O, 769P, and HEK-293 T cells and RCC tissue samples were used for the investigations. The circEHD2 expression in RCC cells and tissues was determined through RT-qPCR. Association of circEHD2 with RCC histological grade of RCC was done through Chi-square. MiR-4731-5p, ABCF2, and circEHD2 were transfected into RCC cell lines. A dual-luciferase reporter assay was used to determine the interaction between miR-4731-5p, circEHD2, and ABCF2. MTT assay was used to analyze cell viability, while apoptosis was studied using flow cytometry. Colony-formation and transwell experiments were used to assess migration and invasion. The ATP Binding Cassette Subfamily F Member 2 (ABCF2) expression was analyzed through western blot. The results showed increased circEHD2 in SU-resistant RCC tissues and cell lines and implicated in RCC histological grade and SU resistance. Knock-down of circEHD2 down-regulated the resistance of RCC to SU in vitro and vivo ; circEHD2 bound to miR-4731-5p to mediate ABCF2 in RCC; ABCF2 rescued the inhibitory effect of circEHD2 knock-down on SU resistance of RCC. In conclusion, circEHD2 enhances RCC resistance to SU via acting as a miR-4731-5p sponge to mediate ABCF2. MiR-4731-5p can target circEHD2 and ABCF2, thus providing a novel and effective therapeutic against renal cell carcinoma.

Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics

“…These results indicated that circRNA_001895 promoted sunitinib resistance by regulating apoptosis and DNA damage repair (Tan et al, 2021). Additionally, as an upstream signal in the cirEHD2 (homology domain-containing protein 2)/miR-4731-5p/ABCF2 pathway, circEHD2 could cause sunitinib resistance by reducing the accumulation of drugs (Li et al, 2022).…”

“…Furthermore, the ABCB1 (1236C/T, 2677G/T and 3435C/T) polymorphisms influenced the transport capacity of P‐gp‐mediated sunitinib in the Caco‐2 cell line and enhanced resistance to sunitinib (Tan, 2020). And the ABC subfamily F member 2 (ABCF2) in this family subpopulation was demonstrated to participate in renal cell carcinoma tolerance to sunitinib by mediating the circEHD2/microRNA(miR)‐4731‐5p/ABCF2 pathway (Li et al, 2022).…”

“…These results indicated that circRNA_001895 promoted sunitinib resistance by regulating apoptosis and DNA damage repair (Tan et al, 2021). Additionally, as an upstream signal in the cirEHD2 (homology domain‐containing protein 2)/miR‐4731‐5p/ABCF2 pathway, circEHD2 could cause sunitinib resistance by reducing the accumulation of drugs (Li et al, 2022). Recent studies have identified a necessary circRNA for sunitinib resistance, circME1, which might interact with U1 small nuclear ribonucleoprotein (snRNP) at the promoter of ME1 to increase the expression of its parental gene ME1 , thereby enhancing aerobic glycolysis of clear cell renal cell carcinoma and promoting its malignant phenotype (Zhang et al, 2022).…”

Extracellular vesicle-circEHD2 promotes the progression of renal cell carcinoma by activating cancer-associated fibroblasts

“…Additionally, owing to their unique circular structure, circRNAs exhibit characteristics of high conservation and stability, which make circRNAs promising biomarkers [ 5 ]. Emerging evidence has suggested that circRNAs are involved in the progression of various diseases, including cancer [ 6 – 8 ]. Until now, circRNAs have been demonstrated to play a vital oncogenic or anti-oncogenic roles in multiple cancers, including prostate cancer [ 9 ], breast cancer [ 10 ],colorectal cancer [ 11 ], and hepatocellular carcinoma [ 12 ].…”

Molecular mechanism of circRNAs in drug resistance in renal cell carcinoma

“…Chen et al [ 60 ] revealed that circRNA-001895 expression in tumor cells was related to sunitinib resistance in RCC and that hsa-circ-001895 regulated the downstream target gene FOX2 through miR-296-5P. Li et al [ 61 ] reported increased circEHD2 expression in sunitinib-resistant cell lines and tissues, which was linked to sunitinib resistance. Conversely, the knockdown of CircEHD2 reduced the progression of sunitinib-resistant cancer cells.…”