CircRNA_001895 promotes sunitinib resistance of renal cell carcinoma through regulation of apoptosis and DNA damage repair

Abstract

Sunitinib, an inhibitor of receptor tyrosine kinase, possesses anti-tumor activity in renal cell carcinoma (RCC) through its anti-angiogenic effects. However, patients with advanced RCC are resistant to sunitinib. Dysregulated circRNAs has been shown to be associated with drug resistance in various tumors. However, little is known about the effect of circRNA_001895 on sunitinib resistance of RCC. First, the expression of circRNA_001895 was found to be higher in sunitinib-resistant RCC tissues than chemosensitive tumor tissues. Half maximal inhibitory concentration of sunitinib-resistant RCC cells (786-O/R and ACHN/R) was higher than sunitinib-sensitive 786-O and ACHN cells. CircRNA_001895 was also upregulated in 786-O/R and ACHN/R cells. Second, data from colony formation and flow cytometry analysis showed that knockdown of circRNA_001895 suppressed cell proliferation and promoted cell apoptosis in 786-O/R and ACHN/R cells. Moreover, the protein expression of phosphorylated histone H2AX (γH2AX) was enhanced, while phosphorylated DNA-dependent protein kinase (p-DNA-PK) and Rad51 were reduced in 786-/R and ACHN/R by knockdown of circRNA_001895. Lastly, knockdown of circRNA_001895 conferred sensitivity of in vivo tumor growth to sunitinib. In conclusion, circRNA_001895 was implicated in the sunitinib resistance in RCC through regulation of apoptosis and DNA damage repair, suggesting that circRNA_001895 might be a potential therapeutic target for advanced RCC.

Graphical Abstract

The role of circRNA_001895 in sunitinib resistance of RCC.

Keywords:

• CircRNA_001895
• sunitinib resistance
• RCC
• apoptosis
• DNA damage repair

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the standards upheld by the Ethics Committee of the Ethics Committee of Nanfang Hospital, Southern Medical University and with those of the 1964 Helsinki Declaration and its later amendments for ethical research involving human subjects. All animal experiments were approved by the Ethics Committee of the Ethics Committee of Nanfang Hospital, Southern Medical University for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.

Author’s contribution

Lei Tan and Zehai Huang designed the study, supervised the data collection, Zerong Chen and Shijun Chen analyzed the data, interpreted the data, Yunlin Ye, Tong Chen and Zhuangfei Chen prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Additional information

Funding

This work was financially supported by President Foundation of Nanfang Hospital, Southern Medical University (Grant no. 2019B022).