Circular RNA circEYA3 promotes the radiation resistance of hepatocellular carcinoma via the IGF2BP2/DTX3L axis

Pan Hu; Letao Lin; Tao Huang; Zhenyu Li; Meigui Xiao; Huanqing Guo; Guanyu Chen; Dengyao Liu; Miaola Ke; Hongbo Shan; Fujun Zhang; Yanling Zhang

doi:10.1186/s12935-023-03168-2

Circular RNA circEYA3 promotes the radiation resistance of hepatocellular carcinoma via the IGF2BP2/DTX3L axis

Cancer Cell Int. 2023 Dec 2;23(1):308. doi: 10.1186/s12935-023-03168-2.

Authors

Pan Hu^#¹, Letao Lin^#¹, Tao Huang¹, Zhenyu Li², Meigui Xiao¹, Huanqing Guo¹, Guanyu Chen¹, Dengyao Liu¹, Miaola Ke³, Hongbo Shan⁴, Fujun Zhang⁵, Yanling Zhang⁶

Affiliations

¹ Department of Minimally Invasive Intervention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.
² Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou,, 510060, People's Republic of China.
³ Department of Blood Transfusion, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou,, 510060, People's Republic of China.
⁴ Department of Endoscopy, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China. shanhb@sysucc.org.cn.
⁵ Department of Minimally Invasive Intervention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China. zhangfj@sysucc.org.cn.
⁶ School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 South Shatai Road, Guangzhou, Guangdong, 510515, People's Republic of China. drzyl@smu.edu.cn.

^# Contributed equally.

Abstract

Background: Hepatocellular carcinoma (HCC) has a high incidence and mortality rate despite various treatment options, including ¹²⁵I seed implantation. However, recurrence and radiation resistance remain challenging issues. Hsa_circ_0007895 (circEYA3)-derived from exons 2-6 of EYA3-facilitates the proliferation and progression of pancreatic ductal adenocarcinoma. However, the role of circEYA3 in HCC ¹²⁵I radiation resistance remains unclear. Thus, we aimed to investigate the functions and underlying molecular mechanisms of circEYA3 in HCC under ¹²⁵I and X-ray irradiation conditions.

Methods: CircEYA3 was identified by RNA-seq in patients with HCC before and after ¹²⁵I seed implantation treatment, followed by fluorescence in situ hybridization and RNase R assays. The radiosensitivity of HCC cell lines irradiated with ¹²⁵I seeds or external irradiation were evaluated using the Cell Counting Kit 8, flow cytometry, γH2A.X immunofluorescence and comet assays. RNA pull-down and RNA immunoprecipitation assays were performed to explore the interactions between circEYA3 and IGF2BP2. DTX3L mRNA was identified by RNA-seq in PLC/PRF/5 cells with overexpressed circEYA3. The corresponding in vitro results were verified using a mouse xenograft model.

Results: CircEYA3 decreased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified IGF2BP2 as a novel and robust interacting protein of circEYA3. Mechanistically, circEYA3 binds to IGF2BP2 and enhances its ability to stabilize DTX3L mRNA, thereby specifically alleviating radiation-induced DNA damage in HCC cells.

Conclusions: Our findings demonstrate that circEYA3 increases the radioresistance of HCC to ¹²⁵I seeds and external irradiation via the IGF2BP2/DTX3L axis. Thus, circEYA3 might be a predictive indicator and intervention option for ¹²⁵I brachytherapy or external radiotherapy in HCC.

Keywords: 125I brachytherapy; Circular RNA; RNA-binding protein; Radiation resistance.

Abstract

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