cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence

Ruan, YeLing; Chen, TianYi; Zheng, LongBo; Cai, JingWei; Zhao, Hu; Wang, YaLi; Tao, LiYe; Xu, JunJie; Ji, Lin; Cai, XiuJun

doi:10.7150/ijbs.86227

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Int J Biol Sci 2023; 19(14):4608-4626. doi:10.7150/ijbs.86227 This issue Cite

Research Paper

cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence

YeLing Ruan^1,2*, TianYi Chen^1,2*, LongBo Zheng^5*, JingWei Cai^1,2, Hu Zhao^1,2, YaLi Wang^1,2, LiYe Tao^1,2, JunJie Xu^1,2,3,4✉, Lin Ji^1,2,✉, XiuJun Cai^1,2,3,4#✉

1. Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine - Hangzhou, China.
2. Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment - Hangzhou, China.
3. Zhejiang University Cancer Center - Hangzhou, China.
4. Liangzhu Laboratory, Zhejiang University Medical Center - Hangzhou, China.
5. Department of Gastroenterology, The Affiliated Hospital of Qingdao University - Qingdao, China
*These authors contributed equally to this work and share first authorship.
#Lead contact.

Citation:

Ruan Y, Chen T, Zheng L, Cai J, Zhao H, Wang Y, Tao L, Xu J, Ji L, Cai X. cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. Int J Biol Sci 2023; 19(14):4608-4626. doi:10.7150/ijbs.86227. https://www.ijbs.com/v19p4608.htm

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Abstract

Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.

Keywords: HCC, sorafenib, circRNA, miRNA345-5p, TOP2A

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APA

Ruan, Y., Chen, T., Zheng, L., Cai, J., Zhao, H., Wang, Y., Tao, L., Xu, J., Ji, L., Cai, X. (2023). cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. International Journal of Biological Sciences, 19(14), 4608-4626. https://doi.org/10.7150/ijbs.86227.

ACS

Ruan, Y.; Chen, T.; Zheng, L.; Cai, J.; Zhao, H.; Wang, Y.; Tao, L.; Xu, J.; Ji, L.; Cai, X. cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. Int. J. Biol. Sci. 2023, 19 (14), 4608-4626. DOI: 10.7150/ijbs.86227.

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CSE

Ruan Y, Chen T, Zheng L, Cai J, Zhao H, Wang Y, Tao L, Xu J, Ji L, Cai X. 2023. cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. Int J Biol Sci. 19(14):4608-4626.

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