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

Abstract

Abstract Background 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.Methods Use in vitro and in vivo experiments to study the function of cDCBLD2. Immunohistochemical detection of type IIA topoisomerase (TOP2A) expression in HCC tissue. The downstream molecules of cDCBLD2 were identified by differential gene analysis after knocking down cDCBLD2. QPCR, pull-down assay, FISH, Western blotting, dual-Luciferase reporter, cck8 assay, flow cytometry and patient-derived xenograft (PDX) mice were used to determine the molecular mechanism.Results We found that cDCBLD2 was upregulated in sorafenib-resistant 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 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 PDX mouse model of liver cancer.Conclusion We found that cDCBLD2 can competitively bind to the TOP2A coding sequence region through the miR-345-5p sponge mechanism, and thus affect sorafenib resistance and caspase-3 mediated apoptosis of HCC cells. 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.