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Published on: September 12, 2019
cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding
YeLing Ruan1,2, TianYi Chen1,2, LongBo Zheng3
1Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine - Hangzhou, China.
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.
Insights
Circular RNA cDCBLD2 promotes sorafenib resistance in hepatocellular carcinoma (HCC) by sponging miR-345-5p and stabilizing TOP2A. Targeting cDCBLD2 with siRNA overcomes resistance in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sorafenib is a key treatment for advanced hepatocellular carcinoma (HCC).
- Sorafenib resistance significantly limits its therapeutic efficacy in HCC patients.
- The molecular mechanisms driving sorafenib resistance in HCC remain largely unknown.
Purpose of the Study:
- To investigate the role of circular RNAs in sorafenib resistance in HCC.
- To identify novel therapeutic targets for overcoming sorafenib resistance in HCC.
Main Methods:
- Quantitative real-time PCR to measure cDCBLD2 and TOP2A expression.
- Western blotting to assess protein levels.
- Luciferase reporter assays to confirm miRNA-target interactions.
- Cell viability assays to evaluate cytotoxicity.
- Animal studies using patient-derived xenograft (PDX) models.
Main Results:
- Circular RNA cDCBLD2 is upregulated in sorafenib-resistant HCC cells.
- Knockdown of cDCBLD2 enhances sorafenib-induced cytotoxicity and apoptosis.
- cDCBLD2 acts as a molecular sponge for miR-345-5p, increasing TOP2A mRNA stability.
- Targeting cDCBLD2 with siRNA reverses sorafenib resistance in HCC PDX models.
Conclusions:
- cDCBLD2 is a critical driver of sorafenib resistance in HCC.
- The cDCBLD2/miR-345-5p/TOP2A axis represents a potential therapeutic target.
- Targeting cDCBLD2 offers a promising strategy to overcome sorafenib resistance in HCC.
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