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Published on: September 12, 2019
Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy
Yuxin Zhang1, Yujie Zhang2, Haisu Tao3
1Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.
Insights
Lenvatinib resistance in liver cancer (HCC) involves reduced ROS levels. LINC01607 enhances this resistance via mitophagy and antioxidant pathways, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lenvatinib is a standard treatment for advanced hepatocellular carcinoma (HCC).
- Drug resistance remains a significant challenge, limiting Lenvatinib's clinical efficacy.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Lenvatinib resistance in HCC.
- To identify novel therapeutic targets for overcoming Lenvatinib resistance.
Main Methods:
- RNA sequencing and whole-genome CRISPR-Cas9 screening were employed.
- In vitro and in vivo experiments were conducted to validate findings.
- Patient-derived organoid models were utilized.
Main Results:
- Lenvatinib-resistant HCC exhibited inhibited ROS levels and reduced redox status.
- LINC01607 acts as a competing endogenous RNA (ceRNA) for miR-892b, upregulating P62.
- This process enhances mitophagy, reduces ROS, and promotes drug resistance.
- A positive feedback loop involving LINC01607 and the P62-Nrf2 axis was identified.
- Silencing LINC01607 reversed Lenvatinib resistance in preclinical models.
Conclusions:
- A novel mechanism of Lenvatinib resistance involving ROS homeostasis and the LINC01607/P62/Nrf2 axis was discovered.
- LINC01607 is a potential therapeutic target for overcoming Lenvatinib resistance in HCC.
- This study provides new strategies for treating HCC patients resistant to Lenvatinib.
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