Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy

Yuxin Zhang; Yujie Zhang; Haisu Tao; Jinghan Zhu; Yuanxiang Lu; Fangling Cheng; Yixiao Xiong; Junjie Liu; Guangzhen Cai; Zhanguo Zhang; Huifang Liang; Yifa Chen; Wanguang Zhang

doi:10.1016/j.canlet.2023.216405

Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy

Cancer Lett. 2023 Nov 1:576:216405. doi: 10.1016/j.canlet.2023.216405. Epub 2023 Sep 30.

Authors

Yuxin Zhang¹, Yujie Zhang², Haisu Tao³, Jinghan Zhu⁴, Yuanxiang Lu⁴, Fangling Cheng⁴, Yixiao Xiong⁴, Junjie Liu⁴, Guangzhen Cai⁴, Zhanguo Zhang⁵, Huifang Liang⁶, Yifa Chen⁷, Wanguang Zhang⁸

Affiliations

¹ Hepatic 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.
² Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Hepatic 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 Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
⁴ Hepatic 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.
⁵ Hepatic 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. Electronic address: zhanguo_tjh@hust.edu.cn.
⁶ Hepatic 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. Electronic address: lianghuifang1997@126.com.
⁷ Hepatic 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. Electronic address: yfchen4533@163.com.
⁸ Hepatic 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. Electronic address: wgzhang@tjh.tjmu.edu.cn.

PMID: 37783391
DOI: 10.1016/j.canlet.2023.216405

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.

Keywords: Hepatocellular carcinoma; LINC01607; Lenvatinib resistance; Mitophagy; Nrf2; P62.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Cell Line, Tumor
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Mitophagy
Reactive Oxygen Species

Substances

lenvatinib
Reactive Oxygen Species