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NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma

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Abstract

Objective

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management.

Methods

Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry.

Results

PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells.

Conclusion

The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.

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Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Wei Xue, Ting Wang, Wen-jing Tian, Si-qi Pang, Hua-feng Zhang & Wei-dong Jia

  2. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China

    Wei Xue, Si-qi Pang & Hua-feng Zhang

  3. The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Wei Xue, Ting Wang, Wen-jing Tian, Si-qi Pang & Hua-feng Zhang

Authors
  1. Wei Xue
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  2. Ting Wang
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  3. Wen-jing Tian
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  4. Si-qi Pang
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  5. Hua-feng Zhang
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  6. Wei-dong Jia
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Corresponding authors

Correspondence to Hua-feng Zhang or Wei-dong Jia.

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All authors declare that they have no conflicts of interest.

Additional information

This work was supported by the Global Select Project (No. DJK-LX-2022001) of the Institute of Health and Medicine, Hefei Comprehensive National Science Center.

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Xue, W., Wang, T., Tian, Wj. et al. NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma. CURR MED SCI 44, 168–179 (2024). https://doi.org/10.1007/s11596-023-2804-8

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  • DOI: https://doi.org/10.1007/s11596-023-2804-8

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