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EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis

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Abstract

Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment.

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Acknowledgements

We thank Prof. Yingyu Chen from Peking University Health Science Center for providing us with EVA1A shRNA plasmids.

Funding

This research was funded by National Natural Science Foundation of China (grant number 81600470) and Natural Science Foundation of Shandong Province (grant number ZR2022MC053).

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Authors and Affiliations

  1. School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China

    Xiaokun Liu, Xiao Gao, Di Yang, Lianhui Li, Lin Hou, Bin Wang & Ning Li

  2. Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, China

    Yuling Yang

  3. Clinical Laboratory, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China

    Qingming Guo

  4. Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, China

    Shunlong Liu & Wanxin Cong

  5. Department of Medical Laboratory, Qingdao Medical College, Qingdao University, Qingdao, China

    Sen Lu

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  1. Xiaokun Liu
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  2. Xiao Gao
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  11. Bin Wang
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  12. Ning Li
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Contributions

Xiaokun Liu designed and performed the experiments, analyzed data, wrote the initial manuscript, and conducted bioinformatics analysis. Xiao Gao and Di Yang performed animal experiments. Yuling Yang analyzed the clinical samples. Xiao Gao, Di Yang, Lianhui Li, Shunlong Liu, Wanxin Cong helped to analyze data. Qingming Guo, Sen Lu, Lin Hou and Bin Wang helped to revise the draft. Ning Li conceived the study, organized, reviewed the manuscript, and made significant revisions to the draft. All the authors read and approved the final manuscript.

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Correspondence to Ning Li.

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The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Medical College of the of Qingdao University under the project approval QDU-AEC-2023378 on Jul 18, 2023.

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Liu, X., Gao, X., Yang, Y. et al. EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01967-0

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