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Loss of NUMB promotes hepatomegaly and hepatocellular carcinoma through the AKT/glycogen/hippo signaling

Oncogene volume 44, pages 2574–2587 (2025)Cite this article

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Abstract

Excessive glycogen deposition is a common feature of liver enlargement, liver adenoma, and liver cancer, yet the underlying mechanisms remain poorly understood. In this study, we found that NUMB, a well-known cell fate determinant, is downregulated in glycogen-rich adenomas and hepatocellular carcinoma (HCC). NUMB-deficient livers developed excessive glycogen accumulation and adenoma formation particularly in aged mice. Surprisingly, the Alb-Cre:Trp53loxP/loxP liver displayed no similar defective morphology and function, although p53 is considered an important downstream target of NUMB and closely related to glucose metabolism. Instead, we observed a synergistic interaction between NUMB and p53 in regulating glycogen metabolism in HCC tissues and cell lines. Combined knockout of NUMB and p53 in mice significantly enhances glycogen accumulation and hepatomegaly, particularly when mice are subjected to a high sugar diet (HSD), leading to higher cancer incidence. Mechanistically, NUMB deficiency disrupts the PTEN-PI3K/AKT signaling pathway, promoting glycogen accumulation. Subsequently, successive glycogen deposition triggers hepatomegaly and tumorigenesis via the Hippo signaling pathway. Our results suggest that NUMB plays a crucial role in maintaining the homeostasis of glucose metabolism and suppressing the development of liver tumors associated with glycogen deposition.

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Fig. 1: NUMB is downregulated in glycogen-accumulating liver adenomas and HCC.
Fig. 2: NUMB ablation induces liver enlargement and liver adenoma due to abnormal glycometabolism.
Fig. 3: The concurrent absence of NUMB and p53 synergistically enhances glycogen accumulation.
Fig. 4: Double deletion of NUMB and p53 exacerbates hepatomegaly.
Fig. 5: Double deletion of NUMB and p53 promotes liver cancer driven by abnormal glucose metabolism.
Fig. 6: Loss of NUMB and p53 promotes glycogen accumulation through PTEN/PI3K/AKT signaling.
Fig. 7: Loss of NUMB and p53 fosters hepatocellular carcinoma via the glycogen-HIPPO axis.
Fig. 8: The NUMB&p53-glycogen-Yap module exhibits alterations in human liver cancer specimens.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Guang Yang and Guangneng Liao for their help with mouse management and breeding.

Funding

This study was supported by grants from the Natural Science Foundation of China (U22A20343, 82200691, and 82404060); the Key Research and Development Program and the Young Scientists Fund of the Natural Science Foundation of Sichuan Province (2023YFS0041, 2024NSFSC1901, and 2024NSFSC0637); the Postdoctor Research Fund of West China Hospital, Sichuan University (2024HXBH083).

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  1. These authors contributed equally: Yuke Shu, Qing Tao.

Authors and Affiliations

  1. Department of Pathology & Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Yuke Shu, Qing Tao, Qing Xu, Yuwei Chen, Tingting Ma, Zhiqi Zhu, Zhenru Wu, Yuting Zeng, Menglin Chen, Mingyang Shao, Xiaoyue Cao & Yujun Shi

  2. Institute of Transplantation, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China

    Yuke Shu, Qing Xu, Yuwei Chen, Yahong Xu, Tingting Ma, Zhiqi Zhu, Mingyang Shao, Xiaoyue Cao, Yongjie Zhou & Yujun Shi

  3. Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China

    Xinyu Wei, Wei Peng & Chuan Li

  4. Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China

    Fei Liu

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Contributions

Yuke Shu and Qing Tao performed most of the experiments equally and wrote this manuscript; Yujun Shi, Chuan Li and Qing Xu designed and supervised the study and revised this manuscript; Zhenru Wu, Yahong Xu and Menglin Chen performed histology examination; Tingting Ma, Yuwei Chen, Fei Liu and Zhiqi Zhu collected clinical data; Xinyu Wei, Mingyang Shao,Xiaoyue Cao, Yuwei Chen, and Yuting Zeng performed informatic analysis; Yongjie Zhou and Wei Peng gave critical suggestions. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chuan Li or Yujun Shi.

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The authors declare no competing interests.

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The animal care and experimental procedures were conducted in accordance with national and international laws and policies and were approved by the Animal Care and Use Committee of Sichuan University(Approval No. 20230206006). All patient materials were obtained with written informed consent. Approval for this study was granted by the Ethics Committee of the West China Hospital of Sichuan University.

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Shu, Y., Tao, Q., Xu, Q. et al. Loss of NUMB promotes hepatomegaly and hepatocellular carcinoma through the AKT/glycogen/hippo signaling. Oncogene 44, 2574–2587 (2025). https://doi.org/10.1038/s41388-025-03430-z

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