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Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-β/Smad2/3 pathway

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-β production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-β inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1β and p53, which accounts for the suppression of TGF-β production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-β/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.

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Fig. 1: Parkin deficiency promotes liver cancer metastasis.
Fig. 2: Parkin expression is negatively correlated with TMEFF1 expression.
Fig. 3: Parkin deficiency promotes liver cancer cell migration and metastasis via TMEFF1.
Fig. 4: Parkin deficiency promotes TMEFF1 transcription activation by TGF-β induction.
Fig. 5: TGF-β-upregulated TMEFF1 promotes cell migration.
Fig. 6: Parkin induces TGF-β through p53 and HIF-1α/HIF-1β.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant 81903643 and 82374095), the National Natural Science Foundation of Shaanxi Province (2024JC-YBQN-0891), the Shaanxi Province Science Fund for Distinguished Young Scholars (2023-JC-JQ-59), the Shaanxi Province Science and Technology Development Plan Project (2022ZDLSF05-05). We thank Dr. Wen-juan Tang for reviewing the manuscript.

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  1. These authors contributed equally: Qi Su, Jing-jing Wang

Authors and Affiliations

  1. School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061, China

    Qi Su, Jing-jing Wang, Jia-yan Ren, Qing Wu, Kun Chen, Kai-hui Tu, Yu Zhang, Ammar Sarwar, Xu Han & Yan-min Zhang

  2. Department of Chemistry, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Sze Wei Leong

  3. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China

    Mi Zhang & Wei-feng Dai

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Contributions

QS conceived and designed the experiments and acquired funding. JJW conducted literature search, and worked on the in vitro experiments, animal work, data collection and analysis. JYR, QW, KC, KHT, YZ, AS and XH were involved in animal data collection. SWL, MZ and WFD were involved in review and editing. YMZ is corresponding author, interpreted data and funding acquisition.

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Correspondence to Yan-min Zhang.

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Su, Q., Wang, Jj., Ren, Jy. et al. Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-β/Smad2/3 pathway. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01254-3

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