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TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression

Cancer Gene Therapy volume 32, pages 507–520 (2025)Cite this article

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Abstract

Exosomes mediate cell-to-cell communication by releasing miRNAs, mRNA, etc. However, there is little research about the effects on the donor cells after miRNAs are excreted out of cells through exosomes. Here, we found that miR-378a-3p was specifically enriched in exosomes and inhibited cell proliferation, migration, invasion, and colony formation in ESCC. In addition, miR-378a-3p was sorted into exosomes through TOM1L1 and extracted mainly out of ESCC cells. Overexpression of TOM1L1 led to tumor suppressor miR-378a-3p accumulation in exosomes rather than in donor cells, promoting ESCC progression. Moreover, miR-378a-3p targets DYRK1A that directly binds to NPM1 and the phosphorylation state of NPM1 at Ser125 to suppress tumor growth. Taken together, our findings demonstrate that TOM1L1-mediated the tumor suppressor miR-378a-3p into exosomes and excreted out of cells to promote tumor progression.

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Fig. 1: miR-378a-3p is secreted outside of tumor cells.
Fig. 2: miR-378a-3p suppressed ESCC cell migration and invasion in vitro.
Fig. 3: miR-378a-3p was sorted into exosomes.
Fig. 4: TOM1L1 regulates miR-378a-3p sorting into exosomes.
Fig. 5: TOM1L1-mediated exosome sorting of miR-378a-3p promotes tumor progression.
Fig. 6: DYRK1A is a critical downstream target of miR-378a-3p in ESCC cells.
Fig. 7: DYRK1A physically interacts with NPM1 and phosphorylates it at Ser125.
Fig. 8: The mechanism of miR-378a-3p sorted into exosomes by TOM1L1 in ESCC.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

We would like to thank the Shanxi Medical University Key Laboratory of the Ministry of Education for providing us with the Cell physiology equipment platform.

Funding

This work was supported by the Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project(BYJL027); the Fundamental Research Program of Shanxi Province (20210302123292); the Central Guidance on Local Science and Technology Development Fund of Shanxi Province (YDZJSX2021A018); the Shenzhen Project of Science and Technology (JCYJ20190813094203600).

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  1. Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People’s Republic of China

    Lu Wang, Huijuan Liu, Guohui Chen, Qinglu Wu, Songrui Xu, Qichao Zhou, Yadong Zhao, Qiaorong Wang, Ting Yan & Xiaolong Cheng

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Contributions

Xiaolong Cheng and Ting Yan: Formal analysis, Funding acquisition, Project administration; Lu Wang: Data curation, Validation, Writing—original draft; Huijuan Liu, Guohui Chen and Qinglu Wu: Supervision, Visualization, revised and edited the manuscript; Songrui Xu, Qichao Zhou, Yadong Zhao, and Qiaorong Wang: Formal analysis, Investigation. All authors read and approved the final manuscript.

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Correspondence to Ting Yan or Xiaolong Cheng.

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Wang, L., Liu, H., Chen, G. et al. TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression. Cancer Gene Ther 32, 507–520 (2025). https://doi.org/10.1038/s41417-025-00889-6

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