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PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer

Oncogene (2026) Cite this article

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Abstract

PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, are traditionally regarded as germline factors that partner with PIWI-interacting RNAs (piRNAs) to silence transposons and regulate gene expression. However, growing evidence implicates PIWI proteins as oncogenic drivers in diverse somatic cancers, often acting through piRNA-independent mechanisms that remain incompletely understood. Here, we integrate transcriptomic, translatomic, and proteomic profiling of wild-type versus PIWIL1-knockout gastric cancer cells to uncover a non-canonical, translational role for PIWIL1, one of the four human PIWI proteins. We find that PIWIL1 selectively enhances the translation of 5′-terminal oligopyrimidine (TOP) mRNAs by activating mTOR complex 1 (mTORC1). Mechanistically, PIWIL1 interacts with the R2TP chaperone complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and promotes its association with TELO2, facilitating mTOR-RAPTOR assembly and mTORC1 activation. Functionally, PIWIL1 deficiency sensitizes gastric cancer cells to mTOR inhibition, and in clinical samples, PIWIL1 expression positively correlates with mTORC1 pathway activity. Together, these findings define a novel piRNA-independent mechanism through which PIWIL1 contributes to tumor progression, extend PIWI-mediated translational control from the germline to human cancers, and establish PIWIL1 as a potential therapeutic target for gastric cancer in synergy with mTOR inhibition.

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Fig. 1: Transcriptome and translatome co-profiling reveals PIWIL1 activates the translation of TOP mRNAs.
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Fig. 2: PIWIL1 promotes the mTORC1 pathway to enhance translation of TOP mRNAs.
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Fig. 3: The R2TP complex is identified as a novel binding partner of PIWIL1 in gastric cancer cells through interactome analysis.
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Fig. 4: PIWIL1 cooperates with R2TP–TELO2 to promote the mTORC1 pathway.
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Fig. 5: PIWIL1 loss synergizes with the mTOR inhibitor Torin 1 to treat gastric cancer.
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Fig. 6: PIWIL1 protein abundance positively correlates with mTORC1 activity in human gastric cancer.
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Data availability

High-throughput sequencing data were deposited to the Gene Expression Omnibus with an accession number GSE290652. MS data were deposited to the Proteomics Identifications Database (PRIDE) repository with a dataset identifier PXD061966. Additional data generated during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to express our sincere gratitude to Professor Haifan Lin for valuable suggestions, insightful comments, and continuous guidance throughout the project design and implementation. We also thank Prof. Xingxu Huang for providing the CRISPR-Cas9 knockout system. Our appreciation extends to the Biomedical Big Data Platform at the Shanghai Institute for Advanced Immunochemical Studies, as well as the Animal Core Facility and the Molecular Imaging Core Facility at the School of Life Science and Technology, ShanghaiTech University, for their technical support. We are also grateful to the ShanghaiTech High-Performance Computing Platform for providing computational resources. Finally, we would like to thank Dr. Ting Lu and Dr. Yuanyuan Gong for their valuable comments and suggestions on this work. We acknowledge BioRender (https://www.biorender.com/) for providing the tools used to create figures in this manuscript, under Academic License ZB28TF2XDA, QN28W5664M, and QP28WM06YV.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 32570848 to S.S.) and the Shanghai Natural Science Foundation (Grant No. 25ZR1401254 to S.S.).

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Authors and Affiliations

  1. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China

    Tianqu Fan, Jiangsha Zhao, Ling Li, Meihua Cui, Jiawei Zhang & Shuo Shi

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Tianqu Fan & Tian Chi

  3. Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310000, China

    Jiangsha Zhao

  4. Shanghai Clinical Research and Trial Center, Shanghai, 201210, China

    Ling Li

  5. Department of Immunobiology, Yale University Medical School, New Haven, CT, 06520, USA

    Tian Chi

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  1. Tianqu Fan
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Contributions

S.S. conceived the project and supervised the study. T.C. co-supervised the study. T.F. performed the experiments and analyzed the data. J.Z. (Jiangsha Zhao) contributed to the early identification of key aspects of the study. L.L., J.Z. (Jiawei Zhang), and M.C. assisted with experiments and provided input on the manuscript. S.S. and T.F. wrote the manuscript. T.C. reviewed and edited the manuscript.

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Correspondence to Tian Chi or Shuo Shi.

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The authors declare no competing interests.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. For the use of human clinical samples, ethical approval of the human tissue array was granted by the Ethics Committee of Shanghai Outdo Biotech Co., Ltd (Approval No. SHYJS-CP-1507006). Written informed consent was obtained from all participants. For animal experiments, the study was approved by the Institutional Animal Care and Use Committee (IACUC) of ShanghaiTech University (Approval No. 20210420001 and 20250919001).

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Fan, T., Zhao, J., Li, L. et al. PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer. Oncogene (2026). https://doi.org/10.1038/s41388-026-03791-z

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