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Cytoplasmic localization of IRF5 induces Wnt5a/E-cadherin degradation and promotes gastric cancer cells metastasis

Cancer Gene Therapy volume 30, pages 866–877 (2023)Cite this article

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Abstract

IRF5, a nucleoplasm shuttling protein, is a pivotal transcription factor regulating immune system activity. It’s well known that immunosuppression is involved in the development of gastric cancer. However, no data exist for the expression and function of IRF5 in gastric cancer. This study demonstrated that IRF5 was cytoplasm-enriched in gastric cancer cells. IRF5 promoted gastric cancer cell migration, which involved the inhibition of Wnt5a and E-cadherin proteins expression. IRF5 (LA) localized in nucleus had no significant effect on Wnt5a and E-cadherin expressions, while mutation of IRF5 (ΔNLS), which prevents IRF5 nuclear translocation, had more impact on these inhibitory effects. In addition, degradation rates of both Wnt5a and E-cadherin were enhanced by resiquimod, an IRF5 agonist. Further in vivo experiments indicated that IRF5 knockout of gastric cancer cells repressed their pulmonary metastasis in nude mice. Finally, the expression and clinical significance of IRF5 were analyzed using gastric cancer tissue microarrays, which suggested that the expression of IRF5 varied procedurally in different progressive stages of gastric cancer. Our data revealed that IRF5 cytoplasmic localization were associated with Wnt5a and E-cadherin degradation and gastric cancer cell metastasis. Inhibiting IRF5 expression and/or its cytoplasmic localization may provide a novel target for gastric cancer therapy.

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Fig. 1: Identification of IRF and WNT family members related to immune score and clustering of TCGA-STAD and GEO-GC patients.
Fig. 2: IRF5 regulated E-cadherin, Wnt5a expression and migration of gastric cancer cells.
Fig. 3: IRF5 regulated E-cadherin expression via Wnt5a.
Fig. 4: IRF5 accelerated the degradation of E-cadherin and Wnt5a and resiquimod reduced their expression.
Fig. 5: NLS1 mutation of IRF5 reduced the expression of E-cadherin and Wnt5a.
Fig. 6: IRF5 knockout repressed the pulmonary metastasis of gastric cancer cells in nude mice.
Fig. 7: Analysis of IRF5 expression in human gastric cancer tissues.

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Data availability

The dataset analysed for this study is available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81602561, 82073226, 82003497), Natural Science Foundation of the Jiangsu Higher Education Institution of China (21KJB310002), and Shandong Provincial Natural Science Foundation (ZR2019PH085).

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  1. These authors contributed equally: Jun Du, Chongqi Sun.

Authors and Affiliations

  1. Department of Physiology, Nanjing Medical University, Nanjing, P.R. China

    Jun Du, Xiaoli Wang, Xuyang Zhao, Yueyuan Wang, Yadong Ma, Chenxiang Qi, Qianwen Wang, Tianxiang Xia, Fengwen Ye & Yujie Zhang

  2. Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China

    Chongqi Sun

  3. Assisted Reproductive Centre, Shandong Provincial Maternal and Child Health Care Hospital, Jinan, P.R. China

    Jiaojing Liu

  4. Department of Implantology, Changzhou Stomatological Hospital, Changzhou, P.R. China

    Hui Xie

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Contributions

YZ designed the study. JD, CS, JL, XW, XZ, YW, YM, and HX performed the experiments. CQ, QW, TX, and FY performed the statistical analysis. YZ, JD drafted the manuscript. YZ supervised the experimental work. All authors read and approved the final manuscript.

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Correspondence to Yujie Zhang.

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Du, J., Sun, C., Liu, J. et al. Cytoplasmic localization of IRF5 induces Wnt5a/E-cadherin degradation and promotes gastric cancer cells metastasis. Cancer Gene Ther 30, 866–877 (2023). https://doi.org/10.1038/s41417-023-00596-0

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