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


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.

Data availability

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


  1. Xia C, Dong X, Li H, Cao M, Sun D, He S, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J. 2022;135:584–590.

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: Cancer J Clin. 2022;72:7–33.

    PubMed  Google Scholar 

  3. Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev. 2020;39:1179–203.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535–84.

    Article  CAS  PubMed  Google Scholar 

  5. Ikushima H, Negishi H, Taniguchi T. The IRF family transcription factors at the interface of innate and adaptive immune responses. Cold Spring Harb Symp Quant Biol. 2013;78:105–16.

    Article  PubMed  Google Scholar 

  6. Bi X, Hameed M, Mirani N, Pimenta EM, Anari J, Barnes BJ. Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis. Breast Cancer Res. 2011;13:1–14.

  7. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 2003;63:6424–31.

    CAS  PubMed  Google Scholar 

  8. Guo J, Wang X, Wang Y, Wang L, Hua S. A promising role of interferon regulatory factor 5 as an early warning biomarker for the development of human non-small cell lung cancer. Lung Cancer. 2019;135:47–55.

    Article  PubMed  Google Scholar 

  9. Pimenta EM, De S, Weiss R, Feng D, Hall K, Kilic S, et al. IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media. Immunol Cell Biol. 2015;93:486–99.

    Article  CAS  PubMed  Google Scholar 

  10. Cevik O, Li D, Baljinnyam E, Manvar D, Pimenta EM, Waris G, et al. Interferon regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma. J Biol Chem. 2017;292:21676–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Babaian A, Romanish MT, Gagnier L, Kuo LY, Karimi MM, Steidl C, et al. Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma. Oncogene. 2016;35:2542–6.

    Article  CAS  PubMed  Google Scholar 

  12. Kreher S, Bouhlel MA, Cauchy P, Lamprecht B, Li S, Grau M, et al. Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2014;111:E4513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Massimino M, Vigneri P, Fallica M, Fidilio A, Aloisi A, Frasca F, et al. IRF5 promotes the proliferation of human thyroid cancer cells. Mol Cancer. 2012;11:1–8.

  14. Chen W, Lam SS, Srinath H, Jiang Z, Correia JJ, Schiffer CA, et al. Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5. Nat Struct Mol Biol. 2008;15:1213–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barnes BJ, Kellum MJ, Field AE, Pitha PM. Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. Mol Cell Biol. 2002;22:5721–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020;38:675–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oh SC, Sohn BH, Cheong JH, Kim SB, Lee JE, Park KC, et al. Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype. Nat Commun. 2018;9:1777.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yoon SJ, Park J, Shin Y, Choi Y, Park SW, Kang SG, et al. Deconvolution of diffuse gastric cancer and the suppression of CD34 on the BALB/c nude mice model. BMC Cancer. 2020;20:314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

    Article  PubMed  Google Scholar 

  20. Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26:1572–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innov (N. Y). 2021;2:100141.

    CAS  Google Scholar 

  22. Zhang Y, Du J, Zheng J, Liu J, Xu R, Shen T, et al. EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells. Oncotarget. 2015;6:7244–61.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol. 2003;195:346–55.

    Article  CAS  PubMed  Google Scholar 

  24. Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape. Nat Rev Clin Oncol. 2017;14:155–67.

    Article  CAS  PubMed  Google Scholar 

  25. Algarra I, Garcia-Lora A, Cabrera T, Ruiz-Cabello F, Garrido F. The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol Immunother. 2004;53:904–10.

    Article  CAS  PubMed  Google Scholar 

  26. Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK, Akutsu M, et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature. 2015;522:354–8.

    Article  CAS  PubMed  Google Scholar 

  27. Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J: Off Publ Fed Am Soc Exp Biol. 2016;30:3961–78.

    Article  CAS  Google Scholar 

  28. Ernst R, Mueller B, Ploegh HL, Schlieker C. The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol Cell. 2009;36:28–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duarte JH. Autoimmunity. IRF5 mediates joint inflammation. Nat Rev Rheumatol. 2015;11:562.

    Article  PubMed  Google Scholar 

  30. Almuttaqi H, Udalova IA. Advances and challenges in targeting IRF5, a key regulator of inflammation. FEBS J. 2019;286:1624–37.

    Article  CAS  PubMed  Google Scholar 

  31. Peng L, Ye L, Dong G, Ren LB, Wang CL, Xu P, et al. WNT5A inhibits human dental papilla cell proliferation and migration. Biochem Biophys Res Commun. 2009;390:1072–8.

    Article  CAS  PubMed  Google Scholar 

  32. Prasad CP, Chaurasiya SK, Guilmain W, Andersson T. WNT5A signaling impairs breast cancer cell migration and invasion via mechanisms independent of the epithelial-mesenchymal transition. J Exp Clin Cancer Res. 2016;35:1–15.

  33. Medrek C, Landberg G, Andersson T, Leandersson K. Wnt-5a-CKIα signaling promotes β-catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells. J Biol Chem. 2009;284:10968–79.

  34. Tomai MA, Miller RL, Lipson KE, Kieper WC, Zarraga IE, Vasilakos JP. Resiquimod and other immune response modifiers as vaccine adjuvants. Expert Rev Vaccines. 2007;6:835–47.

    Article  CAS  PubMed  Google Scholar 

  35. Ryzhakov G, Eames HL, Udalova IA. Activation and function of interferon regulatory factor 5. J Interferon Cytokine Res: Off J Int Soc Interferon Cytokine Res. 2015;35:71–8.

    Article  CAS  Google Scholar 

  36. Barnes BJ, Field AE, Pitha-Rowe PM. Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes. J Biol Chem. 2003;278:16630–41.

    Article  CAS  PubMed  Google Scholar 

  37. Andrilenas KK, Ramlall V, Kurland J, Leung B, Harbaugh AG, Siggers T. DNA-binding landscape of IRF3, IRF5 and IRF7 dimers: implications for dimer-specific gene regulation. Nucleic Acids Res. 2018;46:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ning S, Huye LE, Pagano JS. Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit. J Virol. 2005;79:11671–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheng TF, Brzostek S, Ando O, Van Scoy S, Kumar KP, Reich NC. Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection. J Immunol. 2006;176:7462–70.

    Article  CAS  PubMed  Google Scholar 

  40. Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev. 2011;25:1999–2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations



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).

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