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The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway

Cellular & Molecular Immunology volume 17, pages 1163–1179 (2020)Cite this article

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Abstract

The ability to harness innate immunity is a promising solution for improving cancer immunotherapy. Interferon (IFN) induces expression of IFN-stimulated genes (ISGs) by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth, but the functions and mechanisms of most ISGs in cancer regulation are unknown. As an innate immune effector, ISG12a promotes the innate immune response to viral infection. In this study, ISG12a was found to be expressed at low levels in gastrointestinal cancer, represented by hepatocellular cancer (HCC) and gastric cancer (GC), and it identified as a tumor suppressor that affects clinical prognosis. ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells. Mechanistically, ISG12a promoted β-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin, thereby suppressing the canonical Wnt/β-catenin signaling pathway. Notably, β-catenin was identified as a transcription factor for PD-L1. Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PD-L1, rendering cancer cells sensitive to NK cell-mediated killing. This study reveals a mechanism underlying the anticancer effects of IFN. Some ISGs, as represented by ISG12a, may be useful in cancer therapy and prevention. The identified interrelations among innate immunity, Wnt/β-catenin signaling, and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.

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Acknowledgements

We thank Dr. Zhengfan Jiang (Peking University) for providing the pHA-Ub plasmid, Dr. Tianhua Zhou (Zhejiang University) for providing the pEF-Flag-Axin plasmid, Dr. Chen Liu (Yale University) for providing the LH86 and Huh7 cells, and Dr. Weiping Zou (University of Michigan) for discussion consultation. This study was supported by grants from the National Natural Science Foundation of China (81730064 and 81571985 to H.Z.), National Science and Technology Major Project (2017ZX10202201 and 2009ZX10004-312 to H.Z.), National Natural Science Foundation of China (81601383 to S.T., 31571368 and 31871324 to G.L., 81902069 to B.X.), China Postdoctoral Science Foundation (2019M652760 to B.X.), and Hunan Natural Science Foundation (2018JJ3090 to H.Z., 2018JJ3091 to S.T., 2018JJ3713 and 2018RS3006 to G.L.).

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Authors and Affiliations

  1. Institute of Pathogen Biology and Immunology of College of Biology, Hunan Provincial Key Laboratory of Medical Virology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, Hunan, China

    Rilin Deng, Binbin Xue, Zhen Xun, Yanxia Guo, Xiaohong Wang, Yan Xu, Renyun Tian, Shengwen Chen, Qian Liu, Jinwen Chen, Jingjing Wang, Xiang Huang, Huiyi Li, Mengmeng Guo, Xintao Wang, Jiahuan Ma, Songqing Tang & Haizhen Zhu

  2. Research Center of Cancer Prevention and Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Cancer Hospital, Changsha, 410013, Hunan, China

    Chaohui Zuo, Jinfeng Wang & Haizhen Zhu

  3. Institute of Translational Medicine, Institute of Liver Diseases, the First Hospital, Jilin University, Changchun, 130061, Jilin, China

    Yongqi Li, Miaomiao Yang, Zhihui Wu & Zhengkun Tu

  4. Department of Pathology, Hunan Cancer Hospital, Changsha, 410013, Hunan, China

    Jun Hu

  5. Department of Public Health, Central South University, Changsha, 410078, Hunan, China

    Guangdi Li

  6. The State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Hongbin Ji

  7. School of Life Science and Technology, Shanghai Tech University, Shanghai, 200120, China

    Hongbin Ji

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  1. Rilin Deng
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Contributions

R.D. and H.Z. conceived the project and designed the experiments. R.D., Z.X., Y.G., Y.X., and S.C. performed the cell experiments. R.D., B.X., Z.X., Y.G., Y.X., R.T., S.C., Q.L., Jingjing Wang, X.H., H.L., M.G., Xintao Wang, J.M., and S.T. conducted the plasmid construction and molecular experiments. C.Z., Jinfeng Wang, and J.H. provided the human tissue samples and clinical information. R.D., B.X., and Xiaohong Wang performed the immunofluorescence assays. R.D., Xiaohong Wang, Jinfeng Wang, J.H., and H.Z. performed the IHC and H&E staining. R.D., Z.X., Y.G., Xiaohong Wang, Y.X., R.T., J.C., and S.T. performed the animal experiments. G.L. performed the bioinformatics analyses. R.D., Y.L., M.Y., Z.W., and Z.T. performed the NK cell isolation and flow cytometry. R.D., R.T., S.C., and Q.L. performed the dual-luciferase reporter and ChIP assays. R.D., S.T., and H.Z. conducted the RNA sequencing analysis. R.D., Y.L., B.X., S.T., Z.T., H.J., and H.Z. analyzed and interpreted the data. H.Z. supervised the overall execution of the experiments. The manuscript was written by R.D. with support from G.L., Z.T., H.J., and H.Z. All authors have read and approved the final manuscript.

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Correspondence to Haizhen Zhu.

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Deng, R., Zuo, C., Li, Y. et al. The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway. Cell Mol Immunol 17, 1163–1179 (2020). https://doi.org/10.1038/s41423-020-00549-9

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