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Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer

Abstract

Avoiding immune destruction is essential for tumorigenesis. Current research into the interaction between tumor and immunological niches complement tumor pathology beyond cancer genetics. Intrinsic host defense immunity is a specialized innate immunity component to restrict viral infection. However, whether intrinsic immunity participates in tumor pathology is unclear. Previously, we identified a zinc-finger antiviral protein ZAP that is commonly downregulated in a panel of clinical cancer specimens. However, whether ZAP has an impact on tumor development was unknown. Here we report ZAP as a genuine tumor suppressor. Pan-caner analysis with TCGA data from 712 patients and large-scale immunohistochemistry in tissue microarrays from 1552 patients reveal that ZAP is prevalently downregulated, and associated with poor survival in liver, colon, and bladder cancer patients. Ectopic over-expression of ZAP inhibits the malignant phenotypes of colorectal tumor by cell cycle arrest. Using RNA immunoprecipitation and RNA decay assays, we demonstrate that ZAP directly and specifically binds to and degrades the transcript of TRAILR4, which in turn represses TRAILR4 expression and inhibits the aggressiveness of colorectal cancer cells. Furthermore, our CRISPR-engineered mice models show that loss-of-function of ZAP synergizes with APC-deficiency to drive malignant colorectal cancer in vivo. Overall, we identify a previously unknown function of the antiviral factor ZAP in colorectal tumorigenesis, linking intrinsic immunity to tumor pathogenetics.

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Fig. 1: ZAP is downregulated in pan cancer and associated with poor survival.
Fig. 2: ZAP suppresses malignant phenotypes of colorectal cancer in vitro and in vivo.
Fig. 3: ZAP selectively binds and degrades TRAILR4 mRNA.
Fig. 4: ZAP inhibits tumorigenesis by degrading TRAILR4 mRNA.
Fig. 5: Knockout of Zap promotes colorectal carcinogenesis in ApcMin/+ mice.

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Acknowledgements

We acknowledge Prof. Liang Chen and Prof. Tiebang Kang for helps and suggestions to this work. This work was supported by grants from the National Natural Science Foundation of China (No. 81902809 No. 81872886, No. 81773751 No. 81872887, No. 81973342, and No. 81973347), the Fundamental Research Funds for the Central Universities (and No. 18ykpy37), and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the 13th Five-Year Plan Period (No. 2018ZXO9733002).

Funding

JC: the National Natural Science Foundation of China (No. 81902809) and the Fundamental Research Funds for the Central Universities (No. 18ykpy37). WZ: the National Natural Science Foundation of China (No. 81872886). JH: the National Natural Science Foundation of China (No. 81773751). JL: the National Natural Science Foundation of China (No. 81973342). YL: the National Natural Science Foundation of China (No. 81973347). GY: the National Natural Science Foundation of China (No. 81872887) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the 13th Five-Year Plan Period (No. 2018ZXO9733002).

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Conceptualization, JC, JKL and GMY; Methodology, JC, SHW and WFL; Software, XCL; Validation, WCX and JFZ; Investigation, JC, JYZ, ZQ, LG, JD, YL, YL and CWW; Resources, ZW; Writing-Original Draft, JC and JKL; Writing-Review & Editing, GMY, SHW, MS and YL; Supervision, GMY and JKL; Funding Acquisition, JC, WBZ, YL, JH, JKL and GMY.

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Correspondence to Sihan Wu or Jiankai Liang.

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W.C.X., J.F.Z., and M.S. are employers of Guangzhou Virotech Pharmaceutical Co., Ltd (GVP) and performed the animal experiment and manuscript editing. The present research is not funded by GVP. The authors declare no potential conflicts of interest.

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Cai, J., Liu, W., Wong, C.W. et al. Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer. Oncogene 39, 5995–6008 (2020). https://doi.org/10.1038/s41388-020-01416-7

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