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

Jing Cai, Wenfeng Liu, Chun Wa Wong, Wenbo Zhu, Yuan Lin, Jun Hu, Wencang Xu, Jifu Zhang, Max Sander, Zhuo Wang, Jia Dan, Jiayu Zhang, Yang Liu, Li Guo, Zhen Qin, Xincheng Liu, Ying Liu, Guangmei Yan, Sihan Wu, Jiankai Liang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5995-6008
Number of pages14
JournalOncogene
Volume39
Issue number37
DOIs
StatePublished - Sep 10 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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