Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer
Zinc-finger antiviral protein acts as a tumor suppressor in colorectal cancer
复制标题
锌指抗病毒蛋白在结直肠癌中充当肿瘤抑制因子
DOI：
10.1038/s41388-020-01416-7
复制
发表时间：
2020-08-07
期刊：
影响因子：
8
通讯作者：
Liang, Jiankai
中科院分区：
文献类型：
--
作者：
Cai, Jing;Liu, Wenfeng;Liang, Jiankai
避免免疫破坏对于肿瘤发生是至关重要的。目前对肿瘤和免疫小生境之间相互作用的研究补充了癌症遗传学以外的肿瘤病理学。宿主固有防御免疫是一种特异性的天然免疫成分，用于限制病毒感染。然而，内源性免疫是否参与肿瘤病理尚不清楚。以前，我们发现了一种锌指抗病毒蛋白ZAP，该蛋白在一组临床癌症标本中通常下调。然而，ZAP是否对肿瘤发展有影响尚不清楚。在这里，我们报告ZAP作为一个真正的肿瘤抑制剂。712例患者的TCGA数据和1552例患者组织微阵列中的大规模免疫组织化学的泛癌分析表明，ZAP是predicted下调，并与肝癌，结肠癌和膀胱癌患者的生存率低相关。ZAP异位表达通过细胞周期阻滞抑制结直肠肿瘤恶性表型使用RNA免疫沉淀和RNA衰变测定，我们证明ZAP直接特异性结合并降解TRAILR4的转录物，这反过来又抑制TRAILR4的表达并抑制结直肠癌细胞的侵袭性。此外，我们的CRISPR工程小鼠模型表明，ZAP功能丧失与APC缺陷协同作用，在体内驱动恶性结直肠癌。总的来说，我们确定了一个以前未知的功能，抗病毒因子ZAP在结直肠肿瘤的发生，连接固有免疫肿瘤发病机制。
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.