本课题组发现，新型溶瘤病毒M1的肿瘤靶向性依赖于生物标志物Zc3hav1 (ZAP)（PNAS，2014；2017）。申请者的预实验发现：ZAP在多种恶性肿瘤中低表达，且ZAP表达量越低，病人生存期越短；细胞和动物实验发现，过表达ZAP抑制肿瘤恶性表型；ZAP敲除导致小鼠发生肿瘤，生存期显著缩短；初步的机制研究提示ZAP抑制抗凋亡蛋白TRAILR4的表达。这些证据强烈提示，ZAP可能是一个新的抑癌基因，这构成了本项目的科学问题。本项目拟在更多细胞上确证ZAP的肿瘤抑制作用；利用已构建和获得的ZAP敲除且p53突变或c-myc过表达或Apc突变小鼠，确证ZAP的抑癌功能；使用大规模临床患者标本进一步确证ZAP表达水平与肿瘤发生和病人生存期间的关系；深入阐明ZAP抑制肿瘤的分子机制。本项目有望发现和阐释一种新的抑癌基因，为肿瘤的发生学提供重要理论成果；同时为溶瘤病毒M1的治疗学提供生物标志物。

Our group found that tumor-targeting of the novel oncolytic virus M1 depends on the biomarker of tumor: Zc3hav1 (ZAP) （PNAS，2014；2017）. Pre-experiments from the applicant discovered that: ZAP exhibts deficiency in a variety of malignant tumors, and the lower the expression of ZAP, the shorter the patient's survival; Cellular and animal experiments indicated that the overexpression of ZAP inhibits the malignant phenotype of tumor cells; Knockout of ZAP induces tumors occurrence in mice, and significantly shorten survival; Preliminary mechanism studies suggest that ZAP inhibits the expression of the anti-apoptotic protein TRAILR4. These evidences strongly suggest that ZAP may function as a new tumor suppressor gene. This project intends to confirm the tumor suppressive function of ZAP on more cell lines; To utilize the constructed and obtained ZAP knockout and p53 mutant or c-myc overexpression or Apc mutant genetically engineered mice to confirm the tumor suppressor function of ZAP; To use large-scale clinical patient specimens to further confirm the relationship between ZAP expression levels and tumorigenesis and survival in patients; To elucidation the detail molecular mechanism by which ZAP inhibits tumorigenesis. This project is expected to identify and elucidate a kind of new tumor suppressor gene that provides important results for tumorigenesis; More over, the project is also expected to provide biomarker for oncolytic virus M1.