| 韩秋月,王正阳,曲扬,等.在斑马鱼DNA损伤模型中Ypel3与p53互作关系的研究[J].中国海洋药物,2024,43(4):51-59. |
| 在斑马鱼DNA损伤模型中Ypel3与p53互作关系的研究 |
| Exploration the relationship between Ypel3 and p53 in zebrafish DNA lesion models |
| 投稿时间：2023-04-04 修订日期：2023-05-08 |
| DOI：10.13400/j.cnki.cjmd.2024.04.003 |
| 中文关键词: ypel3 斑马鱼 抗肿瘤药物筛选模型 p53 |
| English Keywords:ypel3 zebrafish model of screening anti-tumor drugs p53 |
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| 中文摘要: |
| 目的 YPEL3(Yippee-like 3)是p53(tumor protein 53)信号通路的靶基因,其与肿瘤的发生发展密切相关。DNA损伤的靶向治疗可以增强抗肿瘤免疫反应,但目前机制还有待完善。本研究利用紫外线(UV)和依托泊苷(Epotoside,ETO)分别诱导DNA损伤,随后检测Ypel3与p53信号通路在DNA损伤后的应答反应,以期揭示物理损伤和化疗药物产生的DNA损伤应答差异,探索增强抗肿瘤免疫反应的新靶点。方法 利用CRISPR/Cas9基因编辑技术,在模式生物斑马鱼中构建ypel3基因敲除突变体,通过UV辐射及抗癌药物ETO处理斑马鱼胚胎,结合实时荧光定量PCR技术,探究在物、化异常产生的DNA损伤环境中,Ypel3与p53信号通路间的互作关系。结果 在受精后24小时(hpf,hours post fertilization),UV辐射诱导DNA损伤引起野生型斑马鱼胚胎p53转录水平上调, ypel3也随之显著上调；与野生型胚胎相比,ypel3突变体受UV辐射后p53转录水平上调更为显著。然而,在ETO诱导的斑马鱼DNA损伤模型中,ypel3突变对p53转录水平的调控略有下调,不同于UV辐射。结论 本研究在斑马鱼中验证了ypel3是p53信号通路的靶基因,在UV物理损伤及ETO化学物质诱导的DNA损伤模型中,Ypel3对 p53转录水平发挥不同的作用,提示Ypel3对抗肿瘤免疫反应有重要影响。本研究聚焦于肿瘤相关DNA损伤,构建UV诱导的皮肤癌相关药物筛选模型,为抗肿瘤和抗肿瘤免疫反应相关研究提供新思路。 |
| English Summary: |
| Objective YPEL3 is the target of p53 pathway, which is closely related to the occurrence and development of tumors. Targeted therapy of DNA lesion enhances anti-tumor immune response, but the mechanism remains to be perfected. In this study, ultraviolet (UV) and Epotoside (ETO) were used to induce DNA lesion to investigate the relationship of Ypel3 and p53 pathway. Besides, we want to reveal the differences in DNA lesion response caused by physical damage and chemotherapy drugs to explore new target for enhancing anti-tumor immune response. Methods The ypel3 knockout mutant was constructed using CRISPR/Cas9 system. The relationship of Ypel3 and p53 pathway were investigated by the UV and ETO treatment of zebrafish embryos and real-time quantitative PCR. Results In wild-type (WT) zebrafish, when its DNA lesion was induced by exposing UV and the transcriptional level of p53 was upregulated, ypel3 was also significantly upregulated, which is not the case in ypel3 mutant. In addition, compared with wild-type embryos, the upregulation of p53 in ypel3 mutant was more significant after exposing UV. However, in zebrafish DNA lesion model induced by ETO, p53 up-regulation degree of ypel3 MZ mutants was less than that of WT, which is different from UV radiation. Conclusion In summary, ypel3 is the target gene of P53 in zebrafish. In addition, in DNA lesion models induced by UV and ETO, Ypel3 plays different roles on p53, suggesting that Ypel3 has an important effect on anti-tumor immune response. This study focused on tumor-related DNA lesion and constructed an skin cancer drug screening model related to UV, providing new ideas for the study of anti-tumor immune response. |
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