三尖杉酯碱靶向PARP-1通过METTL3介导TS的甲基化修饰抑制肺癌血管新生的机制研究

三尖杉酯碱（HT）是三尖杉属植物的主要活性成分，临床用于治疗血液瘤疾病。申请者发现HT具有抗肺癌血管新生的作用，但其机制尚不清楚。进一步研究发现HT能够靶向抑制PARP-1酶活性且抑制肺癌细胞分泌VEGF。此外申请者还发现PARP-1能够与TS mRNA结合并促进TS表达。申请者已报道过TS调控肺癌细胞分泌VEGF促进血管新生的机制。但HT对肺癌细胞分泌VEGF的抑制是否与TS和PARP-1相关，尚待研究。本研究拟在明确HT与PARP-1构效关系的基础上，通过研究PARP-1与TS mRNA结合招募METTL3介导TS的甲基化修饰的作用，进而阐明PARP-1调控METTL3/TS/VEGF/VEGFR-2信号通路促进肺癌血管新生的机制，并在荷瘤鼠和肺原位癌鼠模型上验证HT靶向抑制PARP-1酶活性发挥抗肺癌血管新生的作用。该研究为拓展三尖杉属中药活性成分的应用提供了新的方向。

Harringtonine (HT) is the main active component of Cephalotaxus, which is used to treat the hematoma. The applicant found that HT has an anti-angiogenesis effect on lung cancer, but its mechanism is still unclear. Further studies showed that HT could inhibit the activity of PARP-1 and the secretion of VEGF in lung cancer cells. Besides, the applicant also found that PARP-1 could bind to TS mRNA and promote TS expression. The applicant has reported the mechanism of TS regulating VEGF secretion and promoting angiogenesis in lung cancer cells. However, whether the inhibition of VEGF secretion by HT is related to TS and PARP-1 remains to be studied. Based on the clarification of the structure-activity relationship between HT and PARP-1, this study intends to study PARP-1 and TS mRNA's role in recruiting METTL3 to mediate the methylation modification of TS. To elucidate the mechanism of PARP-1 regulating the METTL3/TS/VEGF/VEGFR-2 signaling pathway to promote angiogenesis of lung cancer, we also verified the anti-angiogenesis effect of HT targeting inhibition of PARP-1 enzyme activity in Xenograft tumor mice and lung cancer in situ mouse models. This study provides a new direction for expanding the application of the active components of Cephalotaxus.