假尿苷酸合酶7(PUS7)促进神经母细胞瘤发生发展的作用及机制研究

Neuroblastoma (NB) is the most common malignant extracranial solid tumor in children. MYCN gene amplification is closely related to the occurrence and development of disease and the poor prognosis. However, the mechanism of MYCN mediating neuroblastoma is still not fully understood. Pseudouridine synthase 7 (PUS7) is a novel gene that we screened for possibly regulated by MYCN and plays an important role in NB. Our preliminary experiments showed that PUS7 gene could promote the proliferation and colony forming ability of NB cells and inhibit the apoptosis of NB cells. Animal experiments suggest that down-regulation of PUS7 expression significantly inhibits the growth of xenografts in nude mice; PUS7 may affect the expression of BCL2, EGFR and other genes via RNA pseudouridine modification; high expression of PUS7 is closely related to poor prognosis of NB. It is speculated that PUS7 in NB is regulated by N-myc, and PUS7 regulates the expression of a series of functional genes by affecting RNA pseudouridine modification, thereby promoting the development of NB. This project intends to further study the entry point of PUS7-mediated RNA pseudouridine modification and study the function and mechanism of PUS7 in promoting the development of NB, and provide a new theoretical basis and potential targets for the prevention and treatment of NB.

神经母细胞瘤(NB)是儿童最常见的恶性颅外实体肿瘤，MYCN基因扩增与疾病的发生发展和不良预后密切相关，而MYCN在其中发挥的具体机制仍不完全清楚。假尿苷酸合酶7(PUS7)是我们筛选发现的一个新的可能受MYCN调控的基因，并且在NB中发挥重要作用。预初实验显示：PUS7基因可以促进NB细胞的增殖和集落形成能力，抑制NB细胞的凋亡；动物实验提示下调PUS7基因表达显著抑制裸鼠移植瘤的生长；PUS7可能通过影响RNA假尿苷修饰调控BCL2、EGFR等基因的表达；PUS7高表达与NB预后不良密切相关。据此推测，NB中PUS7受MYCN转录调控，PUS7通过影响RNA假尿苷修饰，调控一系列功能基因的表达，从而推动NB发生发展。本项目拟进一步以PUS7介导RNA假尿苷修饰为机制研究切入点，系统研究PUS7促进NB发生发展的功能，揭示其机制，为NB的防治提供新的理论依据和潜在的干预靶标。

神经母细胞瘤(Neuroblastoma,NB)是儿童最常见的恶性颅外实体肿瘤，MYCN基因扩增与疾病的发生发展和不良预后密切相关，而MYCN在其中发挥的具体机制仍不完全清楚。因此，以筛选神经母细胞瘤中的MYCN靶基因为切入点，深入研究并完善神经母细胞瘤的发病机制，可为改善临床治疗、提高患者的生活质量及无瘤生存率提供新的策略。我们筛选发现假尿苷酸合酶7(PUS7)是一个新的可能受MYCN调控的基因，PUS7高表达与NB预后不良密切相关。我们的研究表明PUS7可以促进NB细胞的增殖和集落形成能力，抑制NB细胞的凋亡；动物实验提示，干扰PUS7基因表达显著抑制裸鼠移植瘤的生长。我们筛选发现SAPCD2是PUS7的潜在下游基因，首次提出SAPCD2表达水平可影响NB细胞E2F7核质分布和E2F通路活性，调控NB发生发展。本研究明确了PUS7及其下游基因SAPCD2在神经母细胞瘤中的功能，并进一步揭示了其作用机制，为儿童神经母细胞瘤中的防治提供新的理论依据和潜在的干预靶标。相关成果在本领域著名期刊发表第一作者、通讯作者SCI论文4篇。