神经母细胞瘤（Neuroblastoma，NB）是最常见的一种婴儿癌症，前期研究发现高风险NB中，MYCN及信号素4D（Sema4D）均高表达，并检测到Sema4D 5’UTR区域上同时含有MYCN及HIF-1α的转录调控元件，提示Sema4D可能同时在NB的癌基因活化及适应微环境过程中发挥作用。本课题旨在利用CRISPR/Cas9基因编辑技术和基因敲除动物，联合临床标本病理检测等，研究MYCN及HIF-1α两种上游调控元件经Sema4D的促癌作用机制。探讨缺氧微环境存在与否时，MYCN与HIF-1α对Sema4D的调控互作关系。阐明Sema4D通过激活Plexin-B1/Lck信号，促进血管新生及细胞生长多种途径促进NB的转移和形成的分子机制。研究结果将进一步揭示NB中MYCN癌基因及HIF-1α下游新的信号调控网络，发现其中的关键信号分子，探索NB治疗的新靶点和新途径。

Neuroblastoma (NB) is the most common type of infant cancer. Previous studies have found that MYCN and semaphorin 4D (Sema4D) are highly expressed in high-risk NB, and it is detected that Sema4D 5'UTR region contains both MYCN binding sites and hypoxia response elements. These evidences suggest that Sema4D may play a role in both NB oncogene activation and adaptation to the microenvironment ways. This project aims to use the CRISPR/Cas9 gene editing technology and gene knockout animals, combined with clinical specimen pathology, to study the mechanism of Sema4D regulated by MYCN and HIF-1α. We also want to explore the interaction between MYCN and HIF-1α to Sema4D in the presence or absence of hypoxic microenvironment, and then elucidate the molecular mechanism by which Sema4D promotes the tumor metastasis and proliferation of NB by activating multiple pathways of angiogenesis and cell growth by activating Plexin-B1/Lck signaling. The results will further elucidate the new signaling network downstream of MYCN oncogene in NB, and explore the pathogenesis of NB cells that promote cancer by abnormal transcription regulation, ultimately explore new targets and new approaches for NB therapy.