NIPBL通过RAD21激活Wnt信号通路促进非小细胞肺癌侵袭转移的机制研究

Lung cancer is one of the most common malignant tumors. Currently, although the targeted therapy for lung cancer is progressing rapidly, some lung cancer patients are still not obatining the best precise treatment. NIPBL, a loading factor of Cohesin, its desregulation is closely related to the occurrence and development of many tumors. RAD21, a key subunit of Cohesin complex, has been found in our previous studies that it is not only associated with NIPBL, but also may be involved in the invasion and metastasis of lung cancer via Wnt signaling pathways. Therefore, we speculate whether the interactions between NIPBL and RAD21 could modulate the progression of lung cancer? According to the previous studies, we firstly collected samples from clinical lung cancer patients to detect the expression level of RAD21 and explored its significance. Then, we used the in vitro lung cancer cell model to investigate the biological role of RAD21 in lung cancer cell lines and its upstream regulatory mechanism of NIPBL and downstream pathways; Finally, nude mice transplantation tumor experiment was performed to further verify the role of NIPBL and RAD21 in the pathogenesis of lung cancer and their regulatory mechanisms. Through this research, we aimed to provide new ideas for the future diagnosis and treatment of lung cancer.

肺癌是呼吸系统常见的恶性肿瘤之一。尽管目前对肺癌的靶向治疗进展迅速，但仍有部分肺癌患者无法得到最佳的精准治疗。NIPBL作为染色体黏着素（Cohesin）的装载因子，其过表达与多种肿瘤的发生发展有着密切的关系。RAD21作为Cohesin复合体的一个重要组成亚基，前期研究发现，RAD21不仅与转录因子NIPBL密切相关，还可能通过Wnt信号通路参与肺癌的侵袭转移。因此，我们猜测是否NIPBL与RAD21相互作用调控着肺癌的进展？本课题拟在前期研究的基础上，首先，采集临床肺癌患者样本，检测RAD21的表达水平及其意义；随后，利用体外肺癌细胞模型，探讨RAD21在肺癌细胞株中的生物学作用及其上游分子NIPBL和下游通路的调控机制；最后，采用裸鼠移植瘤实验，验证NIPBL与RAD21在肺癌发病中的作用及其调控机制。通过此研究，我们希望能够为未来肺癌的诊断及治疗提供新的思路。

肺癌是癌症相关死亡的主要原因，也是当今世界的第一大恶性肿瘤。然而，肺癌患者的5年生存率仅为4-17%。因此，迫切需要探索新的肺癌早期诊断标志物和治疗靶点。本研究表明，RAD21在肺癌组织和细胞系中上调，RAD21表达是肺癌患者OS的独立预后因素。此外，RAD21在体外和体内的肺癌中都发挥了致癌作用。在机制上，Nipped-B 样蛋白 (NIPBL) 通过将赖氨酸去甲基化酶 6B (KDM6B) 募集到 RAD21 基因启动子来增强 组蛋白 H3 赖氨酸 27 (H3K27)去甲基化来促进 RAD21 基因转录。此外，RAD21 增强 PI3K 基因转录作为转录因子。此外，NIPBL 通过破坏 EZH2 和 RAD21 蛋白之间的关联，逆转了 zeste 2 多梳抑制复合物 2 亚基 (EZH2) 对 RAD21 介导的 PI3K 基因转录的影响。此外，RNA甲基化通过提高NIPBL mRNA稳定性提高了NIPBL mRNA水平。这些发现有助于发现新的肺癌诊断标志物和治疗靶点。