BACKGROUND Abnormal expression of the orphan nuclear receptor Nurr1 is a critical factor in the etiology of multiple cancers. However, its potential role in gastric cancer (GC) remains elusive. In this study, we have demonstrated that the expression of Nurr1 was elevated and had an oncogenic function in GC. METHODS Nurr1 expression was analyzed in clinical specimens and the GEO database. Functions of Nurr1 in GC cells were analyzed using Nurr1 knockdown and overexpression. Various cell and molecular biological methods were used to explore the potential mechanisms of Nurr1 upregulation and its role in promoting GC. FINDINGS Overexpression of Nurr1 was directly related to the poor prognosis of GC patients. What's more, Nurr1 was induced by Helicobacter pylori (H. pylori) via the PI3K/AKT-Sp1 pathway. Sp1 enhanced Nurr1 expression by binding to its promoter to activate the transcription. Upregulated Nurr1 then directly targeted CDK4 by binding to its promoter region to increase its expression, thereby facilitated GC cells proliferation both in vitro and in vivo. INTERPRETATION We identified Nurr1 as a driving oncogenic factor in GC. In addition, Nurr1 could be used as a potential therapeutic target for the diagnosis and treatment of H. pylori-associated GC. FUNDING This work was supported by the National Natural Science Foundation of China (Nos 81801983, 81871620, 81971901, 81772151 and 81571960), and the Department of Science and Technology of Shandong Province (2018CXGC1208).

中文翻译：

---

孤儿核受体 Nurr1 通过直接增强 CDK4 表达促进幽门螺杆菌相关胃癌发生。


背景孤儿核受体Nurr1的异常表达是多种癌症病因学的关键因素。然而，它在胃癌（GC）中的潜在作用仍然难以捉摸。在本研究中，我们证明 Nurr1 的表达升高并在 GC 中具有致癌功能。方法分析临床标本和GEO数据库中的Nurr1表达。使用 Nurr1 敲低和过表达分析 Nurr1 在 GC 细胞中的功能。采用各种细胞和分子生物学方法探索Nurr1上调的潜在机制及其促进GC的作用。研究发现 Nurr1 过度表达与 GC 患者预后不良直接相关。此外，Nurr1 是由幽门螺杆菌 (H. pylori) 通过 PI3K/AKT-Sp1 途径诱导的。 Sp1 通过结合 Nurr1 的启动子来激活转录，从而增强 Nurr1 的表达。上调的Nurr1然后通过结合CDK4的启动子区域来直接靶向CDK4以增加其表达，从而促进GC细胞在体外和体内的增殖。解释 我们确定 Nurr1 是 GC 的驱动致癌因子。此外，Nurr1可作为诊断和治疗幽门螺杆菌相关GC的潜在治疗靶点。资助这项工作得到了国家自然科学基金（Nos 81801983、81871620、81971901、81772151和81571960）和山东省科学技术厅（2018CXGC1208）的支持。