Jin Minhan, Wang Yuhui, Song Mingze, Guo Wenfei, Li Shirong, Pu Zeqing
Department of Clinical Laboratory, WeiFang People's Hospital, Shandong Second Medical University, Weifang, China.
School of Medical Laboratory, Shandong Second Medical University, Weifang, China.
Front Oncol. 2025 Jul 1;15:1566598. doi: 10.3389/fonc.2025.1566598. eCollection 2025.
As a malignant tumor with high morbidity and mortality, lung cancer is associated with a variety of risk factors, including smoking, exposure to occupational carcinogens, familial inheritance, and chronic lung disease. Lung cancer is often detected late and has a complex pathogenesis, so early diagnosis and intervention of lung cancer are essential. Finding effective targets is important to develop new treatments for lung cancer. As a member of Group 4A of the nuclear receptor subfamily, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) is an immediate early gene that encodes a transcription factor that plays a regulatory role when the cell and tissue microenvironment changes. NR4A1 plays a pro-cancer role in solid tumors including lung cancer, but a tumor suppressor role in hematological malignancies. NR4A1 palys a role through multiple mechanisms in lung cancer, including promoting cell proliferation by forming a complex with p300/specific protein 1 (Sp1) and acting on the survivin and AMP-activated protein kinase (AMPK)/mechanistic Target of Rapamycin Complex 1 (mTORC1) pathways, promoting metastasis and invasion by inducing the occurrence of transforming growth factor-β (TGF-β) dependent epithelial-mesenchymal transition (EMT), promoting vascular remodeling by acting on vascular endothelial growth factor A (VEGF-A), promoting immune escape by acting on programmed cell death-1 (PD-1) dependent T cell exhaustion, promoting cell apoptosis interacted with B-cell lymphoma-2 (Bcl-2) and promoting metabolic reprogramming by increasing fatty acid oxidation. In recent years, several studies on NR4A1-related agonists and inhibitors in lung cancer have been reported. These compounds are expected to become drugs for targeted tumor therapy, but current research is limited to cellular and animal experiments. It still takes time to verify and evaluate clinical applications, other biological effects and potential side effects. This review summarizes the biological role of NR4A1 in lung cancer and describes the molecular mechanisms and signaling pathways regulated by NR4A1. This paper will provide a theoretical basis for the early treatment of lung cancer by using NR4A1-related compounds in the clinic.
肺癌作为一种发病率和死亡率都很高的恶性肿瘤，与多种风险因素相关，包括吸烟、接触职业致癌物、家族遗传和慢性肺病。肺癌往往发现较晚且发病机制复杂，因此肺癌的早期诊断和干预至关重要。寻找有效的靶点对于开发肺癌新疗法很重要。作为核受体亚家族4A组的成员，核受体亚家族4A组成员1（NR4A1）是一种立即早期基因，编码一种转录因子，在细胞和组织微环境变化时发挥调节作用。NR4A1在包括肺癌在内的实体瘤中发挥促癌作用，但在血液系统恶性肿瘤中发挥抑癌作用。NR4A1在肺癌中通过多种机制发挥作用，包括与p300/特异性蛋白1（Sp1）形成复合物并作用于生存素和AMP激活蛋白激酶（AMPK）/雷帕霉素复合物1（mTORC1）途径来促进细胞增殖，通过诱导转化生长因子-β（TGF-β）依赖性上皮-间质转化（EMT）的发生来促进转移和侵袭，通过作用于血管内皮生长因子A（VEGF-A）来促进血管重塑，通过作用于程序性细胞死亡蛋白1（PD-1）依赖性T细胞耗竭来促进免疫逃逸，通过与B细胞淋巴瘤-2（Bcl-2）相互作用促进细胞凋亡以及通过增加脂肪酸氧化来促进代谢重编程。近年来，已有几项关于肺癌中NR4A1相关激动剂和抑制剂的研究报道。这些化合物有望成为靶向肿瘤治疗药物，但目前的研究仅限于细胞和动物实验。验证和评估其临床应用、其他生物学效应和潜在副作用仍需时间。本综述总结了NR4A1在肺癌中的生物学作用，并描述了NR4A1调节的分子机制和信号通路。本文将为临床使用NR4A1相关化合物早期治疗肺癌提供理论依据。
