Chen Shiqi, Hao Qian, Gan Yu, Tong Jing, Xiong Chen, Liao Quan, Zhang Yang, Ye Ting, Zhou Xiang, Chen Haiquan
Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China.
Cell Death Differ. 2025 Apr 9. doi: 10.1038/s41418-025-01501-y.
Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients, is characterized by its aggressive nature and poor prognosis. In this study, we identify decapping mRNA 1B (DCP1B) as a tumor suppressor gene that is transcriptionally regulated by p53. DCP1B is found to inhibit the growth and migration of NSCLC cells. Consistently, the level of DCP1B expression is decreased in NSCLC tissues, and its low expression is associated with NSCLC patients' unfavorable outcomes. Mechanistic investigations reveal that DCP1B promotes the turnover of mitogen-activated protein kinase 4 (MAPK4) mRNA, and the activation of p53 reduces the expression level of MAPK4 partially through DCP1B. Notably, overexpression of MAPK4 can drive AKT phosphorylation independent of phosphoinositide 3-kinase (PI3K), thus neutralizing the anti-tumor activity of the PI3K inhibitor in NSCLC cells. Moreover, the p53 agonist combined with the PI3K inhibitor can suppress NSCLC proliferation synergistically in vitro and in vivo. Collectively, this study not only uncovers the function and mechanism of the p53-DCP1B-MAPK4 axis in suppressing NSCLC progression but also suggests a promising combination strategy for treating NSCLC.
非小细胞肺癌（NSCLC）约占肺癌患者的85%，其特点是侵袭性强、预后差。在本研究中，我们确定去帽mRNA 1B（DCP1B）为一种受p53转录调控的肿瘤抑制基因。发现DCP1B可抑制NSCLC细胞的生长和迁移。一致的是，NSCLC组织中DCP1B表达水平降低，其低表达与NSCLC患者的不良预后相关。机制研究表明，DCP1B促进丝裂原活化蛋白激酶4（MAPK4）mRNA的周转，p53的激活部分通过DCP1B降低MAPK4的表达水平。值得注意的是，MAPK4的过表达可独立于磷酸肌醇3激酶（PI3K）驱动AKT磷酸化，从而抵消PI3K抑制剂在NSCLC细胞中的抗肿瘤活性。此外，p53激动剂与PI3K抑制剂联合应用可在体外和体内协同抑制NSCLC增殖。总的来说，本研究不仅揭示了p53-DCP1B-MAPK4轴在抑制NSCLC进展中的功能和机制，还提出了一种有前景的NSCLC治疗联合策略。
