Wang Zhipeng, Wu Yan, Ding Ziqi, Xiao Xinru, Huang Yanhua, Liu Zhiguang, Zhang Qian
Department of Respiratory and Critical Care Medicine, the Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213164, China.
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Cell Mol Biol Lett. 2025 Apr 2;30(1):40. doi: 10.1186/s11658-025-00718-6.
Lung cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related mortality worldwide. Similar to other solid tumors, the development of non-small cell lung cancer (NSCLC) is believed to be a multistep process involving the accumulation of genetic and epigenetic alterations. A-to-I RNA editing is a widespread posttranscriptional epigenetic modification that confers specific nucleotide changes in selected RNA transcripts and plays a critical role in the pathogenesis of many human cancers. However, the mechanisms underlying A-to-I RNA editing that act as a potential driver in the pathogenesis of NSCLC progression remain incompletely elucidated.
Sanger sequencing was performed to validate the CYP1A1_I462V RNA editing event in NSCLC patients. In vitro and in vivo experiments were used to assess the effects of an ADAR1-regulated CYP1A1 and its editing on NSCLC cell growth and metastasis. The crosstalk between CYP1A1_I462V RNA editing and PI3K-AKT signaling was analyzed using RNA sequencing and molecular methods. The functional role of CYP1A1_I462V in the response to oxidative stress was verified through proteomics analysis, co-IP assay, and immunofluorescence assay.
Sanger sequencing analysis identified an increased A-to-I RNA editing ratio of CYP1A1 in NSCLC specimens. This specific RNA editing, regulated by ADAR1, resulted in gain-of-function phenotypes characterized by enhanced tumor progression and more aggressive behavior. The edited form induced the expression of heme oxygenase-1 (HO-1) via PI3K/Akt-dependent activation compared with the wild-type CYP1A1, which led to an enhanced interaction with CYP1A1, thereby promoting the translocation of abundant HO-1 into the nucleus to resist oxidant stress in NSCLC cells.
Our findings highlight that the I462V A-to-I RNA editing event of CYP1A1 drives pulmonary carcinogenesis through inhibiting oxidative stress and suggest that the CYP1A1-HO-1-PI3K/Akt axis may be a potential therapeutic target for NSCLC.
肺癌是全球最常被诊断出的恶性肿瘤，也是癌症相关死亡的主要原因。与其他实体瘤相似，非小细胞肺癌（NSCLC）的发展被认为是一个多步骤过程，涉及遗传和表观遗传改变的积累。A到I RNA编辑是一种广泛存在的转录后表观遗传修饰，它会在选定的RNA转录本中引起特定的核苷酸变化，并在许多人类癌症的发病机制中起关键作用。然而，作为NSCLC进展发病机制中潜在驱动因素的A到I RNA编辑的潜在机制仍未完全阐明。
采用桑格测序法验证NSCLC患者中CYP1A1_I462V RNA编辑事件。利用体外和体内实验评估ADAR1调节的CYP1A1及其编辑对NSCLC细胞生长和转移的影响。使用RNA测序和分子方法分析CYP1A1_I462V RNA编辑与PI3K-AKT信号通路之间的相互作用。通过蛋白质组学分析、免疫共沉淀试验和免疫荧光试验验证CYP1A1_I462V在氧化应激反应中的功能作用。
桑格测序分析确定NSCLC标本中CYP1A1的A到I RNA编辑比率增加。这种由ADAR1调节的特定RNA编辑导致了功能获得性表型，其特征是肿瘤进展增强和行为更具侵袭性。与野生型CYP1A1相比，编辑后的形式通过PI3K/Akt依赖性激活诱导血红素加氧酶-1（HO-1）的表达，这导致与CYP1A1的相互作用增强，从而促进大量HO-1易位到细胞核中以抵抗NSCLC细胞中的氧化应激。
我们的研究结果表明，CYP1A1的I462V A到I RNA编辑事件通过抑制氧化应激驱动肺癌发生，并表明CYP1A1-HO-1-PI3K/Akt轴可能是NSCLC的潜在治疗靶点。
Zotero 插件
