Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization
Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization
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DOI：
10.1016/j.phymed.2022.154299
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发表时间：
2022-07-08
期刊：
影响因子：
7.9
通讯作者：
Pan, Zhanyu
中科院分区：
文献类型：
--
作者：
Cui, Yameng;Wu, Yulin;Pan, Zhanyu
背景资料：N-6-甲基腺苷（m（6）A）已被确定为调节各种肿瘤的发生和发展，包括非小细胞肺癌（NSCLC）。异甘草素（Isoliquiritigenin，ISL）是一种具有抗肿瘤活性的天然药物。目的：研究ISL对非小细胞肺癌（NSCLC）的抑制作用，探讨ISL是否通过调节m（6）A修饰而影响NSCLC的表型。用m（6）A定量分析法测定M（6）A富集。结果：ISL能显著抑制NSCLC细胞的增殖、迁移和侵袭能力。此外，m（6）A阅读器IGF 2BP 3在NSCLC组织中的表达显著高于癌旁组织，并且与NSCLC患者的不良生存率呈正相关。在机制上，ISL减少了m（6）A修饰，下调了NSCLC中IGF 2BP 3的表达。IGF 2BP 3还以m（6）A依赖的方式增强twist家族bHLH转录因子1（TWIST 1）mRNA的稳定性。结论：ISL可能通过靶向IGF 2BP 3/m（6）A/TWIST 1轴发挥抗肿瘤作用。
Background: N-6-methyladenosine (m(6)A) has been identified to regulate the tumorigenesis and development of various tumors, including non-small cell lung cancer (NSCLC). Isoliquiritigenin (ISL), derived from the Chinese herb licorice, shows a significant anti-tumor activity on multiple human cancers. However, the role of ISL on NSCLC through m(6)A is still unclear.Purpose: Here, we investigated the anti-tumor effect of ISL on NSCLC, and explored whether ISL affected the NSCLC phenotype by modulating its m(6)A modification.Methods: Cell proliferation, migration and invasion assays were performed to evaluate the inhibitory effects of ISL on NSCLC cells. M(6)A enrichment was determined by m(6)A quantitative analysis. The mechanism regarding IGF2BP3 was explored using RIP-PCR, MeRIP-qPCR and RNA decay analysis.Results: ISL significantly repressed the proliferation, migration and invasion of NSCLC cells in vitro. In addition, m(6)A reader IGF2BP3 expression significantly increased in NSCLC tissues compared to adjacent tissues, and was positively correlated with NSCLC patients' poor survival. Mechanistically, ISL reduced m(6)A modification and down-regulated IGF2BP3 expression in NSCLC. Furthermore, IGF2BP3 enhanced the mRNA stability of twist family bHLH transcription factor 1 (TWIST1) in m(6)A-dependent manner. Moreover, ISL treatment combined with TWSIT1 knockdown effectively reversed IGF2BP3 overexpression-induced NSCLC cells' proliferation, migration and invasion.Conclusion: Our findings uncover that ISL might function as an anticarcinogen through targeting IGF2BP3/m(6)A/ TWIST1 axis for NSCLC.