Guo Yuefan, Wang Guangxue, Wang Zhongrui, Ding Xin, Qian Lu, Li Ya, Ren Zhen, Liu Pengfei, Ma Wenjing, Li Danni, Li Yuan, Zhao Qian, Lü Jinhui, Li Qinchuan, Wang Qinhong, Yu Zuoren
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Jinzhou Medical University, School of Basic Medical, Jinzhou, China.
Front Cell Dev Biol. 2021 Apr 20;9:663279. doi: 10.3389/fcell.2021.663279. eCollection 2021.
Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133 CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.
癌症干细胞（CSCs）在非小细胞肺癌（NSCLC）的癌症起始、转移和耐药性中发挥作用。在此，我们鉴定出miR-221/222簇是NSCLC中CSCs的一种新型调节因子。在NSCLC细胞中靶向过表达或敲低miR-221/222揭示了miR-221/222在调节肺癌细胞增殖、乳腺球形成、CD133 CSCs亚群以及包括OCT4、NANOG和h-TERT在内的干性基因表达中的重要作用。动物研究表明，miR-221/222的过表达显著增强了肺癌细胞形成肿瘤和生长更快的能力，表明miR-221/222在肿瘤发生和肿瘤生长中的重要性。机制上，发现Reck是NSCLC中miR-221/222的关键直接靶基因。miR-221/222的过表达显著抑制Reck表达，激活Notch1信号并增加NICD水平。作为Notch1的激活形式，NICD导致NSCLC细胞干性增强。此外，用siRNA敲低Reck不仅模拟了miR-221/222的作用，还证明了Reck参与miR-221/222诱导的Notch1信号激活，验证了miR-221/222-Reck-Notch1轴在调节NSCLC细胞干性中的重要作用。这些发现揭示了一种新机制，即miR-221/222可显著调控肺CSCs，并为NSCLC的治疗提供了一个潜在的治疗靶点。
