Department of Cardiovascular and Thoracic Surgery, Jingzhou Central Hospital, Second Clinical Medical College of Yangtze University, Jingzhou, Hubei, China.
Anticancer Drugs. 2021 Apr 1;32(4):376-385. doi: 10.1097/CAD.0000000000000979.
Activation and proliferation of cancer stem cells exert an important role in the invasion, metastasis, and recurrence of malignant tumors, including lung cancer. Therefore, exploring molecular targets related to self-renewal and mobility of lung cancer stem cells has important clinical significance. In our present study, we aimed to explore the effects of miR-138-5p on lung cancer stem-like cells and associated regulatory mechanism. In our present study, enhanced self-renewal capacity and elevated expression of cancer stem cells markers CD133, CD44, aldehyde dehydrogenase 1 of lung cancer stem-like cells derived from A549 cells were firstly verified. Then, obviously enhanced autophagy was found in lung cancer stem-like cells compared with parental cells A549. Besides, we found that enhanced autophagy induced by rapamycin promoted self-renewal and cell mobility of lung cancer stem-like cells and suppression of autophagy by 3-methyladenine exerted just opposite effects. In addition, miR-138-5p was found to be downregulated in lung cancer stem-like cells compared with that in parental cell A549. At the same time, overexpression of miR-138-5p by transfected with miR-138-5p mimic was found to effectively suppress self-renewal and invasion of lung cancer stem-like cells. Further study revealed that ATG7 was a target of miR-138-5p and overexpressed miR-138-5p suppressed ATG7-mediated autophagy. In addition, specific small interference RNA-ATG7 strengthened the inhibiting effect of miR-138-5p mimic on self-renewal and invasion of lung cancer stem-like cells. Taken together, we found that autophagy helped to maintain self-renewal and invasion ability of lung cancer stem-like cells and overexpressed miR-138-5p exerted anti-tumor effects by blocking the self-renewal and invasion of lung cancer stem-like cells through suppressing ATG7-mediated autophagy.
癌症干细胞的激活和增殖在包括肺癌在内的恶性肿瘤的侵袭、转移和复发中发挥着重要作用。因此，探索与肺癌干细胞自我更新和迁移相关的分子靶点具有重要的临床意义。在本研究中，我们旨在探讨 miR-138-5p 对肺癌干细胞样细胞的影响及其相关调控机制。
在本研究中，我们首先验证了来自 A549 细胞的肺癌干细胞样细胞的自我更新能力增强和癌症干细胞标志物 CD133、CD44、乙醛脱氢酶 1 的表达升高。然后，与亲本细胞 A549 相比，我们发现肺癌干细胞样细胞中明显增强的自噬。此外，我们发现雷帕霉素诱导的自噬增强促进了肺癌干细胞样细胞的自我更新和细胞迁移，而 3-甲基腺嘌呤抑制自噬则产生相反的效果。此外，与亲本细胞 A549 相比，我们发现 miR-138-5p 在肺癌干细胞样细胞中下调。同时，通过转染 miR-138-5p 模拟物过表达 miR-138-5p 发现可有效抑制肺癌干细胞样细胞的自我更新和侵袭。进一步研究表明，ATG7 是 miR-138-5p 的靶标，过表达 miR-138-5p 抑制 ATG7 介导的自噬。此外，特异性小干扰 RNA-ATG7 增强了 miR-138-5p 模拟物对肺癌干细胞样细胞自我更新和侵袭的抑制作用。
综上所述，我们发现自噬有助于维持肺癌干细胞样细胞的自我更新和侵袭能力，而过表达 miR-138-5p 通过抑制 ATG7 介导的自噬来阻断肺癌干细胞样细胞的自我更新和侵袭，从而发挥抗肿瘤作用。
