miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1
miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1
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miR-30 家族减少通过靶向癌基因 TM4SF1 维持 NSCLC 起始细胞的自我更新并促进肿瘤发生
DOI：
10.1016/j.ymthe.2018.09.006
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发表时间：
2018-12-05
影响因子：
12.4
通讯作者：
Fu, Da
中科院分区：
文献类型：
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作者：
Ma, Yu-Shui;Yu, Fei;Fu, Da
越来越多的证据表明，肿瘤起始细胞（TIC）与肿瘤的发生、发展、复发和耐药性的形成有关。microRNA（miRNA）通过直接调节TIC触发的非小细胞肺癌（NSCLC）的靶点发挥重要的功能作用，但miR-30家族在TIC中的功能知之甚少。在这项研究中，我们发现miR-30家族在NSCLC细胞球体形成过程中下调，miR-30 a/c表达较低的患者的总生存期（OS）和无进展生存期（PFS）较短。此外，跨膜4超家族成员1（transmembrane 4 super family member 1，TM 4SF 1）被证实是miR-30 a/c的直接靶点。伴随的miR-30 a/c低表达和TM 4SF 1高表达与NSCLC患者中较短的中位OS和PFS相关。miR-30 a/c通过抑制其靶基因TM 4SF 1，在体内外显著抑制干细胞样特征，进而抑制mTOR/AKT信号通路的活性。因此，我们的数据提供了第一个证据，即TM 4SF 1是miR-30 a/c的直接靶点，并且miR-30 a/c通过靶向TM 4SF 1抑制NSCLC细胞的干细胞性和增殖，这表明miR-30 a/c和TM 4SF 1可能可用作NSCLC患者诊断和治疗的肿瘤生物标志物。
Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.