C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer
C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer
复制标题
C-myc/miR-150/EPG5轴介导的自噬功能障碍促进非小细胞肺癌的发生
DOI：
10.7150/thno.34887
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
--
作者：
Li, Hui;Liu, Juan;Zhang, Bin
理由：肺癌是全世界癌症死亡的主要原因，治疗选择主要限于细胞毒性药物。在这里，我们揭示了 miR-150 在非小细胞肺癌 (NSCLC) 发展中的新作用，并寻找潜在的新治疗靶点。方法：采用体外和体内分子方法检测 miR-150 介导的 NSCLC 细胞自噬功能障碍。 miR-150 的上游调控元件和下游靶标在体外得到鉴定并在体内得到验证。潜在的治疗方法（抗 c-myc 或抗 miR-150）在体外和体内进行了测试。 c-myc/miR-150/EPG5 轴在 NSCLC 中的临床相关性在人类临床样本和大型基因组数据库中得到了验证。结果：miR-150通过直接抑制EPG5来阻断自噬体和溶酶体的融合。 miR-150介导的自噬缺陷诱导内质网应激并增加细胞ROS水平和DNA损伤反应，并促进NSCLC细胞增殖和肿瘤生长。 EPG5 的敲低促进了 NSCLC 细胞增殖，并减弱了 miR-150 的作用。 c-myc基因被确定为miR-150转录因子，可增加miR-150的积累，因此从药理学或遗传学上抑制c-myc/miR-150表达可显着抑制体外和体内NSCLC细胞的生长。 c-myc 和 miR-150 在 NSCLC 中均显着过表达，而 EPG5 在 NSCLC 中下调。这些分子的表达水平具有良好的相关性，并且与患者的存活率也具有良好的相关性。结论：我们的研究结果表明，c-myc/miR-150/EPG5 介导的自噬功能障碍有助于 NSCLC 的发展，这可能为 NSCLC 提供潜在的新诊断和治疗靶点。
Rationale: Lung cancer is the leading cause of cancer death worldwide, and treatment options are limited to mainly cytotoxic agents. Here we reveal a novel role of miR-150 in non-small cell lung cancer (NSCLC) development and seek potential new therapeutic targets. Methods: The miR-150-mediated autophagy dysfunction in NSCLC cells were examined using molecular methods in vitro and in vivo. The upstream regulatory element and downstream target of miR-150 were identified in vitro and validated in vivo. Potential therapeutic methods (anti-c-myc or anti-miR-150) were tested in vitro and in vivo. Clinical relevance of the c-myc/miR-150/EPG5 axis in NSCLC was validated in human clinical samples and large genomics database. Results: miR-150 blocked the fusion of autophagosomes and lysosomes through directly repressing EPG5. The miR-150-mediated autophagy defect induced ER stress and increased cellular ROS levels and DNA damage response, and promoted NSCLC cell proliferation and tumor growth. Knockdown of EPG5 promoted NSCLC cell proliferation, and attenuated the effects of miR-150. c-myc gene was identified as a miR-150 transcriptional factor which increased miR-150 accumulation, therefore pharmacologically or genetically inhibiting c-myc/miR-150 expression significantly inhibited NSCLC cell growth in vitro and in vivo. Both c-myc and miR-150 were significantly over-expressed in NSCLC, while EPG5 was down-regulated in NSCLC. Expression levels of these molecules were well correlated, and also well correlated with patient survival. Conclusions: Our findings suggest that c-myc/miR-150/EPG5 mediated dysfunction of autophagy contributes to NSCLC development, which may provide a potential new diagnostic and therapeutic target in NSCLC.