miR-4448/Girdin/Akt/AMPK 轴抑制小细胞肺癌中 EZH2 介导的 EMT 和肿瘤发生。
miR-4448/Girdin/Akt/AMPK axis inhibits EZH2-mediated EMT and tumorigenesis in small-cell lung cancer.
机构信息
Department of Respiratory Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.
Department of Pathology, School of Medicine, International University of Health and Welfare, Minato-ku, Tokyo, Japan.
出版信息
Cancer Med. 2024 Oct;13(19):e70093. doi: 10.1002/cam4.70093.
BACKGROUND
Small-cell lung cancer (SCLC) shows high enhancer of zeste homolog 2 (EZH2) expressions. EZH2-mediated epigenetics promote epithelial-mesenchymal transition (EMT), enhancing invasive and metastatic potential in malignancies. MicroRNAs (miRNAs), small noncoding RNAs, modulate EMT, determining tumor phenotypes. However, the association between miRNAs and EZH2 in SCLC remains to be clarified-we aimed to identify a novel tumorigenic mechanism through miRNAs, EZH2, and EMT in SCLC, leading to future therapeutic applications.
METHODS
We analyzed EZH2 and E-cadherin expressions in lung cancer cell lines and tumor tissues from 34 SCLC patients and confirmed EZH2 siRNA-mediated EMT inhibition. miRNA expression profiles were compared between EZH2 knockdown SCLC cells and negative control SCLC cells using miRNA array. We identified a target miRNA of EZH2 showing expressional differences in EZH2-knockdown cells and analyzed the impact of the miRNA on EZH2-mediated EMT and tumorigenesis.
RESULTS
All SCLC cells showed increased EZH2 and decreased E-cadherin expressions. SCLC tissues had higher EZH2 and lower E-cadherin expressions than other lung cancer tissues. miRNA array revealed that miR-4448 expression increased in EZH2-knockdown SCLC cells. miR-4448 overexpression reduced tumor cell growth and prevented EMT. miR-4448 bound to the 3'UTR of the girdin gene and suppressed its expression, thereby decreasing Akt phosphorylation at Ser473. Attenuated Akt phosphorylation resulted in AMP-activated protein kinase (AMPK) phosphorylation at Thr172 and 183, enhancing EZH2 phosphorylation at Thr311.
CONCLUSION
SCLC characterized high EZH2 expression and promoted EMT, compared with non-small cell lung cancer. miR-4448 inhibited Girdin expression, reducing Akt phosphorylation, and enhancing AMPK and EZH2 phosphorylation. Eventually, miR-4448 prevented EZH2-mediated EMT and tumorigenesis by modulating the Girdin/Akt/AMPK axis in SCLC. miR-4448 might be a potential SCLC inhibitor.
背景
小细胞肺癌（SCLC）表现出高的增强子的锌指蛋白 2（EZH2）表达。EZH2 介导的表观遗传学促进上皮-间充质转化（EMT），增强恶性肿瘤的侵袭和转移潜能。microRNAs（miRNAs），小的非编码 RNA，调节 EMT，决定肿瘤表型。然而，miRNAs 与 SCLC 中的 EZH2 之间的关联仍有待阐明——我们旨在通过 miRNAs、EZH2 和 EMT 来确定 SCLC 的一种新的致癌机制，从而为未来的治疗应用提供依据。
方法
我们分析了肺癌细胞系和 34 例 SCLC 患者的肿瘤组织中的 EZH2 和 E-钙黏蛋白的表达，并证实了 EZH2 siRNA 介导的 EMT 抑制。通过 miRNA 芯片比较了 EZH2 敲低 SCLC 细胞和阴性对照 SCLC 细胞之间的 miRNA 表达谱。我们鉴定了一个靶 miRNA，其在 EZH2 敲低细胞中的表达差异，并分析了该 miRNA 对 EZH2 介导的 EMT 和肿瘤发生的影响。
结果
所有 SCLC 细胞均表现出 EZH2 表达增加和 E-钙黏蛋白表达减少。与其他肺癌组织相比，SCLC 组织的 EZH2 表达较高，E-钙黏蛋白表达较低。miRNA 芯片显示，EZH2 敲低 SCLC 细胞中 miR-4448 的表达增加。miR-4448 的过表达降低了肿瘤细胞的生长并阻止了 EMT。miR-4448 与 girdin 基因的 3'UTR 结合并抑制其表达，从而降低 Akt 在 Ser473 处的磷酸化。减弱的 Akt 磷酸化导致 AMP 激活的蛋白激酶（AMPK）在 Thr172 和 183 处的磷酸化，增强 EZH2 在 Thr311 处的磷酸化。
结论
与非小细胞肺癌相比，SCLC 具有高 EZH2 表达并促进 EMT。miR-4448 抑制 Girdin 表达，降低 Akt 磷酸化，并增强 AMPK 和 EZH2 磷酸化。最终，miR-4448 通过调节 SCLC 中的 Girdin/Akt/AMPK 轴，防止 EZH2 介导的 EMT 和肿瘤发生。miR-4448 可能是一种潜在的 SCLC 抑制剂。
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