miR-4448/Girdin/Akt/AMPK axis inhibits EZH2-mediated EMT and tumorigenesis in small-cell lung cancer

IF 2.9 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2024-10-14 DOI:10.1002/cam4.70093

Nobuyuki Koyama, Yuichi Ishikawa, Hiromitsu Ohta, Takuya Aoki, Hiroyuki Kyoyama, Kazutetsu Aoshiba, Kazutsugu Uematsu

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Abstract

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.

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miR-4448/Girdin/Akt/AMPK 轴抑制 EZH2- 介导的小细胞肺癌 EMT 和肿瘤发生

背景小细胞肺癌（SCLC）显示出较高的泽斯特同源增强子 2（EZH2）表达。EZH2 介导的表观遗传学促进了上皮-间质转化（EMT），增强了恶性肿瘤的侵袭和转移潜力。微RNA（miRNA）是一种小型非编码RNA，可调节EMT，决定肿瘤表型。然而，miRNAs 和 EZH2 在 SCLC 中的关联仍有待明确--我们的目的是通过 miRNAs、EZH2 和 SCLC 中的 EMT 找出一种新的致瘤机制，从而为未来的治疗应用提供依据。方法我们分析了 34 例 SCLC 患者的肺癌细胞系和肿瘤组织中 EZH2 和 E-cadherin 的表达，证实了 EZH2 siRNA 介导的 EMT 抑制作用。我们发现了EZH2的一个靶miRNA在EZH2敲除细胞中的表达差异，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 细胞都显示 EZH2 表达增加，E-cadherin 表达减少。miRNA 阵列显示，在 EZH2- 敲除的 SCLC 细胞中，miR-4448 的表达增加。Akt 磷酸化减弱导致 AMP 激活蛋白激酶（AMPK）在 Thr172 和 183 处磷酸化，从而增强了 EZH2 在 Thr311 处的磷酸化。 miR-4448 可抑制 Girdin 的表达，减少 Akt 磷酸化，增强 AMPK 和 EZH2 的磷酸化。最终，miR-4448通过调节SCLC中的Girdin/Akt/AMPK轴防止了EZH2介导的EMT和肿瘤发生。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.