論文 - 詳細
| RRC ID | 86325 |
|---|---|
| 著者 | Koyama N, Ishikawa Y, Ohta H, Aoki T, Kyoyama H, Aoshiba K, Uematsu K. |
| タイトル | miR-4448/Girdin/Akt/AMPK axis inhibits EZH2-mediated EMT and tumorigenesis in small-cell lung cancer. |
| ジャーナル | Cancer Med |
| 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. |
| 巻・号 | 13(19) |
| ページ | e70093 |
| 公開日 | 2024-10-1 |
| DOI | 10.1002/cam4.70093 |
| PMID | 39400978 |
| PMC | PMC11476246 |
| MeSH | AMP-Activated Protein Kinases / metabolism Animals Cadherins / genetics Cadherins / metabolism Carcinogenesis / genetics Cell Line, Tumor Cell Movement Cell Proliferation Enhancer of Zeste Homolog 2 Protein* / genetics Enhancer of Zeste Homolog 2 Protein* / metabolism Epithelial-Mesenchymal Transition* / genetics Female Gene Expression Regulation, Neoplastic* Humans Lung Neoplasms* / genetics Lung Neoplasms* / metabolism Lung Neoplasms* / pathology Male Mice MicroRNAs* / genetics MicroRNAs* / metabolism Microfilament Proteins / genetics Microfilament Proteins / metabolism Middle Aged Proto-Oncogene Proteins c-akt* / metabolism Signal Transduction Small Cell Lung Carcinoma* / genetics Small Cell Lung Carcinoma* / metabolism Small Cell Lung Carcinoma* / pathology |
| IF | 3.491 |
| リソース情報 | |
| ヒト・動物細胞 | RERF-LC-AI(RCB0444) LC-2/ad(RCB0440) |