Author of

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  P64 - Tumor Biology and Systems Biology - Basic and Translational Science - miRNA (ID 202)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35839

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    P64.04 - Novel Inhibitory Action of microRNA on EZH2-Mediated Oncogenesis Through Girdin-AMPK Signaling in Small Cell Lung Cancer (ID 3204)

    00:00 - 00:00  |  Presenting Author(s): Nobuyuki Koyama
    • Abstract
    • Slides

    Introduction
    

    Enhancer of zeste homolog 2 (EZH2) belonging to the polycomb repressive complex 2 promotes tumor growth and metastasis. High EZH2 expressions were frequently observed in cell lines and tumor tissues of small cell lung cancer (SCLC). Of non-coding RNAs, microRNA (miRNA) is involved in epithelial-mesenchymal transition (EMT), which contributes to invasiveness and metastatic potentials characterizing SCLC. However, the association of miRNA with the molecular mechanism of invasiveness and metastasis in SCLC remains to be fully elucidated. The present study aimed to identify a novel miRNA determining EZH2-mediated EMT and tumor aggressiveness in SCLC.

    Methods
    

    A total of 34 patients who received the surgical intervention and were diagnosed with SCLC at Jichi Medical University Saitama Medical Center from 2000 to 2013 were enrolled. Patients consisted of 16 with stage I (47%), 10 with stage II (29%), 7 with stage III (21%), and 1 with stage IV (3%). Stage-matched 34 patients with adenocarcinoma and 34 patients with squamous cell carcinoma who underwent surgical resection were also enrolled, respectively. After obtaining the approval of the institutional review board, surgical specimens from a total of 102 patients with SCLC, adenocarcinoma, and squamous cell carcinoma were applied to immunohistochemistry. Multiple lung cancer cell lines were used in the present study; three SCLC cell lines, six adenocarcinoma cell lines, two squamous cell carcinoma cell lines, and one large cell neuroendocrine carcinoma cell lines. As a control, BEAS-2B (human bronchial epithelium) was employed.

    Results
    

    Transcriptional and translational expressions of EZH2 were increased in three types of SCLC cell lines and tumor tissues from 34 patients with SCLC. Small interfering RNA (siRNA) against EZH2 suppressed its expression and EMT in SBC3 and SBC5 cell lines. Using comprehensive miRNA expression analysis comparing between EZH2 siRNA-transfected cells and mock-transfected cells, miR-4448 expression was significantly increased in SCLC cells transfected with EZH2 siRNA. Overexpression of miR-4448 significantly inhibited cell growth and negatively regulated EMT. Luciferase assay demonstrated that miR-4448 targeted at the 3’-untranslated region of Girdin mRNA. We confirmed that miR-4448 overexpression suppressed Girdin expressions, leading to enhanced phosphorylation of AMP-activated protein kinase (AMPK) and reduced Akt phosphorylation.

    Conclusion
    

    As a novel miRNA associated with EZH2-mediated oncogenesis, we identified miR-4448. The inhibitory action of miR-4448 on EZH2-mediated EMT and tumor growth was attributed to the disruption of the cell signaling pathway through suppressing Girdin expressions and promoting AMPK phosphorylation. The findings of the present study may shed light on a novel therapeutic strategy for SCLC, a refractory neoplastic disease.

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