State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
EMBO Rep. 2019 Dec 5;20(12):e48170. doi: 10.15252/embr.201948170. Epub 2019 Oct 10.
Long non-coding RNAs (lncRNAs) are critical regulators in cancer. However, the involvement of lncRNAs in TGF-β-regulated tumorigenicity is still unclear. Here, we identify TGF-β-activated lncRNA LINC00115 as a critical regulator of glioma stem-like cell (GSC) self-renewal and tumorigenicity. LINC00115 is upregulated by TGF-β, acts as a miRNA sponge, and upregulates ZEB1 by competitively binding of miR-200s, thereby enhancing ZEB1 signaling and GSC self-renewal. LINC00115 also promotes ZNF596 transcription by preventing binding of miR-200s to the 5'-UTR of ZNF596, resulting in augmented ZNF596/EZH2/STAT3 signaling and GBM tumor growth. Inhibition of EZH2 by genetic approaches or a small molecular inhibitor markedly suppresses LINC00115-driven GSC self-renewal and tumorigenicity. Moreover, LINC00115 is highly expressed in GBM, and LINC00115 expression or correlated co-expression with ZEB1 or ZNF596 is prognostic for clinical GBM survival. Our work defines a critical role of LINC00115 in GSC self-renewal and tumorigenicity, and suggests LINC00115 as a potential target for GBM treatment.
长链非编码 RNA（lncRNA）是癌症中重要的调控因子。然而，lncRNA 在 TGF-β 调节的肿瘤发生中的作用尚不清楚。在这里，我们鉴定出 TGF-β 激活的 lncRNA LINC00115 是神经胶质瘤干细胞（GSC）自我更新和致瘤性的关键调节因子。LINC00115 受 TGF-β 上调，作为 miRNA 海绵，通过竞争性结合 miR-200s 而上调 ZEB1，从而增强 ZEB1 信号和 GSC 自我更新。LINC00115 还通过防止 miR-200s 与 ZNF596 的 5'-UTR 结合来促进 ZNF596 的转录，导致 ZNF596/EZH2/STAT3 信号增强和 GBM 肿瘤生长。通过遗传方法或小分子抑制剂抑制 EZH2 可显著抑制 LINC00115 驱动的 GSC 自我更新和致瘤性。此外，LINC00115 在 GBM 中高度表达，LINC00115 的表达或与 ZEB1 或 ZNF596 的相关共表达与临床 GBM 患者的生存预后相关。我们的工作定义了 LINC00115 在 GSC 自我更新和致瘤性中的关键作用，并表明 LINC00115 可能是 GBM 治疗的潜在靶点。
