Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820960748. doi: 10.1177/1533033820960748.
Glioblastoma multiforme (GBM) is the most aggressive and most frequently diagnosed malignant human glioma. Despite the best available standard of care (surgery, radiation, and chemotherapy), the median survival of GBM patients is less than 2 years. Many recent studies have indicated that microRNAs (miRNAs) are important for promoting or reducing/limiting GBM growth. In particular, we previously showed that GBMs express decreased levels of miR-100 relative to control tissue and that restoring miR-100 expression reduced GBM tumorigenicity by modulating SMRT/NCOR2 (Nuclear Receptor Corepressor 2). Here, we demonstrate that miR-100 overexpression decreases expression of the stem cell markers, nestin and L1CAM, and decreases proliferation of GBM tumor-initiating cells (cancer stem cells). We further show that miR-100-mediated anti-tumorigenic activity limits the activity of SMARCA5 and its downstream target STAT3 (known as mTOR-STAT3-Notch pathway). In addition, we report ErbB3 (Her3) as a putative miR-100 target, including inhibition of its downstream AKT and ERK signaling pathways.
多形性胶质母细胞瘤（GBM）是最具侵袭性和最常诊断出的恶性人类神经胶质瘤。尽管采用了最佳的现有标准治疗方法（手术、放疗和化疗），但 GBM 患者的中位生存期仍不到 2 年。许多最近的研究表明，microRNAs（miRNAs）对于促进或减少/限制 GBM 生长非常重要。特别是，我们之前曾表明，与对照组织相比，GBM 表达的 miR-100 水平降低，并且恢复 miR-100 的表达通过调节 SMRT/NCOR2（核受体共抑制因子 2）降低了 GBM 的致瘤性。在这里，我们证明了 miR-100 的过表达降低了干细胞标志物 nestin 和 L1CAM 的表达，并降低了 GBM 肿瘤起始细胞（癌症干细胞）的增殖。我们进一步表明，miR-100 介导的抗肿瘤活性限制了 SMARCA5 及其下游靶标 STAT3（称为 mTOR-STAT3-Notch 途径）的活性。此外，我们报告 ErbB3（Her3）是一个假定的 miR-100 靶标，包括抑制其下游 AKT 和 ERK 信号通路。
