过表达的 let-7a 通过直接靶向 K-ras，独立于 PTEN，抑制神经胶质瘤细胞的恶性转化。
Overexpressed let-7a inhibits glioma cell malignancy by directly targeting K-ras, independently of PTEN.
机构信息
Corresponding Authors: Yong-Ping You, PhD, Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
出版信息
Neuro Oncol. 2013 Nov;15(11):1491-501. doi: 10.1093/neuonc/not107. Epub 2013 Oct 3.
BACKGROUND
Altered expression of micro(mi)RNAs has been shown to be associated with tumorigenesis and tumor progression. The expression of phosphatase and tensin homolog (PTEN) plays an important role in glioma and is regarded as a prognostic marker of glioma patients. The goal of this study was to investigate the function of lethal (let)-7a miRNA in glioma cell lines with different PTEN phenotypes.
METHODS
One hundred ninety-eight glioma tissues were used to profile miRNA expression.
RESULTS
Let-7a was shown to have lower expression in high-grade glioma than in low-grade glioma. Low expression of let-7a was correlated with poor prognosis of primary glioblastoma patients. We demonstrated that K-ras was a functional target for let-7a to induce cell cycle arrest, apoptosis, and inhibition of cell migration and invasion in vitro. Our further results showed no difference in malignancy inhibition induced by let-7a in 4 glioma cells, including U87 (PTEN null), U251 (PTEN mutant), LN229 (PTEN wild type), and LN229 (PTEN small interfering RNA). The phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were inhibited by let-7a, and the inhibition effects had no difference in 4 glioma cells. We demonstrated that let-7a could induce suppression of glioma in vivo by generating a glioma xenograft model.
CONCLUSION
Our results indicated that let-7a suppresses its target transcript K-ras and inhibits glioma malignancy independent of PTEN expression.
背景
已有研究表明，微小 RNA（miRNA）的表达改变与肿瘤发生和肿瘤进展有关。磷酸酶和张力蛋白同源物（PTEN）的表达在神经胶质瘤中起着重要作用，被认为是神经胶质瘤患者的预后标志物。本研究旨在探讨致死（let）-7a miRNA 在具有不同 PTEN 表型的神经胶质瘤细胞系中的功能。
方法
使用 198 例神经胶质瘤组织进行 miRNA 表达谱分析。
结果
let-7a 在高级别神经胶质瘤中的表达低于低级别神经胶质瘤。let-7a 的低表达与原发性胶质母细胞瘤患者的预后不良相关。我们证明 K-ras 是 let-7a 诱导细胞周期停滞、细胞凋亡以及体外抑制细胞迁移和侵袭的功能靶标。我们的进一步结果表明，let-7a 在 4 种神经胶质瘤细胞（包括 U87（PTEN 缺失）、U251（PTEN 突变）、LN229（PTEN 野生型）和 LN229（PTEN 小干扰 RNA））中诱导的恶性抑制作用没有差异。let-7a 抑制了磷脂酰肌醇-3 激酶/蛋白激酶 B（Akt）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路，在 4 种神经胶质瘤细胞中，抑制效果没有差异。我们证明 let-7a 可以通过生成神经胶质瘤异种移植模型在体内诱导神经胶质瘤的抑制。
结论
我们的结果表明，let-7a 抑制其靶转录物 K-ras，并独立于 PTEN 表达抑制神经胶质瘤的恶性程度。
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