MicroRNA-30e*promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop
MicroRNA-30e*promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop
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DOI：
10.1172/jci58849
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发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
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作者：
Jiang, Lili;Lin, Chuyong;Li, Mengfeng
NF-κ B B的组成性激活是人类癌症中的常见事件，在癌症的发生和发展中起重要作用。在非转化细胞中，NF-κ B B的活化受I κ B的严格控制。I κ B结合细胞质中的NF-κ B，阻止其易位至细胞核以调节基因表达。激活NF-κ B信号传导的刺激物触发I κ B降解，使得NF-κ B能够核转位。在NF-κ B调控的基因中有编码I κ B的基因，其提供限制NF-κ B活性的负反馈环。转化细胞如何克服这种NF-κ B/I κ B负反馈回路仍不清楚。在此，我们报道了在人脑胶质瘤细胞系中microRNA-30 e *（miR-30 e *）直接靶向I kappa B alpha 3 '-UTR并抑制I kappa B alpha表达。miR-30 e * 在人脑胶质瘤细胞系中的过表达导致NF-κ B的过度活化和NF-κ B调节基因的表达增强，这在体外测定和原位异种移植模型中促进胶质瘤细胞的侵袭力。miR-30 e * 的这些作用被证明是临床相关的，因为发现miR-30 e * 在原代人神经胶质瘤细胞中上调，并且与恶性进展和较差的存活率相关。因此，miR-30 e * 提供了一种破坏NF-κ B/I κ B α环的表观遗传机制，并可能代表一种新的治疗靶点和预后标志物。
Constitutive activation of NF-kappa B is a frequent event in human cancers, playing important roles in cancer development and progression. In nontransformed cells, NF-kappa B activation is tightly controlled by I kappa Bs. I kappa Bs bind NF-kappa B in the cytoplasm, preventing it from translocating to the nucleus to modulate gene expression. Stimuli that activate NF-kappa B signaling trigger I kappa B degradation, enabling nuclear translocation of NF-kappa B. Among the genes regulated by NF-kappa B are those encoding the I kappa Bs, providing a negative feedback loop that limits NF-kappa B activity. How transformed cells override this NF-kappa B/I kappa B negative feedback loop remains unclear. Here, we report in human glioma cell lines that microRNA-30e* (miR-30e*) directly targets the I kappa B alpha 3'-UTR and suppresses I kappa B alpha expression. Overexpression of miR-30e* in human glioma cell lines led to hyperactivation of NF-kappa B and enhanced expression of NF-kappa B-regulated genes, which promoted glioma cell invasiveness in in vitro assays and in an orthotopic xenotransplantation model. These effects of miR-30e* were shown to be clinically relevant, as miR-30e* was found to be upregulated in primary human glioma cells and correlated with malignant progression and poor survival. Hence, miR-30e* provides an epigenetic mechanism that disrupts the NF-kappa B/I kappa B alpha loop and may represent a new therapeutic target and prognostic marker.