日前，來(lái)自第四軍醫(yī)大學(xué),、西安醫(yī)學(xué)院和上海交通大學(xué)的研究人員證實(shí),，miR-218通過(guò)靶向多梳基因家族(Polycomb group genes， PcG)成員Bmi1,，抑制了神經(jīng)膠質(zhì)細(xì)胞侵襲,、遷移、增殖及腫瘤干細(xì)胞的自我更新,。這一研究成果正式發(fā)布在10月1日出版的《癌癥研究》（Cancer Research）雜志上,。主持這一研究的是上海交通大學(xué)的金衛(wèi)林副研究員和第四軍醫(yī)大學(xué)的張永生教授。
惡性神經(jīng)膠質(zhì)瘤（Malignant gliomas）是一種最常見(jiàn)的原發(fā)性中樞神經(jīng)系統(tǒng)（CNS）腫瘤,。它們的特點(diǎn)是具有高侵襲,、遷移和增殖能力。外科手術(shù),、放療和化療是目前神經(jīng)膠質(zhì)瘤治療的常用手段,。然而，盡管接受了這些治療,，患有這種惡性神經(jīng)膠質(zhì)瘤的患者中位生存期也只有大約1-2年,。諸多因素影響了神經(jīng)膠質(zhì)瘤的治療效果，其中包括癌基因激活,、抑癌基因突變和表觀遺傳引起的快速和極具侵襲性的腫瘤生長(zhǎng)以及腫瘤干細(xì)胞的放化療抗性,。因此，揭示抑制神經(jīng)膠質(zhì)瘤細(xì)胞增殖,、遷移和腫瘤干細(xì)胞干性維持的分子機(jī)制對(duì)理解膠質(zhì)瘤腫瘤生物學(xué)和開(kāi)發(fā)新的膠質(zhì)瘤治療策略具有重要的意義,。
MicroRNAs (miRNAs)是一種內(nèi)源性的非編碼小RNA，可通過(guò)與特異性靶標(biāo)mRNA反向互補(bǔ)調(diào)控基因的表達(dá),。越來(lái)越多的證據(jù)表明,，miRNAs調(diào)控了細(xì)胞遷移、侵襲,、增殖,、凋亡、抗逆性、干細(xì)胞維持和分化等各種生物學(xué)過(guò)程,。重要的是,，miRNAs可下調(diào)包括癌基因和抑癌基因在內(nèi)的多個(gè)靶基因，一些miRNAs充當(dāng)?shù)氖悄[瘤抑制子,，而另一些則充當(dāng)了癌基因,。在腫瘤生物學(xué)方面miRNAs越來(lái)越被重視,。
多種miRNA分子被報(bào)道參與調(diào)控了神經(jīng)膠質(zhì)瘤的形成,，其中包括miR-10b、miR-124,、miR-128,、miR-137、miR-138,、miR-21和 miR-218,，尤其是miR-218分子已被多種microRNA微陣列芯片和組織學(xué)研究發(fā)現(xiàn)，相比于正常腦組織,，miR-218在人類神經(jīng)膠質(zhì)瘤中顯著下調(diào),，而且其表達(dá)水平與膠質(zhì)瘤病人的惡性程度負(fù)相關(guān)。然而,，目前對(duì)于miR-218在調(diào)控神經(jīng)膠質(zhì)瘤形成中所起的作用仍知之甚少,。
在這篇文章中，研究人員證實(shí)上調(diào)miR-218表達(dá)可顯著抑制神經(jīng)膠質(zhì)瘤細(xì)胞的遷移,、侵襲和增殖,。進(jìn)一步機(jī)制研究證明PRC1復(fù)合物核心成員原癌基-Bmi1是miR-218的下游功能性靶點(diǎn)。功能實(shí)驗(yàn)證實(shí)Bmi1介導(dǎo)miR-218抑制神經(jīng)膠質(zhì)瘤細(xì)胞的遷移,、增殖和神經(jīng)膠質(zhì)瘤干細(xì)胞的自我更新,。并且，研究者通過(guò)微陣列分析發(fā)現(xiàn)miR-218調(diào)控了廣泛的與神經(jīng)膠質(zhì)瘤細(xì)胞發(fā)育相關(guān)的基因,，如 miR-218可以通過(guò)影響Wnt等信號(hào)通路抑制了神經(jīng)膠質(zhì)瘤干性,。研究揭示，miR-218負(fù)向調(diào)控了促進(jìn)神經(jīng)膠質(zhì)瘤形成的基因,。
新研究首次證明了,，腫瘤抑制因子miR-218通過(guò)下調(diào)癌基因Bmi1來(lái)調(diào)控神經(jīng)膠質(zhì)瘤細(xì)胞遷移、遷徙,、增殖和腫瘤干細(xì)胞的功能,。(生物谷Bioon.com)
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Cancer Research doi： 10.1158/0008-5472.CAN-13-0358
MicroRNA-218 Inhibits Glioma Invasion， Migration,， Proliferation and Cancer Stem-like Cell Self-renewal by Targeting the Polycomb Group Gene Bmi1
Yanyang Tu,， Xingchun Gao， Gang Li， Hualin Fu,， Daxiang Cui,， Hui Liu1， Weilin Jin,， and Yongsheng Zhang
Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown,， which greatly limits the successful treatment of this disease. Increasing evidence indicates that microRNAs (miRNAs) play key roles in tumor progression by regulating gene expression. In particular， miR-218 has previously been shown to be downregulated in gliomas. Here,， we demonstrate that upregulation of miR-218 dramatically reduced the migration,， invasion and proliferation of glioma cells. Quantitative RT-PCR and western blotting analysis revealed that the mRNA and protein expression of Bmi1 was significantly decreased after overexpression of miR-218 in three human glioma cell lines we examined. Furthermore， we demonstrate that Bmi1 was a functional downstream target of miR-218 through the use of a luciferase assay and miR-218 regulated glioma cell migration and proliferation through Bmi1 downregulation. Bmi1 has previously been reported to regulate cell stemness. Therefore,， we investigated the effects of miR-218 overexpression on the self-renewal capacity of glioma stem-like cells. The results indicated that miR-218 blocked glioma stem-like cell self-renewal. Finally,， we show that miR-218 regulated a broad range of genes involved in glioma cell development by DNA microarray analysis， and also miR-218 regulate some pathway such as Wnt pathways to suppress glioma stemness,， we discovered show that miR-218 negatively regulates genes that promote glioma development. Taken together,， our findings reveal miR-218 as a tumor suppressor that prevents glioma cells migration， invasion,， proliferation and cancer cell stemness.
