來自中山大學中山醫(yī)學院的研究人員近日在國際權(quán)威腫瘤學雜志《癌癥研究》（Cancer research）上發(fā)表了題為“Loss of miR-204 expression enhances glioma migration and stem cell like phenotype”的研究論文，證實miR-204表達喪失與神經(jīng)膠質(zhì)瘤的遷移和干細胞樣表型密切相關(guān),。
領導這一研究的是中山大學副校長兼中山醫(yī)學院院長,、“長江學者”特聘教授黎孟楓。主要研究方向為病毒致癌與腫瘤發(fā)生的分子機制,；分子病毒學與分子腫瘤學,。
神經(jīng)膠質(zhì)瘤(Glioma)亦稱膠質(zhì)細胞瘤簡稱膠質(zhì)瘤，是發(fā)生于神經(jīng)外胚層的腫瘤,，故亦稱神經(jīng)外胚層腫瘤或神經(jīng)上皮腫瘤腫瘤,。神經(jīng)膠質(zhì)瘤是一種致死性癌癥，主要特征是腫瘤細胞彌漫性浸潤生長、無明確邊界,、無限增殖并具有高度侵襲性,。雖然目前腫瘤綜合治療技術(shù)已取得長足進步，但膠質(zhì)瘤治療效果仍不理想,，預后差,，是困擾臨床醫(yī)生的難題。
當前對于膠質(zhì)瘤發(fā)生的病因尚不明確,。近年來一些研究發(fā)現(xiàn)部分膠質(zhì)瘤表面同時表達神經(jīng)元和神經(jīng)膠質(zhì)細胞的標志物,，表明其分化狀態(tài)紊亂，可能起源于一種具有多項分化潛能的細胞,。相關(guān)研究也證實膠質(zhì)瘤中確實存在這種細胞,。由于它們具有與神經(jīng)干細胞（neural stem cells, NSCs）相似的特征，故稱之為膠質(zhì)瘤干細胞（glioma stem cells, GSCs）,。隨著腫瘤干細胞（tumor stem cells, TSCs）假說的提出和盛行,，GSCs被視為是驅(qū)動這一疾病的重要原因，然而目前對于這類細胞分子機制仍知之甚少,。
在這篇文章中,，研究人員篩查比較了膠質(zhì)瘤干細胞和神經(jīng)干細胞之間的差異miRNA表達，發(fā)現(xiàn)在兩種類型的細胞中miR-204均顯著下調(diào),。機制研究揭示miR-204可通過靶向干細胞特性支配轉(zhuǎn)錄因子SOX4以及遷移促進受體EphB2,，抑制膠質(zhì)瘤細胞的自我更新、干細胞相關(guān)表型和遷移,。在膠質(zhì)瘤細胞中恢復miR-204表達,，可以抑制體內(nèi)的腫瘤形成和侵襲，提高宿主存活率,。進一步的研究揭示,，miR-204啟動子存在超甲基化，減弱miR-204啟動子甲基化可以上調(diào)膠質(zhì)瘤細胞中的miR-204表達,。
這些結(jié)果表明miR-204是惡性膠質(zhì)瘤細胞干細胞樣表型和細胞運動的一個極其重要的調(diào)控因子,。新研究對于了解膠質(zhì)瘤的發(fā)生發(fā)展分子機制，尋找膠質(zhì)瘤預防判斷和生物治療的新潛在靶標具有重要意義,。(生物谷Bioon.com)
doi: 10.1158/0008-5472.CAN-12-2895
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Loss of miR-204 expression enhances glioma migration and stem cell like phenotype
Zhe Ying1, Yun Li2, Jueheng Wu2, Xun Zhu2, Yi Yang3, Han Tian2, Wei Li2, Bo Hu4, Shi-Yuan Cheng4, and Mengfeng Li5,*
Phenotypic similarities have long been recognized between subpopulations of glioma cells and neural stem cells. Many of these similar properties, including the robust abilities to self-renew, migrate and invade, are hallmarks of glioma cells that render them extremely aggressive. However, the molecular mechanisms underlying this character, particularly in glioma stem-like cells that drive this disease, remain poorly understood. Here we report the results of a differential miRNA expression screen that compared glioma cells and neural stem cells, where we found that miR-204 was markedly down-regulated in both types of cells. Mechanistic investigations revealed that miR-204 simultaneously suppressed self-renewal, stem cell associated phenotype and migration of glioma cells via targeting the stemness-governing transcriptional factor SOX4 and the migration-promoting receptor EphB2. Restoring miR-204 expression in glioma cells suppressed tumorigenesis and invasiveness in vivo and increased overall host survival. Further evaluation revealed that the miR-204 promoter was hypermethylated and that attenuating promoter methylation was sufficient to upregulate miR-204 in glioma cells. Together, our findings reveal miR-204 as a pivotal regulator of the development of stem cell-like phenotypes and cell motility in malignant glioma cells.
