來自中山大學中山醫(yī)學院的研究人員近日在國際權威腫瘤學雜志《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表達喪失與神經膠質瘤的遷移和干細胞樣表型密切相關,。
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,。
神經膠質瘤(Glioma)亦稱膠質細胞瘤簡稱膠質瘤,，是發(fā)生于神經外胚層的腫瘤,，故亦稱神經外胚層腫瘤或神經上皮腫瘤腫瘤,。神經膠質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已取得長足進步，但膠質瘤治療效果仍不理想,，預后差,，是困擾臨床醫(yī)生的難題。
當前對于膠質瘤發(fā)生的病因尚不明確,。近年來一些研究發(fā)現部分膠質瘤表面同時表達神經元和神經膠質細胞的標志物,，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,。相關研究也證實膠質瘤中確實存在這種細胞,。由于它們具有與神經干細胞（neural stem cells, NSCs）相似的特征，故稱之為膠質瘤干細胞（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瘤干細胞和神經干細胞之間的差異miRNA表達，發(fā)現在兩種類型的細胞中miR-204均顯著下調,。機制研究揭示miR-204可通過靶向干細胞特性支配轉錄因子SOX4以及遷移促進受體EphB2,，抑制膠質瘤細胞的自我更新、干細胞相關表型和遷移,。在膠質瘤細胞中恢復miR-204表達,，可以抑制體內的腫瘤形成和侵襲，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膠質瘤細胞中的miR-204表達,。
這些結果表明miR-204是惡性膠質瘤細胞干細胞樣表型和細胞運動的一個極其重要的調控因子,。新研究對于了解膠質瘤的發(fā)生發(fā)展分子機制,，尋找膠質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.
