Cancer Res：miR-204表达丧失与神经胶质瘤的迁移和干细胞样表型密切相关

来自中山大学中山医学院的研究人员近日在国际权威肿瘤学杂志《癌症研究》（Cancer research）上发表了题为“Loss of miR-204 expression enhances glioma migration and stem cell like phenotype”的研究论文，证实miR-204表达丧失与神经胶质瘤的迁移和干细胞样表型密切相关。

领导这一研究的是中山大学副校长兼中山医学院院长、“***”特聘教授黎孟枫。主要研究方向为病毒致癌与肿瘤发生的分子机制；分子病毒学与分子肿瘤学。

神经胶质瘤(Glioma)亦称胶质细胞瘤简称胶质瘤，是发生于神经外胚层的肿瘤，故亦称神经外胚层肿瘤或神经上皮肿瘤肿瘤。神经胶质瘤是一种致死性癌症，主要特征是肿瘤细胞弥漫性浸润生长、无明确边界、无限增殖并具有高度侵袭性。虽然目前肿瘤综合治疗技术已取得长足进步，但胶质瘤治疗效果仍不理想，预后差，是困扰临床医生的难题。

当前对于胶质瘤发生的病因尚不明确。近年来一些研究发现部分胶质瘤表面同时表达神经元和神经胶质细胞的标志物，表明其分化状态紊乱，可能起源于一种具有多项分化潜能的细胞。相关研究也证实胶质瘤中确实存在这种细胞。由于它们具有与神经干细胞（neural stem cells, NSCs）相似的特征，故称之为胶质瘤干细胞（glioma stem cells, GSCs）。随着肿瘤干细胞（tumor stem cells, TSCs）假说的提出和盛行，GSCs被视为是驱动这一疾病的重要原因，然而目前对于这类细胞分子机制仍知之甚少。

在这篇文章中，研究人员筛查比较了胶质瘤干细胞和神经干细胞之间的差异miRNA表达，发现在两种类型的细胞中miR-204均显着下调。机制研究揭示miR-204可通过靶向干细胞特性支配转录因子SOX4以及迁移促进受体EphB2，抑制胶质瘤细胞的自我更新、干细胞相关表型和迁移。在胶质瘤细胞中恢复miR-204表达，可以抑制体内的肿瘤形成和侵袭，提高宿主存活率。进一步的研究揭示，miR-204启动子存在超甲基化，减弱miR-204启动子甲基化可以上调胶质瘤细胞中的miR-204表达。

这些结果表明miR-204是恶性胶质瘤细胞干细胞样表型和细胞运动的一个极其重要的调控因子。新研究对于了解胶质瘤的发生发展分子机制，寻找胶质瘤预防判断和生物治疗的新潜在靶标具有重要意义。

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.