2012年9月3日 訊 /生物谷BIOON/ --間變性星形細(xì)胞瘤(anaplastic astrocytoma)和多形性膠質(zhì)母細(xì)胞瘤(glioblastoma multiforme, GBM)都屬于惡性神經(jīng)膠質(zhì)瘤,，它們都是高度浸潤(rùn)性的?；颊哌@些高度侵襲性的和經(jīng)常是致命性的顱內(nèi)惡性腫瘤的病人平均存活期小于12個(gè)月,。
盡管當(dāng)前人們采取多種方法來治療惡性神經(jīng)膠質(zhì)瘤，但是它們經(jīng)常復(fù)發(fā),?？茖W(xué)家們將復(fù)發(fā)的原因歸結(jié)于內(nèi)在性抵抗這些治療方法的膠質(zhì)瘤干細(xì)胞(glioma stem cells, GSCs)的存在，并且認(rèn)為GSCs在神經(jīng)膠質(zhì)瘤發(fā)生中發(fā)揮著至關(guān)重要的作用,。它們抵抗化療和放療,，因而負(fù)責(zé)導(dǎo)致腫瘤惡化和復(fù)發(fā)。正正因?yàn)镚SCs具有浸潤(rùn)性,，再加上它們抵抗常規(guī)治療方法,，所以至今人們都沒有成功地找到一種方法來治療這類疾病。
與此同時(shí),，人們對(duì)促進(jìn)神經(jīng)膠質(zhì)瘤發(fā)生的分子機(jī)制仍然知之甚少,。內(nèi)源性小分子非編碼性RNA---微RNA(microRNAs, miRNAs)---的變化可能在腫瘤起始、惡化和轉(zhuǎn)移中發(fā)揮著關(guān)鍵性的作用,。
在這項(xiàng)研究中，為此證實(shí)是否如此,，來自新加坡A*STAR機(jī)構(gòu),、新加坡國立大學(xué)和奧地利格拉茨醫(yī)科大學(xué)的研究人員比較了神經(jīng)膠質(zhì)瘤、胚胎干細(xì)胞和神經(jīng)前體細(xì)胞(neural precursor cells, NPCs)和正常成人大腦組織的miRNA表達(dá)譜,，結(jié)果表明除了證實(shí)之前的發(fā)現(xiàn)：原發(fā)性神經(jīng)膠質(zhì)瘤擁有類似于NPC的miRNA表達(dá)譜,；miR-34a、miR-137和miR-451的過量表達(dá)相應(yīng)地抑制GSCs增殖,、破壞GSCs形成神經(jīng)球和誘導(dǎo)GSCs分化,，但是并不導(dǎo)致GSCs發(fā)生凋亡，他們還鑒定出miR-138為GSCs的分子標(biāo)記,，并證實(shí)它在促進(jìn)GSCs生長(zhǎng)和存活中發(fā)揮著關(guān)鍵性的作用,。序列特異性抑制miR-138的功能在體外阻止GSCs形成神經(jīng)球，在體內(nèi)抑制腫瘤產(chǎn)生,。
此外,，研究人員還發(fā)現(xiàn)與正常組織相比，GSCs中miR-138更高水平的表達(dá)與腫瘤復(fù)發(fā)和存活相關(guān)聯(lián),，這就突出表明miR-138作為預(yù)后生物標(biāo)志物和醫(yī)治惡性神經(jīng)膠質(zhì)瘤的治療性靶標(biāo)具有重要的臨床意義,。相關(guān)研究結(jié)果刊登在Cell Reports期刊上。(生物谷Bioon.com)
doi: 10.1016/j.celrep.2012.07.012
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Targeting Glioma Stem Cells by Functional Inhibition of a Prosurvival OncomiR-138 in Malignant Gliomas
Xin Hui Derryn Chan, Srikanth Nama, Felicia Gopal, Pamela Rizk, Srinivas Ramasamy, Gopinath Sundaram, Ghim Siong Ow, Ivshina Anna Vladimirovna, Vivek Tanavde, Johannes Haybaeck, Vladimir Kuznetsov, Prabha Sampath
Malignant gliomas are the most aggressive forms of brain tumors, associated with high rates of morbidity and mortality. Recurrence and tumorigenesis are attributed to a subpopulation of tumor-initiating glioma stem cells (GSCs) that are intrinsically resistant to therapy. Initiation and progression of gliomas have been linked to alterations in microRNA expression. Here, we report the identification of microRNA-138 (miR-138) as a molecular signature of GSCs and demonstrate a vital role for miR-138 in promoting growth and survival of bona fide tumor-initiating cells with self-renewal potential. Sequence-specific functional inhibition of miR-138 prevents tumorsphere formation in vitro and impedes tumorigenesis in vivo. We delineate the components of the miR-138 regulatory network by loss-of-function analysis to identify specific regulators of apoptosis. Finally, the higher expression of miR-138 in GSCs compared to non-neoplastic tissue and association with tumor recurrence and survival highlights the clinical significance of miR-138 as a prognostic biomarker and a therapeutic target for treatment of malignant gliomas.
