若診斷結(jié)果顯示某人患有一種大腦腫瘤多形性膠質(zhì)母細(xì)胞瘤(GBM),這對(duì)他往往是具有打擊性的,因?yàn)榭捎糜谥委熯@種腫瘤的方法很少,并且該癌癥具有較差的預(yù)后.那些可以消除其他惡性腫瘤的療法,例如化療或外科手術(shù),對(duì)于GBM患者來(lái)說(shuō)只是可以延長(zhǎng)一點(diǎn)有限的生命罷了.
新加坡A*STAR生物工程和納米技術(shù)研究所的Shu Wang解釋到：“由于腫瘤細(xì)胞會(huì)大量入侵正常腦組織,而且又容易產(chǎn)生治療抵抗性,因此這種疾病經(jīng)常復(fù)發(fā).該癌癥高度致命的自然特性導(dǎo)致惡性GBM患者的平均生存期大約只有一年.”科學(xué)家們一直在尋找針對(duì)該疾病的有效治療方法,而現(xiàn)在Wang等人的研究可以為對(duì)抗這種致命疾病提供一個(gè)有用的策略.
一些基因并不編碼生產(chǎn)蛋白質(zhì)的mRNA,而是編碼小片段的microRNAs來(lái)調(diào)控其他mRNA的表達(dá).一些miRNAs會(huì)被酶進(jìn)一步編輯,其中特定的腺嘌呤核苷酸被改為了肌苷,即經(jīng)歷了“由A到I”的改變,這會(huì)顯著的改變microRNA的靶標(biāo)偏好性.之前的研究已經(jīng)證實(shí)了異常的mRNA編輯與腦癌之間的聯(lián)系,而現(xiàn)在,Wang的研究團(tuán)隊(duì)又調(diào)查了一組miR-376簇的作用.
這一基因簇的其中一個(gè)產(chǎn)物是miR-376a*,它在健康的人類組織中通常會(huì)經(jīng)歷“由A到I”的編輯過(guò)程.通過(guò)分析原發(fā)性腫瘤組織和膠質(zhì)瘤癌細(xì)胞系,研究人員確定了,許多GBM細(xì)胞往往會(huì)攜帶未經(jīng)編輯的miR-376a*.更重要的是,對(duì)患者腫瘤的比較分析顯示,未編輯miR-376a*的過(guò)高水平與腫瘤的較大體積有關(guān)(圖1).
上:未編輯的miR-376a*促進(jìn)了小鼠腦瘤模型中惡性腫瘤的生長(zhǎng)(深紅色); 下:編輯過(guò)的miR-376a*限制了腫瘤的生長(zhǎng)(深紅色),使之轉(zhuǎn)變?yōu)榱朔乔秩胄缘哪[瘤.
該小組接下來(lái)的研究證實(shí)了這種聯(lián)系.研究人員向體外培養(yǎng)的非擴(kuò)散性膠質(zhì)瘤細(xì)胞系中引入了未編輯的miR-376a*模擬物,并將這些細(xì)胞移植到了小鼠體內(nèi)；之后,他們發(fā)現(xiàn)這些細(xì)胞形成了大而無(wú)規(guī)則的腫瘤,并且腫瘤能快速殺死它們的宿主.通過(guò)比較,表達(dá)編輯過(guò)的miR-376a*的細(xì)胞則是相對(duì)靜止的,腫瘤的生長(zhǎng)也很有限.Wang和他的同事們還檢測(cè)到,未編輯的miR-376a*與編輯過(guò)的miR-376a*所影響的基因種類是完全不同的,其中的一些似乎負(fù)責(zé)了它的有害影響.
Wang說(shuō)：“miR-376a*中由A到I的單堿基改變影響了該miRNA對(duì)靶標(biāo)基因的選擇,進(jìn)而轉(zhuǎn)變了它的功能,使之從抑制侵入轉(zhuǎn)向了促進(jìn)膠質(zhì)瘤細(xì)胞的侵入力.”他補(bǔ)充到,這些結(jié)果還強(qiáng)調(diào)了,強(qiáng)制表達(dá)編輯過(guò)的miR-376a*有望成為治療GBM的一個(gè)新策略.現(xiàn)在,Wang和他的研究小組正探索不同的遞送機(jī)制來(lái)實(shí)現(xiàn)這項(xiàng)療法.（生物谷Bioon.com）
doi:10.1172/JCI62925
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PMID:
Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells
Yukti Choudhury1, Felix Chang Tay2, Dang Hoang Lam1,2, Edwin Sandanaraj3, Carol Tang4, Beng-Ti Ang3,4 and Shu Wang1,2
In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed “seed” sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells.
