近日,，溫希普癌癥研究所（Winship Cancer Institute）的研究人員發(fā)現(xiàn)了一種新的功能基因,，它能抑制癌癥的發(fā)展。
科學(xué)家們已知該基因通過編碼p14ARF蛋白質(zhì),，調(diào)控腫瘤細(xì)胞的增殖和分化,。埃爾溫·范·梅厄（Erwin Van Meir）博士所帶領(lǐng)的團(tuán)隊發(fā)現(xiàn)p14ARF也參與腫瘤血管新生過程，癌細(xì)胞生長需要血液供能,，因此腫瘤細(xì)胞會誘導(dǎo)血管生成,。
該項(xiàng)研究發(fā)現(xiàn)給理解腫瘤如何發(fā)生發(fā)展，腫瘤細(xì)胞與周圍血管細(xì)胞之間的交流提供了新的見解,，相關(guān)研究論文發(fā)表在J Clin Invest上,。研究人員表示借此新發(fā)現(xiàn)，將來可能開發(fā)出靶向抑制P14ARF蛋白腫瘤的生長的新方法,。
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范·梅厄（Van Meir）是埃默里大學(xué)醫(yī)學(xué)院血液及腫瘤內(nèi)科,、神經(jīng)外科教授，同時也是溫希普癌癥研究所分子神經(jīng)腫瘤實(shí)驗(yàn)室主任,。實(shí)驗(yàn)室副研究員Abdessamad Zerrouqi博士是該篇論文的第一作者,。
如何抑制P14ARF的功能是Zerrouqi博士數(shù)年來的研究成果。他說：該基因是一個很不容易被發(fā)現(xiàn),，因?yàn)樵谂囵B(yǎng)皿中腫瘤細(xì)胞生長過程中往往會不存在或是沉默（未激活）狀態(tài),。P14ARF是在人體大多數(shù)組織中都不表達(dá)，但受到異常生長信號的刺激會激活,。
在多種癌癥類型中包括膠質(zhì)瘤,，編碼P14ARF的基因發(fā)生突變或是沉默。腦膠質(zhì)瘤是成人中最常見的腦腫瘤類型,。那些遺傳了這一基因突變的人，該基因不能發(fā)揮功能最終會發(fā)展成“惡性黑色素瘤-星形細(xì)胞瘤綜合征”,。因ARF的DNA序列與另一蛋白質(zhì)的DNA序列重疊,，ARF代表了“替代讀碼框”,。以前研究已經(jīng)將P14ARF與p53（抑癌基因）相聯(lián)系起來，p53在癌癥中也發(fā)生了突變,。P53能關(guān)閉（阻斷）DNA損傷導(dǎo)致的腫瘤細(xì)胞的分裂,，因此被稱為“基因組的守護(hù)者”。
Zerrouqi博士說：已有一些線索指出了P14ARF的一個功能,。當(dāng)星形細(xì)胞瘤發(fā)展到神經(jīng)母細(xì)胞瘤（一種更致命的腦腫瘤類型）時,，P14ARF經(jīng)常丟失。
“這些腫瘤更大,，更具浸潤性滲透,，血管生成更多，”Zerrouqi博士說：“然而,，p53在腫瘤發(fā)生早期階段就已突變,，也即在星形細(xì)胞瘤發(fā)展到神經(jīng)母細(xì)胞瘤之前，p53抑癌功能就已喪失,。這表明P14ARF獨(dú)立于p53發(fā)揮功能”,。
Zerrouqi博士表示恢復(fù)已經(jīng)在腫瘤細(xì)胞血管生成過程中丟失的P14ARF表達(dá)之后，P14ARF誘導(dǎo)腦腫瘤細(xì)胞分泌一種稱為TIMP3的蛋白質(zhì),，以抑制血管內(nèi)皮細(xì)胞的遷移,。
Zerrouqi和范·梅厄的發(fā)現(xiàn)適用于腦腫瘤以及其他一些癌癥類型。TIMP3本身已被證實(shí)在腦,、腎,、結(jié)腸癌、乳腺癌和肺癌中是沉默的,，這表明TIMP3可以用來抑制上述腫瘤的生長,。
這項(xiàng)研究由國家癌癥研究所、美國小兒腦腫瘤基金會,、美國腦瘤協(xié)會和東南腦瘤基金會資助,。（生物谷：Bioon.com)
doi:10.1172/JCI38596
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P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3
Abdessamad Zerrouqi, Beata Pyrzynska, Maria Febbraio, Daniel J. Brat, Erwin G. Van Meir
Malignant gliomas are the most common and the most lethal primary brain tumors in adults. Among malignant gliomas, 60%–80% show loss of P14ARF tumor suppressor activity due to somatic alterations of the INK4A/ARF genetic locus. The tumor suppressor activity of P14ARF is in part a result of its ability to prevent the degradation of P53 by binding to and sequestering HDM2. However, the subsequent finding of P14ARF loss in conjunction with TP53 gene loss in some tumors suggests the protein may have other P53-independent tumor suppressor functions. Here, we report what we believe to be a novel tumor suppressor function for P14ARF as an inhibitor of tumor-induced angiogenesis. We found that P14ARF mediates antiangiogenic effects by upregulating expression of tissue inhibitor of metalloproteinase–3 (TIMP3) in a P53-independent fashion. Mechanistically, this regulation occurred at the gene transcription level and was controlled by HDM2-SP1 interplay, where P14ARF relieved a dominant negative interaction of HDM2 with SP1. P14ARF-induced expression of TIMP3 inhibited endothelial cell migration and vessel formation in response to angiogenic stimuli produced by cancer cells. The discovery of this angiogenesis regulatory pathway may provide new insights into P53-independent P14ARF tumor-suppressive mechanisms that have implications for the development of novel therapies directed at tumors and other diseases characterized by vascular pathology.
