近日,，約翰霍普金斯大學(xué)的研究人員發(fā)表論文稱：他們已經(jīng)發(fā)現(xiàn)腦膜瘤生長的重要的細(xì)胞機(jī)制之一,。
在腦膜瘤細(xì)胞中,，Baia研究激活的蛋白質(zhì)YAP1,，這是由Hippo調(diào)控的蛋白。沒有Hippo,，YAP1會移動(dòng)到細(xì)胞核,，并激活觸發(fā)腫瘤細(xì)胞增殖的基因。
近年來,，已發(fā)現(xiàn)Hippo信號通路在其他類型的癌細(xì)胞生長中發(fā)揮了作用,，但該研究是第一次證實(shí)該通路與腦膜瘤有關(guān)。YAP1也與其他癌癥有關(guān)聯(lián)包括肺癌和卵巢的惡性腫瘤,，NF2突變存在于其他不太常見的腦癌類型中,。
在他們的研究中,，研究人員收集了70例腦膜瘤組織樣本，發(fā)現(xiàn)所有樣品的原子核中都表達(dá)YAP1,，并且不與腫瘤的發(fā)展歷程相關(guān),，這意味著它似乎在腦膜瘤的早期階段就存在。在實(shí)驗(yàn)室研究中,，研究人員敲除細(xì)胞核YAP1后發(fā)現(xiàn),，腫瘤細(xì)胞增會受到抑制。但當(dāng)YAP1表達(dá)增多時(shí),，細(xì)胞生長和遷移也更快,。
研究人員正在開發(fā)針對這一靶基因的新的治療方法。這項(xiàng)研究由Leonard和Phyllis Attman基金會捐款支持,。（生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-12-0116
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Yes-Associated Protein 1 Is Activated and Functions as an Oncogene in Meningiomas
G. S. Baia, O. L. Caballero, B. A. Orr, A. Lal, J. S. Y. Ho, C. Cowdrey, T. Tihan, C. Mawrin, G. J. Riggins.
The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are comprised of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4 and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas and the NF2 gene product, Merlin acts upstream of the Hippo pathway. Here we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using a siRNA transient knockdown of YAP1 in NF2 mutant meningioma cells we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth, and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis.
