Merlin is a potent inhibitor of glioma growth.
Merlin is a potent inhibitor of glioma growth.
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DOI：
10.1158/0008-5472.can-08-0190
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Lau YK;Murray LB;Houshmandi SS;Xu Y;Gutmann DH;Yu Q
神经纤维瘤病2（NF 2）是一种遗传性癌症综合征，其中受影响的个体发展为神经系统肿瘤，包括神经鞘瘤、脑膜瘤和室管膜瘤。NF 2蛋白merlin（或施万诺明）是蛋白质带4.1超家族的成员，其充当跨膜蛋白和肌动蛋白细胞骨架之间的接头。除了在NF 2相关肿瘤中NF 2基因的突变失活之外，在其他类型的癌症中也报道了merlin表达的突变和缺失。在本研究中，我们发现，merlin的表达显着减少，在人类恶性胶质瘤和功能性merlin的再表达显着抑制皮下和颅内生长的人胶质瘤细胞在小鼠。我们进一步表明，merlin的再表达抑制胶质瘤细胞的增殖，促进体内细胞凋亡。使用微阵列分析，我们确定了在细胞增殖，存活和运动中起关键作用的特定分子的表达改变。这些merlin诱导的基因表达的变化，证实了实时定量PCR，蛋白质印迹，和功能测定。这些结果表明，merlin的再表达与哺乳动物不育20-like 1/2-large肿瘤抑制因子2信号通路的激活以及经典和非经典Wnt信号的抑制相关。总的来说，我们的研究结果表明，梅林是一个有效的抑制剂，高级别的人类胶质瘤。
Neurofibromatosis 2 (NF2) is an inherited cancer syndrome in which affected individuals develop nervous system tumors, including schwannomas, meningiomas, and ependymomas. The NF2 protein merlin (or schwannomin) is a member of the Band 4.1 superfamily of proteins, which serve as linkers between transmembrane proteins and the actin cytoskeleton. In addition to mutational inactivation of the NF2 gene in NF2-associated tumors, mutations and loss of merlin expression have also been reported in other types of cancers. In the present study, we show that merlin expression is dramatically reduced in human malignant gliomas and that reexpression of functional merlin dramatically inhibits both subcutaneous and intracranial growth of human glioma cells in mice. We further show that merlin reexpression inhibits glioma cell proliferation and promotes apoptosis in vivo. Using microarray analysis, we identify altered expression of specific molecules that play key roles in cell proliferation, survival, and motility. These merlin-induced changes of gene expression were confirmed by real-time quantitative PCR, Western blotting, and functional assays. These results indicate that reexpression of merlin correlates with activation of mammalian sterile 20-like 1/2–large tumor suppressor 2 signaling pathway and inhibition of canonical and noncanonical Wnt signals. Collectively, our results show that merlin is a potent inhibitor of high-grade human glioma.