Deregulation of the Hippo Pathway Promotes Tumor Cell Proliferation Through YAP Activity in Human Sporadic Vestibular Schwannoma
Deregulation of the Hippo Pathway Promotes Tumor Cell Proliferation Through YAP Activity in Human Sporadic Vestibular Schwannoma
复制标题
在人类散发性前庭神经鞘瘤中，Hippo 通路的失调通过 YAP 活性促进肿瘤细胞增殖
DOI：
10.1016/j.wneu.2018.06.010
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发表时间：
2018
影响因子：
2
通讯作者：
Liu Pinan
中科院分区：
文献类型：
--
作者：
Zhao Fu;Yang Zhijun;Chen Yang;Zhou Qiangyi;Zhang Jing;Liu Jiang;Wang Bo;He Qiyang;Zhang Li;Yu Yanbing;Liu Pinan
目的前庭神经鞘瘤（VSs）可导致严重的神经系统缺陷，包括听力损失和面瘫。本研究的目的是确定 Hippo 信号传导是否可以成为 VS 临床治疗的潜在靶向途径。方法对 10 个散发性 VS 和 4 个正常神经进行基因表达谱分析，以识别 Hippo 途径的异常基因表达。采用Western blotting和免疫组化染色检测20份VS样本中Hippo核心成分的表达情况。还使用桑格测序对所有肿瘤进行了 2 型神经纤维瘤病 (NF2) 基因测序。维替泊芬是 yes 相关蛋白 (YAP)-TEA 结构域家族成员的抑制剂，用于评估人原代 VS 细胞和 RT4-D6P2T 细胞系的增殖抑制效果。结果我们发现 VS 和健康对照之间 Hippo 通路有 51 个差异表达基因。无监督分析确定了与不同 NF2 突变状态显着相关的 2 个分子变异。与野生型 VS 和正常神经相比，NF2 突变 VS 中大肿瘤抑制因子 1 和 YAP 的磷酸化水平显着降低。免疫组织化学染色显示VSs核YAP表达增加与高Ki-67指数和低Merlin表达呈正相关。维替泊芬降低了原代 VS 细胞和 RT4-D6P2T 细胞的活力。结论我们的研究结果表明，Hippo 通路的失调是人类 VS 发病机制的一种分子机制，并表明抑制该通路作为一种潜在的治疗策略。
ObjectiveVestibular schwannomas (VSs) can cause serious neurological defects including hearing loss and facial paralysis. The aim of this study is to identify whether Hippo signaling could be a potential targetable pathway for clinical treatment in VSs.MethodsGene expression profiling was performed in 10 sporadic VSs and 4 normal nerves to identify aberrant genes expression of the Hippo pathway. Western blotting and immunohistochemical staining were used to examine the expression of Hippo core components in 20 VS samples. Neurofibromatosis type 2 (NF2) gene sequencing was also performed in all tumors using sanger sequencing. Verteporfin, inhibitor of yes-associated protein (YAP)-TEA domain family member, was used to assess the effect of proliferation inhibition in human primary VS cells and RT4-D6P2T cell line.ResultsWe found 51 differentially expressed genes of the Hippo pathway between VSs and healthy controls. Unsupervised analysis identified the 2 molecular variants that significantly related with distinctNF2mutation status. The phosphorylation levels of large tumor suppressor 1 and YAP were significantly decreased inNF2-mutated VSs compared with wild-type VSs and normal nerves. Immunohistochemical staining showed that increased nuclear YAP expression in VSs was positively correlated with high Ki-67 index and low Merlin expression. Verteporfin reduced viability of primary VS cells and RT4-D6P2T cells.ConclusionsOur findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human VSs, and suggest inhibition of this pathway as a potential treatment strategy.