(Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway
(Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway
复制标题
DOI：
10.3171/2016.9.jns16431
复制
发表时间：
2017-10-01
影响因子：
4.1
通讯作者：
Tamiya, Takashi
中科院分区：
文献类型：
--
作者：
Kouchi, Masaaki;Shibayama, Yuki;Tamiya, Takashi
目的 肾素（原）受体（PRR）通过激活 Wnt/β-连环蛋白信号通路，在中枢神经系统的早期发育中发挥重要作用。作者研究了 PRR 在神经胶质瘤发病机制中的潜在作用。 方法 作者进行了免疫组织化学分析，在 31 个神经胶质瘤的石蜡切片中检测了 PRR 和含有精氨酸 132 (IDHIR132H) 突变的异柠檬酸脱氢酶 1。采用Western blotting检测培养的人胶质瘤细胞系（U251MG、U87MG和T98G）中PRR和Wnt通路成分的表达，还检测了PRR短干扰RNA（siRNA）对胶质瘤细胞增殖（WST-1检测和直接细胞计数）和凋亡（流式细胞术和caspase-3检测）的影响。 结果 PRR在胶质母细胞瘤中的表达显着高于正常组织或低级别胶质瘤细胞神经胶质瘤，无论 /DH1(R132H) 突变如何。人胶质母细胞瘤细胞系中的 PRR 表达也高于人星形胶质细胞。 PRR表达与Ki-67标记指数呈显着正相关，而与胶质瘤患者的生存时间呈显着负相关。 PRR siRNA 处理显着降低人胶质母细胞瘤细胞系 Wnt2、活化 β-catenin 和细胞周期蛋白 D1 的表达，并降低这些细胞系的增殖能力并诱导细胞凋亡。结论这是 PRR 通过异常激活 Wnt/β-catenin 信号通路在神经胶质瘤发生过程中发挥重要作用的第一个证据。该受体可能既是神经胶质瘤的预后标志物又是治疗靶点。
OBJECTIVE The (pro)renin receptor (PRR) plays an essential role in the early development of the central nervous system by activating the Wnt/beta-catenin signaling pathway. The authors investigated the potential role of the PRR in the pathogenesis of glioma.METHODS The authors performed immunohistochemical analysis to detect both the PRR and isocitrate dehydrogenase 1 with mutations involving arginine 132 (IDHIR132H) in paraffin sections of 31 gliomas. Expression of the PRR and Wnt pathway components in cultured human glioma cell lines (U251MG, U87MG, and T98G) was measured using Western blotting, The effects of PRR short interfering RNA (siRNA) on glioma cell proliferation (WST-1assay and direct cell counting) and apoptosis (flow cytometry and the caspase-3 assay) were also examined.RESULTS PRR expression was significantly higher in glioblastoma than in normal tissue or in lower grade glioma, regardless of /DH1(R132H) mutation. PRR expression was also higher in human glioblastoma cell lines than in human astrocytes. PRR expression showed a significant positive correlation with the Ki-67 labeling index, while it had a significant negative correlation with the survival time of glioma patients. Treatment with PRR siRNA significantly reduced expression of Wnt2, activated beta-catenin, and cyclin D1 by human glioblastoma cell lines, and it reduced the proliferative capacity of these cell lines and induced apoptosis.CONCLUSIONS This is the first evidence that the PRR has an important role in development of glioma by aberrant activation of the Wnt/beta-catenin signaling pathway. This receptor may be both a prognostic marker and a therapeutic target for glioma.