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Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma.
Cell Communication and Signaling ( IF 8.4 ) Pub Date : 2020-02-11 , DOI: 10.1186/s12964-019-0501-9
Wei Yang 1 , Peng-Fei Wu 1 , Jian-Xing Ma 1 , Mao-Jun Liao 1 , Lun-Shan Xu 1 , Min-Hui Xu 1 , Liang Yi 1
Affiliation  

BACKGROUND Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. METHODS Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. RESULTS In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation. CONCLUSION Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/β-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

中文翻译:

Presenilin1通过抑制胶质母细胞瘤中的Wnt /β-catenin途径发挥抗增殖作用。

背景胶质母细胞瘤和阿尔茨海默氏病(AD)是中枢神经系统中最常见和破坏性的疾病。Presenilin1的功能障碍是AD发病机理的主要原因。但是,Presenilin1的分子功能及其在胶质母细胞瘤中的相关机制仍不清楚。方法采用免疫组化法检测早老素1在神经胶质瘤中的表达。CCK-8,集落形成,流式细胞仪,Edu染色用于评估presenilin1对胶质母细胞瘤增殖的作用。通过蛋白质印迹和细胞免疫荧光评估上述过程的机理。小鼠移植胶质母细胞瘤模型和微MRI检测被用来验证体内presenilin1的功能。结果在这项研究中,我们发现,所有级别的神经胶质瘤都维持相对较低的Presenilin1表达,而高级神经胶质瘤中Presenilin1的表达明显低于低级别神经胶质瘤。此外,Presenilin1水平与神经胶质瘤和胶质母细胞瘤患者的预后呈正相关。接下来,我们确定Presenilin1通过下调CDK6,C-myc和Cyclin D1抑制胶质母细胞瘤细胞的生长和增殖,从而使细胞周期停滞在G1 / S期。从机制上讲,Presenilin1促进了45位的β-catenin的直接磷酸化和33/37/41位的间接磷酸化,然后降低了β-catenin的稳定部分并阻碍了其从细胞质到核的转运。此外,我们发现Presenilin1的下调明显促进了皮下胶质母细胞瘤的生长,而Presenilin1的过表达通过阻碍β-catenin依赖性细胞增殖而显着抑制了胶质母细胞瘤的皮下和颅内移植。结论我们的数据通过抑制Wnt /β-catenin信号传导暗示Presenilin1在胶质母细胞瘤中的抗增殖作用,这可能为胶质母细胞瘤提供了一种新型治疗剂。录像摘要。
更新日期:2020-04-22
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