MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells.
MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells.
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DOI：
10.18632/oncotarget.5323
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
He J
中科院分区：
文献类型：
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作者：
Ma Q;Yang Y;Feng D;Zheng S;Meng R;Fa P;Zhao C;Liu H;Song R;Tao T;Yang L;Dai J;Wang S;Jiang WG;He J
胶质瘤是最常见的原发性脑恶性肿瘤，预后较差。在这里，我们发现含有PDZ结构域的蛋白膜相关鸟苷酸激酶倒置3 （MAGI3）在人胶质瘤样本的mRNA和蛋白水平上都下调。在其过表达和敲低研究中，MAGI3抑制胶质瘤细胞的增殖、迁移和细胞周期进展。通过GST下拉和共免疫沉淀实验，我们发现MAGI3通过其PDZ结构域和β-catenin的PDZ结合基序与β-catenin结合。MAGI3过表达通过与β-catenin相互作用抑制β-catenin的转录活性。同样，在胶质瘤细胞C6中，MAGI3的过表达抑制了β-catenin靶基因Cyclin D1和Axin2的表达，而在胶质瘤细胞U373和LN229中，MAGI3的下调增强了它们的表达。MAGI3过表达可抑制小鼠C6皮下肿瘤的生长，抑制异种移植肿瘤中β-catenin靶基因的表达。此外，基于Gene Expression Omnibus （GEO）胶质瘤数据集的分析显示，MAGI3的表达与总体生存和肿瘤分级有关。最后，我们通过三个公开胶质瘤数据集的GSEA和临床胶质瘤样本的免疫组织化学染色证明了MAGI3的表达与Wnt/β-catenin信号活性呈负相关。综上所述，这些结果确定了MAGI3是一种新的肿瘤抑制因子，并为胶质瘤的发病机制提供了新的见解。
Gliomas are the most common primary brain malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both mRNA and protein levels in human glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-catenin through its PDZ domains and the PDZ-binding motif of β-catenin. MAGI3 overexpression inhibited β-catenin transcriptional activity via its interaction with β-catenin. Consistently, MAGI3 overexpression in glioma cells C6 suppressed expression of β-catenin target genes including Cyclin D1 and Axin2, whereas MAGI3 knockdown in glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous tumors in mice, and inhibited expression of β-catenin target genes in xenograft tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO) glioma dataset showed association of MAGI3 expression with overall survival and tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-catenin signaling through GSEA of three public glioma datasets and immunohistochemical staining of clinical glioma samples. Taken together, these results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma.