Oncotarget

Research Papers:

MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells

Qian Ma _, Ying Yang, Duiping Feng, Shuai Zheng, Ran Meng, Pengyan Fa, Chunjuan Zhao, Hua Liu, Ran Song, Tao Tao, Longyan Yang, Jie Dai, Songlin Wang, Wen G. Jiang and Junqi He

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Oncotarget. 2015; 6:35851-35865. https://doi.org/10.18632/oncotarget.5323

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Abstract

Qian Ma1,*, Ying Yang2,*, Duiping Feng3,*, Shuai Zheng1, Ran Meng1, Pengyan Fa1, Chunjuan Zhao1, Hua Liu1, Ran Song1, Tao Tao1, Longyan Yang1, Jie Dai4,5, Songlin Wang1,6, Wen G. Jiang5,7, Junqi He1,5

1Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China

2Core Facilities Center, Capital Medical University, Beijing 100069, China

3Department of Interventional Radiology, First Hospital of Shanxi Medical University, Taiyuan 030001, China

4Department of Pathology, Capital Medical University, Beijing 100069, China

5Beijing Key Laboratory for Tumor Invasion and Metastasis, Capital Medical University-Cardiff University Joint Centre for Biomedical Research, Cancer Institute of Capital Medical University, Beijing 100069, China

6Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing 100050, China

7Metastasis and Angiogenesis Research Group, Department of Surgery, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, U.K

*These authors have contributed equally to this work

Correspondence to:

Junqi He, e-mail: jq_he@ccmu.edu.cn

Keywords: glioma, β-catenin, MAGI3, PDZ, protein-protein interaction

Received: April 23, 2015     Accepted: September 24, 2015     Published: October 06, 2015

ABSTRACT

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.


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