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Oncotarget. 2016 Jan 5;7(1):386-401. doi: 10.18632/oncotarget.6299.

MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma.

Author information

1
Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
2
Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
3
Doctoral Degree Program of Translational Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
4
Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
5
Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.
6
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
7
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
8
Division of Isotope application, Institute of Nuclear Energy Research, Taoyuan, Taiwan.
9
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
10
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
11
Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
12
NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis.

KEYWORDS:

EMT; Slug; Syntenin; invasion; lung adenocarcinoma

PMID:
26561205
PMCID:
PMC4808006
DOI:
10.18632/oncotarget.6299
[Indexed for MEDLINE]
Free PMC Article

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