title: MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma.
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.
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Lu-Kai
authors.initials: LK
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.|Doctoral Degree Program of Translational Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.affiliation: Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Hung
authors.affiliation: Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Kao
authors.affiliation: Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Division of Isotope application, Institute of Nuclear Energy Research, Taoyuan, Taiwan.
authors.forename: Chen-Hsien
authors.initials: CH
authors.lastname: Liang
authors.affiliation: Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D053676:Syntenins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C109621:SDCBP protein, human; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D053676:Syntenins; D014157:Transcription Factors
keywords: EMT; Slug; Syntenin; invasion; lung adenocarcinoma