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.
Highlights
Lung cancer mortality, especially in non-small cell lung cancers (NSCLCs), remains the leading healthcare issue in cancer therapy worldwide [1, 2] and metastasis is the major cause of treatment failure [2,3,4]
Multivariable Cox proportional-hazards regression analyses with a stepwise selection model were made to evaluate the associations of various independent prognostic factors with patient survival (Table 2). The phenotype of both high Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin and Slug expressions was an independent predictor after controlling for all other prognostic factors. These results suggest that patients with both high MDA-9/Syntenin and high Slug expressions is associated with worse clinical outcomes in lung adenocarcinoma
MDA-9/Syntenin has recently been identified to play an important role in controlling cancer invasion www.impactjournals.com/oncotarget and progression [19]
Summary
Especially in non-small cell lung cancers (NSCLCs), remains the leading healthcare issue in cancer therapy worldwide [1, 2] and metastasis is the major cause of treatment failure [2,3,4]. A member of the Snail family, participates in many physiologic processes, including mesoderm formation, cell migration and invasion [6], and Slug expression correlates with clinical outcome in NSCLC [7,8,9]. Slug proteins are maintained at low levels in low invasive cancer cells through various mechanisms such as ubiquitin-mediated proteosomal degradation. Recent reports show that p53/MDM2 and GSK-3β/CHIP are capable of reducing cancer cell invasion by modulating Slug degradation [7, 10, 11]. Slug transcriptionally represses E-cadherin expression, thereby promoting the EMT process in development, as well as cancer invasion and metastasis [12]. The detailed regulatory mechanisms of Slug-mediated transcriptional control of cancer invasion remain unclear
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