期刊
JOURNAL OF PATHOLOGY
卷 231, 期 2, 页码 257-270出版社
WILEY
DOI: 10.1002/path.4236
关键词
DSC2; miR-25; oesophageal squamous cell carcinoma; invasion; E-cadherin
资金
- National Natural Science Foundation of China [81101613]
- Guangdong Provincial Natural Science Foundation of China [S2011040004363]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20114402120005]
- Natural Science Foundation of China-Guangdong Joint Fund [U0932001]
- National Basic Research Program (973 Program) [2012CB526608, 2010CB912802]
- National High Technology Research and Development Program of China [2012AA02A503, 2012AA02A209]
In contrast to the well-recognized loss of adherens junctions in cancer progression, the role of desmosomal components in cancer development has not been well explored. We previously demonstrated that desmocollin-2 (DSC2), a desmosomal cadherin protein, is reduced in oesophageal squamous cell carcinoma (ESCC), and is associated with enhanced tumour metastasis and poor prognosis. Here, we report that restoration of DSC2 in ESCC cells impeded cell migration and invasion both in vitro and in vivo, whereas siRNA-mediated suppression of DSC2 expression increased cell motility. In E-cadherin-expressing ESCC cells, DSC2 restoration strengthened E-cadherin-mediated adherens junctions and promoted the localization of beta-catenin at these junctions, which indirectly inhibited beta-catenin-dependent transcription. These effects of DSC2 were not present in EC109 cells that lacked E-cadherin expression. ESCC patients with tumours that had reduced E-cadherin and negative DSC2 had poorer clinical outcomes than patients with tumours that lacked either E-cadherin or DSC2, implying that the invasive potential of ESCC cells was restricted by both DSC2 and E-cadherin-dependent junctions. Further studies revealed that DSC2 was a downstream target of miR-25. Enhanced miR-25 promoted ESCC cell invasiveness, whereas restoration of DSC2 abolished these effects. Collectively, our work suggests that miR-25-mediated down-regulation of DSC2 promotes ESCC cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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