Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma
Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma
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DOI：
10.1002/path.4236
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发表时间：
2013-10-01
影响因子：
7.3
通讯作者：
Li, En-Min
中科院分区：
文献类型：
--
作者：
Fang, Wang-Kai;Liao, Lian-Di;Li, En-Min
与公认的黏着连接在癌症进展中的丢失相反，桥粒体成分在癌症发展中的作用尚未得到很好的探讨。我们之前已经证明，桥胞蛋白-2 (DSC2)，一种桥胞体钙粘蛋白，在食管鳞状细胞癌（ESCC）中减少，并且与肿瘤转移增强和预后不良相关。在这里，我们报道了ESCC细胞中DSC2的恢复在体外和体内都阻碍了细胞的迁移和侵袭，而sirna介导的DSC2表达抑制增加了细胞的运动性。在表达e -cadherin的ESCC细胞中，DSC2修复增强了e -cadherin介导的粘附连接，促进了β -catenin在这些连接处的定位，间接抑制了β -catenin依赖的转录。DSC2的这些作用在缺乏e -钙粘蛋白表达的EC109细胞中不存在。与缺乏E-cadherin或DSC2的肿瘤患者相比，肿瘤中E-cadherin减少和DSC2阴性的ESCC患者的临床结果更差，这意味着ESCC细胞的侵袭潜力受到DSC2和E-cadherin依赖性连接的限制。进一步的研究表明，DSC2是miR-25的下游靶点。miR-25的增强促进了ESCC细胞的侵袭性，而DSC2的恢复则消除了这些作用。总之，我们的工作表明，mir -25介导的DSC2下调通过重新分配粘附连接和激活β -连环蛋白信号传导来促进ESCC细胞的侵袭性。版权所有(c) 2013大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
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.