Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition
Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition
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DOI：
10.1242/jcs.132779
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Yang, Ruey-Bing
中科院分区：
文献类型：
--
作者：
Lin, Yuh-Charn;Lee, Yi-Ching;Yang, Ruey-Bing
信号肽-CUB-EGF结构域蛋白2（SCUBE 2）属于分泌型、膜结合型多结构域SCUBE蛋白家族。我们之前证明SCUBE 2是一种新型乳腺肿瘤抑制因子，并且可能是一种有用的预后标志物。然而，SCUBE 2在乳腺癌细胞迁移和侵袭中的作用以及它在上皮-间充质转化（EMT）过程中的调节方式仍然不确定。在这项研究中，我们发现，异位SCUBE 2过表达可以通过β-连环蛋白-SOX介导的叉头框A1（E-钙粘蛋白的正调节因子）的诱导和E-钙粘蛋白的上调来增强含E-钙粘蛋白的粘附连接的形成，从而导致上皮转化并抑制侵袭性MDA-MB-231乳腺癌细胞的迁移和侵袭。在TGF-β诱导的EMT中，SCUBE 2的表达与E-钙粘蛋白的表达一起被抑制;单独的SCUBE 2的直接表达足以抑制TGF-β诱导的EMT。此外，定量DNA甲基化，甲基化特异性PCR和染色质免疫沉淀分析表明，SCUBE 2表达被灭活的DNA甲基化在CpG岛招募和结合DNA甲基转移酶1在TGF-β诱导的EMT。总之，我们的研究结果表明，SCUBE 2在抑制乳腺癌细胞的流动性和侵袭性中起着关键作用，通过增加上皮细胞含E-钙粘蛋白的粘附连接的形成，以促进上皮分化和驱动EMT的逆转。
Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. We previously demonstrated that SCUBE2 is a novel breast-tumor suppressor and could be a useful prognostic marker. However, the role of SCUBE2 in breast-cancer cell migration and invasion and how it is regulated during the epithelial-mesenchymal transition (EMT) remain undefined. In this study, we showed that ectopic SCUBE2 overexpression could enhance the formation of E-cadherin-containing adherens junctions by beta-catenin-SOX-mediated induction of forkhead box A1 (a positive regulator of E-cadherin) and upregulation of E-cadherin, which in turn led to epithelial transition and inhibited migration and invasion of aggressive MDA-MB-231 breast-carcinoma cells. SCUBE2 expression was repressed together with that of E-cadherin in TGF-beta-induced EMT; direct expression of SCUBE2 alone was sufficient to inhibit the TGF-beta-induced EMT. Furthermore, quantitative DNA methylation, methylation-specific PCR, and chromatin immunoprecipitation analyses revealed that SCUBE2 expression was inactivated by DNA hypermethylation at the CpG islands by recruiting and binding DNA methyltransferase 1 during TGF-beta-induced EMT. Together, our results suggest that SCUBE2 plays a key role in suppressing breast-carcinoma-cell mobility and invasiveness by increasing the formation of the epithelial E-cadherin-containing adherens junctions to promote epithelial differentiation and drive the reversal of EMT.