Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells
Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells
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DOI：
10.1002/mc.22644
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发表时间：
2017-08-01
影响因子：
4.6
通讯作者：
Spindler, Volker
中科院分区：
文献类型：
--
作者：
Huetz, Katharina;Zeiler, Julian;Spindler, Volker
维持细胞间粘附的能力对于组织的完整性和组织至关重要。因此，内聚性的丧失在癌症侵袭和转移中起关键作用。桥粒是提供强细胞间粘附强度的细胞连接，桥粒组分的失调通过改变的细胞信号传导途径促进癌症进展。在这里，我们专注于桥粒粘附分子桥粒糖蛋白2（Dsg 2）和桥粒胶原蛋白2（Dsc 2），以及它们在胰腺癌细胞迁移和侵袭中的作用。沉默Dsg2而不是Dsc2导致细胞凝聚力的丧失和增强的迁移，以及胰腺癌细胞的侵袭。为了确定Dsg2调节的潜在途径，我们进行了激酶阵列，并检测到ERK和生长因子受体的活性在Dsg2缺陷细胞中显著增强。因此，在Dsg2敲低细胞中抑制ERK磷酸化使迁移正常化。Dsg2的缺失导致桥粒衔接蛋白和转录调节因子斑珠蛋白（PG）以ERK依赖的方式水平降低，而其他桥粒分子没有改变。PG的过表达拯救了由Dsg2沉默诱导的增强的迁移。这些结果鉴定了胰腺癌细胞的一种新的促迁移途径，其中Dsg2的缺失通过失调的MAPK信号传导降低PG的水平。
The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.