Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer.
Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer.
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DOI：
10.18632/oncotarget.2858
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Thuma F
中科院分区：
文献类型：
--
作者：
Philip R;Heiler S;Mu W;Büchler MW;Zöller M;Thuma F
在结肠直肠癌（CoCa）中，EpCAM经常与密蛋白-7相关。有证据表明，肿瘤促进EpCAM活性通过与密蛋白-7的关联来调节。为了支持这一假设，在HT 29和SW 948细胞中敲低了密蛋白-7（kd）。HT 29-cld 7 kd和SW 948-cld 7 kd细胞显示出降低的锚定非依赖性生长，并且全克隆形成的能力分别降低。肿瘤生长延迟，cld 7 kd细胞转移不良。与此一致，cld 7 kd克隆的迁移和侵袭潜力被强烈损害，迁移被抗CD 49 c抑制，但不被抗EpCAM抑制，尽管在EpCAM siRNA处理的细胞中运动性降低。这是由于密蛋白-7将富含糖脂的膜级分中的EpCAM募集至密蛋白-7相关的TACE和早老素2，其切割EpCAM。裂解的细胞内结构域EpIC促进上皮-间质转化（EMT）相关的转录因子表达，其与纤连蛋白和波形蛋白一起在claudin-7 kd细胞中减少。但是，紧密连接蛋白-7kd系对HT 29 wt和SW 948 wt外泌体的摄取足以上调转录因子并恢复运动性。因此，claudin-7有助于运动性和侵袭性，并且是向TACE/早老蛋白2募集EpCAM所需的。EpIC生成通过促进向EMT的转变来进一步支持运动性。值得注意的是，cld 7感受态转移性CoCa细胞的EMT特征可以通过外来体转移到转移性差的细胞。
In colorectal cancer (CoCa) EpCAM is frequently associated with claudin-7. There is evidence that tumor-promoting EpCAM activities are modulated by the association with claudin-7. To support this hypothesis, claudin-7 was knocked-down (kd) in HT29 and SW948 cells. HT29-cld7kd and SW948-cld7kd cells display decreased anchorage-independent growth and the capacity for holoclone-, respectively, sphere-formation is reduced. Tumor growth is delayed and cld7kd cells poorly metastasize. In line with this, migratory and invasive potential of cld7kd clones is strongly impaired, migration being inhibited by anti-CD49c, but not anti-EpCAM, although motility is reduced in EpCAM siRNA-treated cells. This is due to claudin-7 recruiting EpCAM in glycolipid-enriched membrane fractions towards claudin-7-associated TACE and presenilin2, which cleave EpCAM. The cleaved intracellular domain, EpIC, promotes epithelial-mesenchymal transition (EMT)-associated transcription factor expression, which together with fibronectin and vimentin are reduced in claudin-7kd cells. But, uptake of HT29wt and SW948wt exosomes by the claudin-7kd lines sufficed for transcription factor upregulation and for restoring motility. Thus, claudin-7 contributes to motility and invasion and is required for recruiting EpCAM towards TACE/presenilin2. EpIC generation further supports motility by promoting a shift towards EMT. Notably, EMT features of cld7-competent metastatic CoCa cells can be transferred via exosomes to poorly metastatic cells.
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