Claudin-7 promotes the epithelial - mesenchymal transition in human colorectal cancer

Abstract

// Rahel Philip 1 , Sarah Heiler 1 , Wei Mu 1 , Markus W. Büchler 2 , Margot Zöller 1 and Florian Thuma 1 1 Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg 2 University Hospital of General Surgery, Heidelberg Correspondence: Florian Thuma, email: // Margot Zöller, email: // Keywords : Colorectal cancer, claudin 7, EpCAM, cancer initiating cells, metastasis Received : September 15, 2014 Accepted : December 02, 2014 Published : December 03, 2014 Abstract 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-cld7 kd and SW948-cld7 kd cells display decreased anchorage-independent growth and the capacity for holoclone-, respectively, sphere-formation is reduced. Tumor growth is delayed and cld7 kd cells poorly metastasize. In line with this, migratory and invasive potential of cld7 kd 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-7 kd cells. But, uptake of HT29 wt and SW948 wt exosomes by the claudin-7 kd 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.