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

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-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.

Cleavage and Cell Adhesion Properties of Human Epithelial Cell Adhesion Molecule (HEPCAM)

“…Lack of impact on cell-matrix is in accordance with published work (3,4), but the lack of impact on cell-cell adhesion is clearly contradictory to the standard perception of HEPCAM as a CAM. Proof of a cell-cell adhesion function of HEPCAM originates from work in mesenchymal cells (4), which is obviously not its natural cell type, although claudin-7 was reported to recruit Epcam to ADAM protease and ␥-secretase to foster migration and mesenchymal transition via HEPICD formation (63). Inhibition of cleavage was performed throughout a 24-h period before measurement of adhesion and resulted in almost complete lack of HEPICD formation.…”

Claudin7‐dependent exosome‐promoted reprogramming of nonmetastasizing tumor cells

“…A cld7kd severely affects gastrointestinal cancer progression. In vitro studies suggesting amendment by CIC‐TEX, the mode of CIC‐TEX corrections of cld7kd‐deficits and the in vivo impact of CIC‐TEX on tumor progression were explored in the rat PaCa ASML and the human CoCa SW948.…”

“…CIC‐TEX promoting metastasis, we proceeded to search for an impact on migration and invasion, central in tumor progression . ASML‐cld7kd and SW948‐cld7kd cells in vitro wound healing were promoted by CIC‐TEX; cld7kd‐ and cld7mP‐TEX exerted no effect (Fig.…”

Emerging role of exosome signalling in maintaining cancer stem cell dynamic equilibrium

“…Furthermore, exosomes derived from aggressive cancer cells, especially the CSCs could transport oncogenic factors to recipient cells within tumour microenvironment to induce tumour aggression and progression. For example, colorectal cancer‐initiating cells (CoCIC)‐derived exosomes could transfer claudin‐7 to poorly metastatic cells, consequently, significantly enhanced migratory activity of recipient cells . Nasopharyngeal carcinoma (NPC) cell‐derived exosomes are enriched in hypoxia‐inducible factor‐1α (HIF1α), which could increase migration and invasiveness of NPC cells .…”