Abstract
EpCAM has been described as a therapeutically relevant tumor marker. We noted an interaction between EpCAM and the tight junction protein claudin-7 and here explored the nature of this interaction and its effect on EpCAM-mediated functions. The interaction between EpCAM and claudin-7 was defined in HEK293 cells transfected with rat claudin-7 and EpCAM cDNA. Deletions of the epidermal growth factor-like and the thyroglobin repeat domains of EpCAM or the cytoplasmic domain of EpCAM or claudin-7 did not prevent the EpCAM-claudin-7 association. A chimeric EpCAM molecule with an exchange of the cytoplasmic and transmembrane domains and an EpCAM molecule with point mutations in an AxxxG motif in the transmembrane region do not associate with claudin-7. HEK cells and the rat pancreatic tumor line BSp73AS, transfected with (mutated) EpCAM and claudin-7 cDNA, revealed that the association of both molecules severely alters the functional activity of EpCAM. Claudin-7-associated EpCAM is recruited into tetraspanin-enriched membrane microdomains (TEM). The TEM-located claudin-7-EpCAM complex supports proliferation accompanied by sustained extracellular signal-regulated kinase-1/2 phosphorylation, up-regulation of antiapoptotic proteins, and drug resistance, but not EpCAM-mediated cell-cell adhesion. Enhanced motility may be supported by colocalization of claudin-7 with actin bundles, which is only seen in EpCAM-claudin-7-expressing cells. The EpCAM-claudin-7 complex strongly promotes tumorigenicity, accelerates tumor growth, and supports ascites production and thymic metastasis formation. High expression of the tumor marker EpCAM is frequently associated with poor prognosis, which could well rely on the EpCAM-claudin-7 association that prohibits EpCAM-mediated cell-cell adhesion but promotes migration, proliferation, apoptosis resistance, and tumorigenicity.
Highlights
The epithelial cell adhesion molecule EpCAM (EpC) is expressed on many epithelia [1, 2] and its expression is frequently increased in most carcinomas as well as myelomas [1,2,3,4,5,6,7,8,9,10,11,12]
Using EpC/mutated EpC plus cld-7 cDNA transfected tumor lines, we provide evidence that neither EpC nor cld-7, but the EpC-cld-7 complex promotes tumor growth and progression
HEK cells were transfected with deletion mutants of EpC and cld-7 cDNA, which were tagged with myc as long as the deletion included the antibody binding site
Summary
The epithelial cell adhesion molecule EpCAM (EpC) is expressed on many epithelia [1, 2] and its expression is frequently increased in most carcinomas as well as myelomas [1,2,3,4,5,6,7,8,9,10,11,12]. EpC is a type I transmembrane molecule with an epidermal growth factor (EGF) – like domain, followed by a thyroglobin repeat (TG) domain [20], a cysteine-poor region, a transmembrane, and a short cytoplasmic domain [21]. Both the EGF-like domain and the TG domain form a globular structure and are required for the homophilic cell-cell adhesion of EpC. The EGF-like domain is required for the reciprocal and the TG domain for the lateral interaction of EpC molecules [22] Both domains are required for the anchoring of actin microfilaments at the cell membrane via a-actinin, a process regulated by the cytoplasmic tail of EpC [22]. EpC induces upregulation of the proto-oncogene c-myc [30], where EpC cross-linking triggers, together with tumor necrosis factor – converting enzyme and presenilin 2 NH2-terminal fragment, signals that cleave an intracellular peptide of EpC, EpIC, which forms a complex with h-catenin and Lef-1; locates to the nucleus; and, by binding to Lef consensus sites, initiates c-myc transcription [31]
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