title: 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.
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg.
authors.forename: Rahel
authors.initials: R
authors.lastname: Philip
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg.
authors.forename: Sarah
authors.initials: S
authors.lastname: Heiler
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg.
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.affiliation: University Hospital of General Surgery, Heidelberg.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg.
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg.
authors.forename: Florian
authors.initials: F
authors.lastname: Thuma
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition; D055354:Exosomes / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D018874:Spheroids, Cellular / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000951:Antigens, Neoplasm; C473255:CLDN7 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; D000071858:Epithelial Cell Adhesion Molecule