Effects of differential distributed-JUP on the malignancy of gastric cancer.

JUP, a homologue of ß-catenin, is a cell-cell junction protein involved in adhesion junction and desmosome composition. JUP may have a controversial role in different malignancies dependence of its competence with or collaboration with ß-catenin as a transcription factor. In this study, we reveal that the function of JUP is related to its cellular location in GC development process from epithelium-like, low malignant GC to advanced EMT-phenotypic GC. Gradual loss of membrane and/or cytoplasm JUP is closely correlated with GC malignancy and poor prognostics. Knockdown of JUP in epithelium-like GC cells causes EMT and promotes GC cell migration and invasion. Ectopic expression of wild JUP in malignant GC cells leads to an attenuated malignant phenotype such as reduced cell invasive potential. In mechanism, loss of membrane and/or cytoplasm JUP abolishes the restrain of JUP to EGFR at cell membrane and results in increased p-AKT levels and AKT/GSK3ß/ß-catenin signaling activity. In addition, nuclear JUP interacts with nuclear ß-catenin and TCF4 and plays a synergistic role with ß-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion.