JUP, a homologue of β-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 β-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/GSK3β/β-catenin signaling activity. In addition, nuclear JUP interacts with nuclear β-catenin and TCF4 and plays a synergistic role with β-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion.

JUP是β-catenin的同源物，是一种细胞-细胞连接蛋白，参与粘附连接和桥粒的组成。JUP在与β-catenin作为转录因子的能力或与β-catenin协同作用的不同恶性肿瘤中可能具有争议的作用。在这项研究中，我们揭示了JUP的功能与其在GC发育过程中从上皮样低恶性GC到晚期EMT表型GC的细胞位置有关。膜和/或细胞质JUP的逐渐丧失与GC恶性肿瘤和不良预后密切相关。在上皮样GC细胞中敲低JUP会引起EMT，并促进GC细胞迁移和侵袭。恶性GC细胞中野生JUP的异位表达导致恶性表型减弱，例如细胞侵袭潜能降低。在机制上 膜和/或细胞质JUP的丧失消除了JUP对细胞膜上EGFR的抑制作用，并导致p-AKT水平和AKT /GSK3β/β-catenin信号传导活性增加。另外，核JUP与核β-catenin和TCF4相互作用，并与β-catenin协同作用，促进TCF4转录及其下游靶MMP7表达，从而促进GC细胞的入侵。