Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities.
Highlights
Epithelial cell adhesion molecule (EpCAM) is an approximately 40 kilodalton, type I transmembrane glycoprotein
In vitro strated that p53, which frequently mutatedinand inactivated in cancer, analysis demonstrated that EpCAM silencing is associated with increased extracellular signal-regulated kinases (ERK) pathway activation, which is a potent mediator of epithelial-to-mesenchymal transition (EMT)
Upregulated nuclear β-catenin signaling is a major driver in many cancers and promotes EMT [48]. These findings suggest that regulated intramembrane proteolysis (RIP) of EpCAM, which would presumably relieve its adhesive function, likely promotes EMT
Summary
Epithelial cell adhesion molecule (EpCAM) is an approximately 40 kilodalton (kD), type I transmembrane glycoprotein. EpCAM’s different protein domains have unique roles in EMT and their function is dependent on the cellular and/or extracellular location of their expression In some studies, it is not in epithelial cancers, but can have an inhibitory or negligible impact in mesenchymal cancers. The authors noted that the small and sparsely disbursed EpCAM adhesions identified by electron microscopy would not be capable of causing the broad and close approximation of the cell membrane that was being observed [33] While these two reports provide important evidence and critical questions, further investigation is needed for clarification. Show that EpCAM is a CAM that forms homophilic, intercellular adhesions, maintains epithelial integrity, and promotes cellular aggregation
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