ArticleJournal of biomedical science2024
Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression.
Article in Journal of biomedical science, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- A colorectal cancer risk model based on cell adhesion-related genes for predicting prognosis and immunological features.Molecular genetics and genomics : MGG · 2026Article
- Circulating Tumor Cells Detected Using EpAb3-5 as Prognostic Indicators in Head and Neck Squamous Cell Carcinoma.Journal of Cancer · 2026Article
- EpCAM activates the ERK-EGR1 signaling axis and promotes TNF-α-induced the progression of anaplastic thyroid cancer.Journal of translational medicine · 2025Article
- Hinokitiol reduces tumor metastasis by regulating epithelial cell adhesion molecule via protein kinase-B/mammalian target of rapamycin signaling pathway.American journal of cancer research · 2025Article
- Unveiling the dual role of circulating tumor cells in colorectal cancer immunotherapy: a comprehensive review of biomarker utility and immune microenvironment crosstalk.Frontiers in immunology · 2025Review
- Construction of EpCAM overexpression and knockdown vectors and their implications in colorectal cancer research.Frontiers in genome editing · 2025Article
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8 authors.
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Abstract
backgroundEpithelial cell adhesion molecule (EpCAM) has been widely studied as a tumor antigen due to its expression in varieties of solid tumors. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extracellular (EpEX) and intracellular (EpICD) domains. In colorectal cancer (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and β-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes that; however, remains unclear whether Wnt signaling is modulated by EpICD activity.
methodsPatient-derived organoids (PDOs), patient-derived xenografts (PDXs), and various CRC cell lines were used to study the roles of EpCAM and EpICD in Wnt receptor expression. Fluorescence and confocal microscopy were used to analyze tumors isolated from PDX and other xenograft models as well as CRC cell lines. EpCAM signaling was intervened with our humanized form of EpCAM neutralizing antibody, hEpAb2-6. Wnt receptor promoters under luciferase reporters were constructed to examine the effects of EpICD. Luciferase reporter assays were performed to evaluate promoter, γ-secretase and Wnt activity. Functional assays including in vivo tumor formation, organoid formation, spheroid and colony formation experiments were performed to study Wnt related phenomena. The therapeutic potential of EpCAM suppression by hEpAb2-6 was evaluated in xenograft and orthotopic models of human CRC.
resultsEpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the β-Catenin destruction complex (GSK3β and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our hEpAb2-6 antibody blocked EpICD-mediated upregulation of Wnt receptor expressions and conferred therapeutic benefits in both PDX and orthotopic models of human CRC.
conclusionsThis study uncovers relevant functions of EpCAM where Wnt receptors are upregulated via the transcriptional co-factor activity of EpICD. The resultant enhancement of Wnt signaling induces γ-secretase activity further stimulating EpICD cleavage and its nuclear translocation. Our humanized anti-EpCAM antibody hEpAb2-6 blocks these mechanisms and may thereby provide therapeutic benefit in CRC.
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