Predominant expression of truncated EpCAM is associated with a more aggressive phenotype and predicts poor overall survival in colorectal cancer

Abstract

Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM MF (full-length) and EpCAM MT (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Colorectal cancer (CRC) is a common cause of cancer-related mortality worldwide and approximately 30% of patients present with advanced disease at diagnosis.

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

“…The molecular background for such contradicting findings on the role(s) of EpCAM in EMT regulation has, to the best of our knowledge, not been elucidated yet. In accordance with such discrepancies, high expression of EpCAM is frequently associated with poor clinical outcome of breast, colorectal, pancreatic, and nasopharyngeal carcinomas and ovarian and bladder cancers [ 79 , 81 – 89 ] but with a good prognosis of colonic, gastric, and renal cancer [ 90 – 92 ] and of HNSCCs, as shown in the present study.…”

High Expression of EpCAM and Sox2 is a Positive Prognosticator of Clinical Outcome for Head and Neck Carcinoma

“…Low expression of epithelial marker EpCAM significantly correlated with decreased DFS and DSS (univariate). These findings contradict the reported poor prognosis of breast, colorectal, pancreatic, ovarian and bladder cancers over-expressing EpCAM 48 – 56 , but is in line with the association of high levels of EpCAM with improved prognosis of colonic, gastric and renal cancer 57 – 59 . We further confirmed our findings in a validation cohort composed of biospecimen obtained from HNSCC patients treated with primary radio(chemo)therapy.…”

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

“…Mechanistically, nuclear EpICD forms a complex with β‐catenin, FHL2, and Lef‐1 to regulate oncogenic gene expression 1, with typical target genes being cyclin A and E and the pluripotency‐associated transcription factor c‐Myc 47. More recently, our group demonstrated in a large retrospective study that predominant expression of EpCAM MT (indicative of loss of membranous localization of EpICD) correlates with a more aggressive clinical behavior of CRC, resulting in significantly shortened patient survival 5. Importantly in this study, we observed that truncated EpCAM MT is associated with several factors linked to CSCs and EMT, such as poor differentiation, vascular and marginal invasion, and lymph node metastasis.…”

“…Thus, overexpression of EpCAM is associated with cancer progression and poor outcome in several tumor entities including gastric 2 and pancreatic cancer 3. EpCAM is a poor prognosticator particularly in colorectal cancer (CRC), where loss of membranous EpICD associates with unfavorable outcome as compared to patients with predominant expression of the full‐length form 4, 5, 6.…”