EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition

Abstract

Overexpression of epithelial cell adhesion molecule (EpCAM) has been implicated in advanced endometrial cancer, but its roles in this progression remain to be elucidated. In addition to its structural role in modulating cell-surface adhesion, here we demonstrate that EpCAM is a regulatory molecule in which its internalization into the nucleus turns on a transcription program. Activation of EGF/EGFR signal transduction triggered cell-surface cleavage of EpCAM, leading to nuclear internalization of its cytoplasmic domain EpICD. ChIP-seq analysis identified target genes that are co-regulated by EpICD and its transcription partner, LEF-1. Network enrichment analysis further uncovered a group of 105 genes encoding functions for tight junction, adherent and cell migration. Furthermore, nanomechanical analysis by atomic force microscope (AFM) revealed increased softness and decreased adhesiveness of EGF-stimulated cancer cells, implicating acquisition of an epithelial-mesenchymal transition (EMT) phenotype. Thus, genome editing of EpCAM could be associated with altering these nanomechanical properties towards a less aggressive phenotype. Using this integrative genomic-biophysical approach, we demonstrate for the first time an intricate relationship between EpCAM-regulated transcription and altered biophysical properties of cells that promote EMT in advanced endometrial cancer.

Extracellular Vesicles in Cancer

“…Among exosomal proteins, TGF-β1 and MAGE3/6 can be used as reliable biomarkers to discriminate between benign and malignant ovarian tumors, or to ascertain the efficacy of chemotherapy [119]. Although epithelial cell adhesion molecule (EpCAM) was demonstrated to promote epithelial-mesenchymal transition in advanced stages of endometrial cancer [152], studies indicated that EpCAM is not a robust biomarker to classify exosomes derived from benign and malignant ovarian tumors [134] or to detect early stages of the pathology [153]. Besides EpCAM, several exosomal proteins were identified to be overexpressed in ovarian cancer, including proliferation cell nuclear antigen (PCNA), tubulin beta-3 chain (TUBB3), epidermal growth factor receptor (EGFR), apolipoprotein E (APOE), claudin 3 (CLDN3), fatty acid synthase (FASN), ERBB2, and L1CAM (CD171) [127].…”

EGFR-Dependent Regulated Intramembrane Proteolysis of EpCAM—Letter

“…Hsu and colleagues reported on EGF/EGFR-triggered activation of regulated intramembrane proteolysis (RIP) of EpCAM that induces an EMT phenotype (1). This finding is of utmost interest, as it might explain contradicting effects of EpCAM on adhesion, proliferation, and invasion and shed light on EpCAM-based plasticity in cancer progression.…”

Characteristics of Circular RNA Expression in Ishikawa Human Endometrial Carcinoma Cells with Progesterone Treatment

“…Secondly, Epithelial-to-Mesenchymal Transition (EMT) is an important step towards the invasion and metastasis of cancer (19). Hsu et al demonstrated that epithelial cell adhesion molecule (EpCAM)-regulated transcription exerted in uences on nanomechanical properties of EC cells, which promotes EMT (20). Last, a hospitalbased case-control study examined the association between various polymorphisms in base excision repair (BER) DNA pathway genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1) among Japanese postmenopausal women with and without endometrial cancer and found some worthful interaction (21).…”

“…GO terms with Pvalue < 0.05 were selected and ranked by enrichment score (-log10 (P-value)). Among the BP terms, response to cholesterol, epithelial to mesenchymal transition, and base-excision repair have been reported to be associated with tumor (6,(18)(19)(20)(21). In MF terms, WNT-activated receptor activity and WNT-protein binding might play a role in tumors.…”