Epithelial cell adhesion molecule fragments and signaling in primary human liver cells

J Cell Physiol. 2018 Jun;233(6):4841-4851. doi: 10.1002/jcp.26286. Epub 2017 Dec 26.

Abstract

Epithelial Cell Adhesion Molecule (EpCAM), or CD326, is a trans-membrane glycoprotein expressed by multiple normal epithelia as well as carcinoma. Human hepatic stem cells and bile duct epithelium of the liver are EpCAM positive. In tumor cell lines, its intracellular domain can be released after cleavage of the extracellular domain. Within the cell nucleus, it induces cell proliferation, but cleavage depends on cell contact. Fragments of various lengths have been described in tumor cells. Despite its described important role in proliferation in tumor cells, there is not much known about the expression and role of EpCAM fragments in primary human liver cells. Here, we demonstrate that EpCAM protein fragments and function are considerable different between tumor cells, normal fetal and adult liver cells. Contrary to previously reported findings in tumor cells, gene knockdown or treatment with an inhibitor of the cleavage enzyme ADAM17 (TACE) rather increased cell numbers in primary human fetal liver-derived EpCAM-positive cells. EpCAM fragment sizes were not affected by treatment with inhibitor. Knockdown of EPCAM gene expression by siRNA in sorted cells did not significantly affect proliferation-associated genes or cell numbers. The intracellular domain could not be detected within cell nuclei of fetal and adult liver cells. In conclusion, signaling through the intracellular domain of EpCAM appears to be a mechanism that induces proliferation specifically in tumorigenic cells but not in normal primary EpCAM-positive liver cells.

Keywords: CD326; EpCAM; hepatocyte; liver; progenitor; stem cell.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / metabolism*
  • Cell Proliferation* / drug effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Epithelial Cell Adhesion Molecule / genetics
  • Epithelial Cell Adhesion Molecule / metabolism*
  • Fetal Stem Cells / drug effects
  • Fetal Stem Cells / metabolism*
  • Gene Expression Regulation
  • Glycosylation
  • HT29 Cells
  • Humans
  • Hydroxamic Acids / pharmacology
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Peptide Fragments / metabolism*
  • Primary Cell Culture
  • Protein Domains
  • Signal Transduction* / drug effects

Substances

  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • Hydroxamic Acids
  • Peptide Fragments
  • TAPI-2
  • ADAM17 Protein
  • ADAM17 protein, human