Suppression of cell death by the secretory form of N-terminal ERC/mesothelin

Int J Mol Med. 2010 Aug;26(2):185-91. doi: 10.3892/ijmm_00000451.

Abstract

ERC/mesothelin is highly expressed in malignant mesothelioma, pancreatic cancer, and ovarian cancer. It is cleaved to a 30 kDa N-terminal secretory form (N-ERC) and a 40 kDa C-terminal membranous form (C-ERC). Several functions have been reported for full-length ERC (full-ERC) and C-ERC/mesothelin, such as in cell adhesion and invasion, stimulation of cell proliferation, and the suppression of cell death. However, there have been no studies to date on the function of secretory N-ERC, despite the fact that it is abundantly secreted into the sera of mesothelioma patients. In this study, we investigated whether N-ERC could function as a secretory factor to stimulate tumor progression. Full-, N, or C-ERC was overexpressed in the human hepatocellular carcinoma cell line Huh7 that lacks endogenous expression of ERC/mesothelin. Changes in the rates of cell proliferation and cell death were determined, and the state of signal transducers was examined using various endpoints: total cell counts, trypan blue exclusion rate, BrdU incorporation rate, TUNEL assay, and the phosphorylation of ERK1/2 and Stat3. In cells overexpressing N-ERC, phosphorylation of ERK1/2 was enhanced and the rate of cell death decreased, leading to the increase of cell number. The culture medium containing the secretory N-ERC also had the activity to increase the number of cells. Our data suggested that one of the full-ERC functions reported previously was mediated by the secretory N-ERC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Cell Death*
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Survival*
  • Cloning, Molecular
  • Culture Media, Conditioned
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GPI-Linked Proteins
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Microscopy, Fluorescence

Substances

  • Culture Media, Conditioned
  • GPI-Linked Proteins
  • Membrane Glycoproteins
  • Extracellular Signal-Regulated MAP Kinases
  • mesothelin