Suppression of cell death by the secretory form of N-terminal ERC/mesothelin.
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.
Wang
Tegexibaiyin
T
Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Kajino
Kazunori
K
Abe
Masaaki
M
Tan
Ke
K
Maruo
Masumi
M
Sun
Guodong
G
Hagiwara
Yoshiaki
Y
Maeda
Masahiro
M
Hino
Okio
O
D000704:Analysis of Variance; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003001:Cloning, Molecular; D017077:Culture Media, Conditioned; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000090204:Mesothelin; D008856:Microscopy, Fluorescence
D017077:Culture Media, Conditioned; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D048049:Extracellular Signal-Regulated MAP Kinases; D000090204:Mesothelin