Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line

Authors

  • Xin Maggie Wang,

    1. A. W. Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The Discipline of Medicine, University of Sydney, Sydney, Australia
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  • Denise Ming Tse Yu,

    1. A. W. Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The Discipline of Medicine, University of Sydney, Sydney, Australia
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  • Geoffrey W. McCaughan,

    1. A. W. Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The Discipline of Medicine, University of Sydney, Sydney, Australia
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  • Mark D. Gorrell

    Corresponding author
    1. A. W. Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The Discipline of Medicine, University of Sydney, Sydney, Australia
    • Centenary Institute of Cancer Medicine and Cell Biology, Locked bag No. 6, Newtown, NSW, 2042, Australia
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    • fax: (61) 2-9565-6101.


  • Potential conflict of interest: Nothing to report.

Abstract

Injury and repair in chronic liver disease involve cell adhesion, migration, apoptosis, proliferation, and a wound healing response. In liver, fibroblast activation protein (FAP) has both collagenase and dipeptidyl peptidase IV (DPIV) activities and is expressed only by activated hepatic stellate cells (HSC) and myofibroblasts, which produce and degrade extracellular matrix (ECM). FAP was colocalized with collagen fibers, fibronectin, and collagen type I in human liver. FAP function was examined in vitro by expressing green fluorescent protein FAP fusion protein in cell lines cultured on collagen-I, fibronectin, and Matrigel. Glutamates at 203 and 204 as well as serine624 of FAP were essential for peptidase activity. Human embryonic kidney 293T cells overexpressing FAP showed reduced adhesion and migration. FAP overexpression in the human HSC line LX-2 caused increased cell adhesion and migration on ECM proteins as well as invasion across transwells in the absence or presence of transforming growth factor beta-1. FAP overexpression enhanced staurosporine streptomyces–stimulated apoptosis in both cell lines. Interestingly, the enzyme activity of FAP was not required for these functions. Overexpressing FAP increased the expression of matrix metalloproteinase-2 and CD44 and reduced integrin-β1 expression in 293T cells, suggesting potential pathways of FAP-mediated impairment of cell adhesion and migration in this epithelial cell line. In conclusion, these findings further support a pro-fibrogenic role for FAP by indicating that, in addition to its enzymatic functions, FAP has important nonenzymatic functions that in chronic liver injury may facilitate tissue remodeling through FAP-mediated enhancement of HSC cell adhesion, migration, and apoptosis. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:935–945.)

Ancillary