Data di Pubblicazione:
2011
Abstract:
Background and Aims: Hepatocyte growth factor (HGF) is the
most powerful hepatotropic cytokine. However the ability of
HGF to promote tumor cell “scattering” and “invasion” raises
some concern about its therapeutic safety. We have already
reported that Metron factor-1, an engineered cytokine derived
from HGF and macrophage stimulating protein, is as effective
as HGF at preventing liver injury and at promoting hepatocyte
regeneration, but therapeutically safer than HGF (Hepatology,
2008). Here we report the newly engineered agonist of Met,
MAGIC factor (Met-Activating Genetically Improved Chimeric
Factor) that contains two Met-binding domains repeated in tandem,
and tried to elucidate its biological function in the liver.
Methods: CHO cells were transduced MAGIC factor, and the
medium was purified through chelate column to obtain MAGIC
factor. For in vitro study we used mouse hepatocytes, human
HCC cell lines (HepG2, Huh-1) and human umbilical vessel
epithelial cells (HUVECs). Signaling pathway of AKT and ERK,
and cell cycle-related protein, Cyclin D1 and CDK4, were
examined by Western Blot. Mitogenic and apoptotic activity
was determined by BrdU incorporation and cell death detection
kit, respectively. Cell migration and invasion activity were
examined through transwell chambers. ECM remodeling of
HUVECs was determined by the length of pseudopodia.
Results: MAGIC stimulation as well as HGF caused increased
expression of phospho-AKT and phospho-ERK, Cyclin D1,and
CDK-4 in hepatocytes. BrdU incorporation was increased by
MAGIC factor at 2.0 folds, almost as much as HGF. Fas-mediated
apoptosis in hepatocytes was protected by 80% by HGF,
and 70% by MAGIC. Matrigel invasion assay of HCC cells and
migration assay of HUVECs showed the increased cells at 2.2
folds and 2.5 folds by HGF respectively, by but not by MAGIC
factor. Tube length of HUVECs was also stimulated at 2.4 folds
by HGF, but not by MAGIC factor. Conclusions: MAGIC factor
has mitogenic and anti-apoptotic ability on hepatocytes but lacks proangiogenic and invasive activity. MAGIC factor may
act as a safe hepatotropic cytokine.
Tipologia CRIS:
04E-Meeting abstract in rivista
Elenco autori:
T. Takahara; K. Kawai; T. Sugiyama; M. Asahi; P. Michieli
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