Cellular mechanisms of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MAPK signaling in hepatocellular carcinoma.
OBJECTIVE
The hepatocyte growth factor, its receptor c-Met, and urokinase-type plasminogen mediate various cellular responses on activation, including proliferation, survival, invasion, and metastasis. The regulatory mechanisms for the proliferation and the particular invasive phenotypes of hepatocellular carcinoma are not yet fully understood. In order to clarify the intracellular downstream signal for hepatocyte growth factor/c-Met signaling in tumor progression and metastasis in hepatoma, we determined the effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen expression in hepatoma cell lines (HepG2 and Hep3B).


RESULTS
Hepatocyte growth factor treatment induced the phosphorylation of ERK and p38 kinase in a dose-dependent manner, resulting in an early peak of phosphorylation at 3 to 10 min, which then rapidly decreased to a near basal level. Pretreatment with PD 098059 reduced hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen secretion. In contrast, SB 203580 pretreatment enhanced cell proliferation and urokinase-type plasminogen secretion due to induction of ERK phosphorylation. Treatment with PD 098059 and SB 203580 resulted in a decrease in phospho-ERK activity. Stable expression of dominant negative-MEK1 in HepG2 cells showed a decrease in hepatocyte growth factor-mediated urokinase-type plasminogen secretion.


CONCLUSIONS
Such results suggest that interaction of an MEK/ERK and a p38 kinase might be critical in intrahepatic invasion and metastasis of human hepatoma cells.
Lee
Kyung Hee
KH
Department of Hemato-Oncology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Choi
Eun Young
EY
Hyun
Myung Soo
MS
Eun
Jong Ryul
JR
Jang
Byung Ik
BI
Kim
Tae Nyeun
TN
Lee
Heon Ju
HJ
Lee
Dong Shik
DS
Yun
Sung Su
SS
Kim
Hong Jin
HJ
Kim
Jung Hye
JH
Kim
Jae-Ryong
JR
D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D017228:Hepatocyte Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator; C489333:acetyl-lysyl-prolyl-seryl-seryl-prolyl-prolyl-glutamyl-glutamic acid amide; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one