VPB1301 - Mechanism of hepatocyte growth factor-induced decreased expression of protein C inhibitor in HepG2 cells

Background: Protein C inhibitor (PCI), a member of the SERPIN family, inhibits an anticoagulant activated protein C (APC), which inactivates blood coagulation cofactors, factors Va and VIIIa in plasma. We have so far shown that PCI is expressed in various human tissues, including liver and kidneys, suppresses tumor infiltration by inhibiting urinary plasminogen activator (uPA) and tumor metastasis by inhibiting angiogenesis, and regulates liver regeneration by inhibiting hepatocyte growth factor activator (HGFA), which is an activator of hepatocyte growth factor precursor to hepatocyte growth factor (HGF). Recently, we showed that HGF decreases PCI expression in HepG2 cells, although the detailed mechanism is still unclear.

Aims: In the present study, we investigated the detailed signal transduction mechanism of HGF-induced decreased expression of PCI in HepG2 cells.

Methods: HepG2 cells were cultured using RPMI1640 containing 10% fetal bovine serum (FBS). Confluent HepG2 cells were treated with various signal transduction inhibitors such as c-Met inhibitor, MEK inhibitor, PI3K inhibitor, JUN kinase inhibitor and ERK inhibitor, in the absence of FBS for 24 hours, and the culture supernatants were recovered. PCI concentration in the culture supernatants was measured using specific ELISA.

Results: PCI expression in HepG2 cells was decreased by HGF treatment, and this HGF-induced decreased expression of PCI in HepG2 cells was recovered by c-Met inhibitor, MEK inhibitor and PI3K inhibitor treatments, but JUN kinase inhibitor and ERK inhibitor had no effect on it.

Conclusion(s): Our results indicated that HGF decreases PCI expression in hepatocytes via c-Met, MEK and PI3K.