Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines

Abstract

The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (cMet), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time-and dose-dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.

Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer

“…Indeed, our Lfng mutant model of BLBC shows elevated Notch signaling to proliferation/invasion Notch target genes as well as reduced Hes/Hey expression, together with elevated Met and InsR/Igf-1R signaling. Interestingly, elevated Notch signaling and Met/Cav overexpression could potentially also connect through induction of uPA (Lee et al, 2006; Monaghan-Benson et al, 2008; Shimizu et al, 2011) and activation of HGF (Naldini et al, 1995). The specific combination of oncogenic mutations would therefore have the effect of promoting a luminal progenitor fate with lower integrin expression, and therefore reduced survival signaling from the basement membrane.…”

MicroRNA‐23b mediates urokinase and c‐met downmodulation and a decreased migration of human hepatocellular carcinoma cells

“…Furthermore, we cannot exclude an indirect influence of miR‐23b on c‐met, even if it is very unlikely, at least through uPA. Evidence has been provided that c‐met activation may be concomitant with the induction of the uPA proteolysis network [20,21], but not vice versa.…”

“…An essential role of uPA and c‐met in the migration and proliferation of human hepatocellular carcinoma (HCC) cells has been assessed by functional studies carried out using RNA interference technology [18,19]. The evidence suggests that the two systems, uPA–uPA receptor and HGF–c‐met, might cooperate in the acquisition of malignant phenotypes of cancer cells, but little is known about the regulatory mechanisms for expression of these genes [20,21]. uPA can be regulated at the transcriptional and post‐transcriptional levels (i.e.…”

<italic>NGX6</italic> inhibits AP-1 and Ets-1 expression and down-regulates cyclin D1 in human colorectal cancer

“…Therefore, in an attempt to unravel the association of c-jun, c-fos, and Ets-1 with the stress-activated MAP kinases/c-Jun N-terminal kinase (SAPK/JNK) and ERK/MAPK signaling pathways, we used SP600125, a JNK-specific inhibitor [15,16], and PD98059, a specific MEK1 inhibitor [17], to study the expression of these transcription factors (c-jun, c-fos, and Ets-1). Treatment with 40 nM SP600125 for 1 h totally abolished the expression of p-JNK proteins, whereas treatment with 50 nM PD98059 for 15 min completely eliminated the expression of p-ERK1/2 proteins in HT-29 cells [ Fig.…”