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

다국어 초록 (Multilingual Abstract)

The regulatory mechanisms for the proliferation and
the particular invasive phenotypes of stomach can-cers
are not still fully understood. Up-regulations of
hepatocytes growth factor (HGF), its receptor (c-
Met), 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- medi-ated
cell proliferation and uPA secretion. In contrast,
SB203580 pre-treatment enhanced cell proliferation
and uPA secretion due to induction of ERK phos-phorylation.
Stable expression of dominant ne-gative-
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 invasi-veness
of stomach cancer cells.

참고문헌 (Reference)

1 "Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer." 61 : 597-600, 1995

2 "Tumor and stromal expression of matrix metalloproteinases and their role in tumor pro-gression." 14 : 234-45, 1994

3 "Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2." 274 : 26503-10, 1999

4 "Signal transduction through MAP kinase cascades." 74 : 49-139, 1998

5 "Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor" 7 : 292-9, 2000

6 "Prognostic value of urokinase plasminogen acti-vator in primary breast carcinoma comparison of two im-munoassay methods." 77 : 1495-501, 1998

7 "Prognostic relevance of urokinase plasminogen activator de-tection in micrometastatic cells in the bone marrow of patients with primary breast cancer." 76 : 812-8, 1997

8 "Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and activity in prostate cancer cels." 85 : 407-15, 2000

9 "New insights into the control of MAP kinase pathways." 253 : 255-70, 1999

10 "Neurotensin- mediated activation of MAPK pathways and AP-1 binding in the human pancreatic cancer cell line" 269 : 704-, 2000

11 "Mitogen-acti-vated protein kinase conservation of a three-kinase module from yeast to human." 79 : 143-80, 1999

12 "Liotta L. Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. Cancer Res 1992" 4548-9,

13 "Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by trans-forming growth factor-b1 in transformed keratinocytes." 273 : 521-7, 2001

14 "Invasion-Metastasis by He-patocyte Growth Factor/c-Met Signaling Concomitant with Induction of Urokinase plasminogen Activator in Human Pan-creatic Cancer Role as Therapeutic Target." 35 : 207-12, 2003b

15 "Hepatocyte growth uPA secretion via ERK activation growth factor dependent MAPK pathway　35factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase and promotes migration and in-vasion by oral squamous cell carcinoma cells." 31807-13,

16 "Growth factor-dependent activation of the MAPK pathway in human pancretic cancer MEK/ERK and p38 MAP kinase interaction in uPA synthesis." 20 : 499-505, 2003a

17 "Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer." 14 : 35-41, 1999

18 "Effects of synthetic urokinase inhibitors on local invasion and metastasis in a murine mammary tumor model." 40 : 209-23, 1996

19 "Dysregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive pheno-type." 263 : 295-304, 1999

20 "Autocrine and paracrine regulation of tissue inhibitor of metalloproteinases and urokinase gene expression in metastatic and non-me-tastatic mammary carcinoma cells." 335-41,

21 "An analysis of MEK1 signaling in cel proliferation and transformation." 273 : 13280-8, 1998

22 "Activation of MAP kinases in growth responsive pancreatic cancer cells." 11 : 591-602, 1999

23 "A conditionally-active form of MEK1 results in autocrine transformation of human and mouse hematopoietic cells." 27 (27): 526-36, 2000