Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system

Dongho Lee, Young Yang, Soon Jung Lee, Kun Yong Kim, Tae Hyeon Koo, Sun Mi Shin, Kyu Sang Song, Young Ho Lee, Yung Jin Kim, Jung Joon Lee, Inpyo Choi, Jeong Hyung Lee

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor β superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.

Original languageEnglish
Pages (from-to)4648-4655
Number of pages8
JournalCancer Research
Volume63
Issue number15
Publication statusPublished - 2003 Aug 1
Externally publishedYes

Fingerprint

Growth Differentiation Factor 15
Urokinase-Type Plasminogen Activator
Stomach Neoplasms
Urokinase Plasminogen Activator Receptors
Cell Line
MAP Kinase Kinase 2
MAP Kinase Kinase 1
Stomach
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Neoplasms
Transforming Growth Factors
Genes
Transfection
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. / Lee, Dongho; Yang, Young; Lee, Soon Jung; Kim, Kun Yong; Koo, Tae Hyeon; Shin, Sun Mi; Song, Kyu Sang; Lee, Young Ho; Kim, Yung Jin; Lee, Jung Joon; Choi, Inpyo; Lee, Jeong Hyung.

In: Cancer Research, Vol. 63, No. 15, 01.08.2003, p. 4648-4655.

Research output: Contribution to journalArticle

Lee, D, Yang, Y, Lee, SJ, Kim, KY, Koo, TH, Shin, SM, Song, KS, Lee, YH, Kim, YJ, Lee, JJ, Choi, I & Lee, JH 2003, 'Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system', Cancer Research, vol. 63, no. 15, pp. 4648-4655.
Lee, Dongho ; Yang, Young ; Lee, Soon Jung ; Kim, Kun Yong ; Koo, Tae Hyeon ; Shin, Sun Mi ; Song, Kyu Sang ; Lee, Young Ho ; Kim, Yung Jin ; Lee, Jung Joon ; Choi, Inpyo ; Lee, Jeong Hyung. / Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. In: Cancer Research. 2003 ; Vol. 63, No. 15. pp. 4648-4655.
@article{3b725208555f477986ad6aa7b32b1e14,
title = "Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system",
abstract = "In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor β superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.",
author = "Dongho Lee and Young Yang and Lee, {Soon Jung} and Kim, {Kun Yong} and Koo, {Tae Hyeon} and Shin, {Sun Mi} and Song, {Kyu Sang} and Lee, {Young Ho} and Kim, {Yung Jin} and Lee, {Jung Joon} and Inpyo Choi and Lee, {Jeong Hyung}",
year = "2003",
month = "8",
day = "1",
language = "English",
volume = "63",
pages = "4648--4655",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "15",

}

TY - JOUR

T1 - Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system

AU - Lee, Dongho

AU - Yang, Young

AU - Lee, Soon Jung

AU - Kim, Kun Yong

AU - Koo, Tae Hyeon

AU - Shin, Sun Mi

AU - Song, Kyu Sang

AU - Lee, Young Ho

AU - Kim, Yung Jin

AU - Lee, Jung Joon

AU - Choi, Inpyo

AU - Lee, Jeong Hyung

PY - 2003/8/1

Y1 - 2003/8/1

N2 - In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor β superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.

AB - In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor β superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.

UR - http://www.scopus.com/inward/record.url?scp=0042134847&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0042134847&partnerID=8YFLogxK

M3 - Article

VL - 63

SP - 4648

EP - 4655

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 15

ER -