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Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model

Oncogene volume 22, pages 7838–7847 (2003)Cite this article

Abstract

We reconstituted a three-dimensional gastric carcinoma model similar to invasive gastric carcinoma tissue. This model consists of a human gastric carcinoma cell line, GCTM-1, a human fibroblast cell line, TIG-1-20, and transforming growth factor-β (TGF-β)-containing type I collagen gel. Using this model, we were able to observe the growth of the two cell types, especially carcinoma cell invasive growth, in real time for more than 30 days. TGF-β and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-β induced the enhanced expression of matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) in GCTM-1 at both the protein and enzymatic activity levels. The TGF-β-induced invasion of GCTM-1 was inhibited by MMP9- or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-γ (IFN-γ) was added to this model, TGF-β-dependent GCTM-1 invasion was significantly inhibited, concomitant with the decreased expression of MMP9 and uPA. The intracellular signal transduction of Smad was examined to analyse the mechanism of the inhibitory effect of IFN-γ. TGF-β accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3–Smad4 complex in GCTM-1, but these TGF-β-induced effects were significantly inhibited by IFN-γ-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGF-β-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-γ on TGF-β-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-γ inhibits TGF-β-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-γ may be a new therapeutic tool for TGF-β-expressed invasive carcinomas.

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Abbreviations

TGF:

transforming growth factor

MMP:

matrix metalloproteinase

uPA:

urokinase-type plasminogen activator

IFN:

interferon

b-FGF:

basic fibroblast growth factor

AS:

antisense

CBP:

cAMP response element-binding protein

JAK:

janus kinase

STAT:

signal transducer and activator of transcription

FCS:

fetal calf serum

FACS:

fluorescence-activated cell sorter

SDS:

sodium dodecyl sulfate

PAGE:

polyacrylamide gel electrophoresis

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Acknowledgements

We thank Kaori Nomiyama for providing expert technical assistance. This work was supported by grants for General Scientific Research (12557106) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hirotaka Kuga, Takashi Morisaki, Katsuya Nakamura, Hideya Onishi & Mitsuo Katano

  2. Department of Clinical Oncology and Surgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

    Hirokazu Noshiro, Akihiko Uchiyama & Masao Tanaka

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  1. Hirotaka Kuga
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Kuga, H., Morisaki, T., Nakamura, K. et al. Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. Oncogene 22, 7838–7847 (2003). https://doi.org/10.1038/sj.onc.1207046

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