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

Hirotaka Kuga, Takashi Morisaki, Katsuya Nakamura, Hideya Onishi, Hirokazu Noshiro, Akihiko Uchiyama, Masao Tanaka, Mitsuo Katano

研究成果: ジャーナルへの寄稿学術誌査読

27 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)7838-7847
ページ数10
ジャーナルOncogene
22
49
DOI
出版ステータス出版済み - 10月 30 2003

!!!All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 癌研究

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