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

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-b (TGF-b)-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. TGFb and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-b 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-b-induced invasion of GCTM-1 was inhibited by MMP9-or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-c (IFN-c) was added to this model, TGF-bdependent 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-c. TGF-b accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3-Smad4 complex in GCTM-1, but these TGF-b-induced effects were significantly inhibited by IFN-c-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGFb-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-c on TGF-b-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-c inhibits TGF-b-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-c may be a new therapeutic tool for TGF-b-expressed invasive carcinomas.

Mifepristone Inhibits the Migration of Cervical Cancer Cells by Inhibiting Exocrine Secretion

“…It was reported that prolonged exposure to interferon-β decreased the migration of human neural crest cells. In addition, it was demonstrated that interferon-c suppresses the transforming growth factor-β induced invasion of gastric carcinoma cells through the cross-talk of the Smad pathway in a three-dimensional culture model [23]. In our study, IFN, as a stimulus of ISG15, inhibited the migration of CC cells in scratch wound healing assay, and the results are consistent with the above reports.…”

Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

“…It has been shown that IFN-␥ inhibits TGF-␤-induced phosphorylation of Smads-2/3 through the induction of antagonistic Smad-7. 40 Although the crosstalk between TGF-␤ and IFN-␥ has been extensively described, there are no reported studies about cross-talk between TGF-␤ and IFN-␣. Nevertheless, we cannot completely rule out the possibility that IFN-␣2b could be raising inhibitory Smad-7 levels, a fact that could potentially mask a higher increase in p-Smads-2/3.…”

Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies

“…However, the diversity of agents that can mediate MMP production as well as the opposite effects of these factors on the expression of different MMP genes, difficults the selection of the appropriate targets. Nevertheless, recent studies have shown that factors such as IFN-α (interferon-α), IFN-β and IFN-γ can be used to inhibit the transcription of several MMPs in diverse human cancer cells (Kuga et al, 2003;Ma et al, 2001;Slaton et al, 2001). Alternatively, different strategies designed for blocking those cytokine-receptor interactions that up-regulate MMP genes have led to interesting results.…”