Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study,...
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doaj-3a7eb2e6bc42461a8b1211fd7d2d17932020-11-25T00:55:41ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e6091410.1371/journal.pone.0060914Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.Hiroto KinoshitaYoshihiro HirataHayato NakagawaKei SakamotoYoku HayakawaRyota TakahashiWachiko NakataKosuke SakitaniTakako SerizawaYohko HikibaMasao AkanumaWataru ShibataShin MaedaKazuhiko KoikeInterleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.http://europepmc.org/articles/PMC3625204?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hiroto Kinoshita Yoshihiro Hirata Hayato Nakagawa Kei Sakamoto Yoku Hayakawa Ryota Takahashi Wachiko Nakata Kosuke Sakitani Takako Serizawa Yohko Hikiba Masao Akanuma Wataru Shibata Shin Maeda Kazuhiko Koike |
spellingShingle |
Hiroto Kinoshita Yoshihiro Hirata Hayato Nakagawa Kei Sakamoto Yoku Hayakawa Ryota Takahashi Wachiko Nakata Kosuke Sakitani Takako Serizawa Yohko Hikiba Masao Akanuma Wataru Shibata Shin Maeda Kazuhiko Koike Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS ONE |
author_facet |
Hiroto Kinoshita Yoshihiro Hirata Hayato Nakagawa Kei Sakamoto Yoku Hayakawa Ryota Takahashi Wachiko Nakata Kosuke Sakitani Takako Serizawa Yohko Hikiba Masao Akanuma Wataru Shibata Shin Maeda Kazuhiko Koike |
author_sort |
Hiroto Kinoshita |
title |
Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
title_short |
Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
title_full |
Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
title_fullStr |
Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
title_full_unstemmed |
Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
title_sort |
interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis. |
url |
http://europepmc.org/articles/PMC3625204?pdf=render |
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