RRC ID 68719
Author Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K, Hayakawa Y, Takahashi R, Nakata W, Sakitani K, Serizawa T, Hikiba Y, Akanuma M, Shibata W, Maeda S, Koike K.
Title Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.
Journal PLoS One
Abstract 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.
Volume 8(4)
Pages e60914
Published 2013-1-1
DOI 10.1371/journal.pone.0060914
PII PONE-D-12-15460
PMID 23593346
PMC PMC3625204
MeSH Animals Cell Communication* / drug effects Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cell Transformation, Neoplastic / drug effects Cell Transformation, Neoplastic / metabolism Cell Transformation, Neoplastic / pathology* Culture Media, Conditioned / pharmacology Disease Models, Animal Epithelial Cells / drug effects Epithelial Cells / metabolism* Epithelial Cells / pathology* Fibroblasts / drug effects Fibroblasts / metabolism Fibroblasts / pathology Humans Interleukin-6 / deficiency Interleukin-6 / metabolism* Methylnitrosourea Mice Models, Biological Neoplastic Stem Cells / drug effects Neoplastic Stem Cells / metabolism Neoplastic Stem Cells / pathology STAT3 Transcription Factor / metabolism Stomach Neoplasms / metabolism* Stomach Neoplasms / pathology* Stromal Cells / drug effects Stromal Cells / metabolism Stromal Cells / pathology
IF 2.74
Human and Animal Cells MKN45(RCB1001) MKN74(RCB1002)