| 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
|
| Resource |
| Human and Animal Cells |
MKN45(RCB1001)
MKN74(RCB1002) |
