Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis.

Abstract

Interleukin-1 receptor type 2 (IL1R2) acts as a decoy receptor of exogenous IL-1; however, its intracellular activity is poorly understood. We previously demonstrated that IL1R2 intracellularly activates the expression of several proinflammatory cytokines and affects cell migration. In this study, we found that intracellular IL1R2 expression was increased in human colorectal cancer cells (CRCs) compared with normal colon cells. We also observed that the mRNA levels of IL1R2 were highly correlated with IL-6 in tumor tissues of CRC patients. By modulating its expression in CRC cells, we verified that enhanced IL1R2 expression transcriptionally activated the expression of IL-6 and VEGF-A. Conditioned medium harvested from IL1R2-overexpressing CRC cells contained higher levels of IL-6 and VEGF-A than that from vector control cells and significantly enhanced the proliferation, migration, and tube formation of cultured endothelial cells. We further demonstrated a positive association of intracellular IL1R2 levels with tumor growth and microvessel density in xenograft mouse models. These results revealed that IL1R2 activates the expression of angiogenic factors. Mechanistically, we revealed that IL1R2 complexes with c-Fos and binds to the AP-1 site at the IL-6 and VEGF-A promoters. Together, these results reveal a novel function of intracellular IL1R2 that acts with c-Fos to enhance the transcription of IL-6 and VEGF-A, which promotes angiogenesis in CRC.

• Authors: Ai-Chung Mar, Chun-Ho Chu, Hui-Ju Lee, Chia-Wen Chien, Jing-Jy Cheng, Shung-Haur Yang, Jeng-Kai Jiang, Te-Chang Lee
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 36 Pg. 22212-24 (Sep 04 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26209639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• IL1R2 protein, human
• Interleukin-6
• Proto-Oncogene Proteins c-fos
• Receptors, Interleukin-1 Type II
• VEGFA protein, human
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Blotting, Western
• Cell Line
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Colonic Neoplasms (blood supply, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• HT29 Cells
• Humans
• Interleukin-6 (genetics, metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (genetics, metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA Interference
• Receptors, Interleukin-1 Type II (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A (genetics, metabolism)