Interleukin-1 receptor type II acts as a transcriptional activator of AP-1 and promotes tumor malignancy in human colorectal cancer

• Main Authors: Ai-Chung Mar, 馬璦中
• Other Authors: Te-Chang Lee
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/42329893867248483696

博士 === 國立陽明大學 === 分子醫學博士學位學程 === 104 === Interleukin-1 receptor type 2 (IL1R2) acts as a decoy receptor of exogenous IL-1; nonetheless, its intracellular activity and pathological role are poorly understood. We previously demonstrated that IL1R2 intracellularly activates the expression of several pro-inflammatory 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, indicating its pro-inflammatory role. By modulating its expression in CRC cells, we verified that IL1R2 transcriptionally activated the expression and secretion of IL-6 and VEGF-A. We further demonstrated a positive association of intracellular IL1R2 levels with tumor growth and microvessel density in xenograft mouse models. Mechanistically, we revealed that IL1R2 complexes with c-Fos and binds to the AP-1 site at the IL-6 and VEGF-A promoters, indicating IL1R2 might be a transcriptional activator of AP-1. Importantly, we further confirmed a significant association of IL1R2 mRNA expression levels with poor prognosis, distant metastasis, and the 5-year survival of CRC patients. We also demonstrated that IL1R2 protein levels positively correlated with drug resistance of regorafenib, a newly approved multi-kinase inhibitor for late-stage metastatic CRC patients. We demonstrated that IL1R2 increased p-ERK by transcriptionally activating the expression of SETBP-1 through AP-1, thereby decreasing the activity of PP2A by forming a SETBP-1/SET/PP2A complex. Accordingly, our results suggested that IL1R2 is a potential biomarker for prognosis, staging, and the response to targeted therapy in CRC patients. In addition, we found a new biological function of IL1R2 that it might cooperate with AP-1 and modulate the progression, angiogenesis, and drug resistance of human CRC.