Abstract
Chronic inflammation contributes to tumor development through the induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis. Here, we report that IL-1 receptor 1 (IL-1R1) was expressed in 40 of 41 human tongue squamous cell carcinomas (TSCC). IL-1β up-regulated the expression of CXCR4, a CXC chemokine receptor that mediates cancer growth and metastasis, at both mRNA and protein levels in Tca8113 TSCC cells. IL-1β treatment of Tca8113 cells promoted migration in response to CXCR4 ligand stromal-derived factor α (SDF-1α). The inhibition of IL-1R1 by its antagonist IL-1Ra or RNA interference significantly reversed the up-regulation of CXCR4 induced by IL-1β. IL-1R1 activation also up-regulated the expression of IL-1β itself, suggesting a positive feedback regulation of CXCR4 expression. Furthermore, IL-1β induced the activation of Notch, which was originally considered a stem cell regulator. Pharmacological inhibition of Notch signaling reversed the up-regulation of CXCR4 induced by IL-1β, suggesting that Notch signaling may be involved in the growth and metastasis of cancers via up-regulation of CXCR4. In addition, IL-1β induced the activation of extracellular signal regulated kinase (ERK) and ERK inhibition decreased the up-regulation of CXCR4 induced by IL-1β, suggesting the involvement of ERK signaling in cancer metastasis. Taken together these data suggest that IL-1β and IL-1R1 promote cancer growth and metastasis by up-regulating CXCR4 expression and that CXCR4 may be a link between inflammation and cancer.
Highlights
Inflammatory responses play diverse roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis [1]
When we observed the staining patterns of IL-1 receptor 1 (IL-1R1), we found that tongue squamous cell carcinomas were positive in both the cytoplasm and nucleus (Fig 1B)
Some positive nuclear staining was observed in stromal cells. These results indicated that IL-1R1 is widely expressed in tongue squamous cell carcinoma
Summary
Inflammatory responses play diverse roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis [1]. Inflammation caused by bacterial or viral infections increases cancer risk [2]. Chronic Helicobacter pylori infection is associated with gastric cancer [3] and mucosa-associated lymphoid tissue lymphoma [4, 5]. Infections with hepatitis B or C viruses increase the risk of hepatocellular carcinoma [6]. Infection with Schistosoma is linked to bladder cancer [7], and infection with bacteroides species is linked to colorectal cancer [8]. Infection with Epstein-Barr Virus is associated with nasopharyngeal carcinoma [9] and Burkitt lymphoma [10]. Tobacco smoking promotes tumor development in part by triggering chronic inflammation [11]
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