Pro-Inflammatory Cytokine IL-1 beta Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma: e0132677

• Published in: PloS one Vol. 10; no. 7
• Main Authors: Sun, Yi, Zhu, Demao, Wang, Guihua, Wang, Di, Zhou, Huashan, Liu, Xueting, Jiang, Manli, Liao, Lingjuan, Zhou, Zhiguang, Hu, Jinyue
• Format: Journal Article
• Language: English
• Published: 01.07.2015
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0132677

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-1 beta 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-1 beta treatment of Tca8113 cells promoted migration in response to CXCR4 ligand stromal-derived factor alpha (SDF-1 alpha ). The inhibition of IL-1R1 by its antagonist IL-1Ra or RNA interference significantly reversed the up-regulation of CXCR4 induced by IL-1 beta . IL-1R1 activation also up-regulated the expression of IL-1 beta itself, suggesting a positive feedback regulation of CXCR4 expression. Furthermore, IL-1 beta 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-1 beta , suggesting that Notch signaling may be involved in the growth and metastasis of cancers via up-regulation of CXCR4. In addition, IL-1 beta induced the activation of extracellular signal regulated kinase (ERK) and ERK inhibition decreased the up-regulation of CXCR4 induced by IL-1 beta , suggesting the involvement of ERK signaling in cancer metastasis. Taken together these data suggest that IL-1 beta and IL-1R1 promote cancer growth and metastasis by up-regulating CXCR4 expression and that CXCR4 may be a link between inflammation and cancer.