title: Pro-Inflammatory Cytokine IL-1β Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma.
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.
authors.affiliation: Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China; Medical Research Center, Changsha Central Hospital, Changsha, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, Changsha Central Hospital, Changsha, China.
authors.forename: Demao
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Changsha Central Hospital, Changsha, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Oncology, Changsha Central Hospital, Changsha, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pathology, Changsha Central Hospital, Changsha, China.
authors.forename: Huashan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Medical Research Center, Changsha Central Hospital, Changsha, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Liu
authors.affiliation: Medical Research Center, Changsha Central Hospital, Changsha, China.
authors.forename: Manli
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Medical Research Center, Changsha Central Hospital, Changsha, China.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: Liao
authors.affiliation: Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Medical Research Center, Changsha Central Hospital, Changsha, China.
authors.forename: Jinyue
authors.initials: J
authors.lastname: Hu
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014062:Tongue Neoplasms / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D019718:Receptors, CXCR4; D051880:Receptors, Notch; D048049:Extracellular Signal-Regulated MAP Kinases