Abstract
Oral squamous cell carcinoma (OSCC) typically migrates and metastasizes. Interleukin-6 (IL-6) is a multifunctional cytokine associated with disease status and cancer outcomes. The effect of IL-6 on human OSCC cells, however, is unknown. Here, we showed that IL-6 increased cell migration and Intercellular adhesion molecule-1 (ICAM-1) expression in OSCC cells. Pretreatment of OSCC cells with IL-6R monoclonal antibody (mAb) significantly abolished IL-6-induced cell migration and ICAM-1 expression. By contrast, IL-6-mediated cell motility and ICAM-1 upregulation were attenuated by the Syk and c-Jun N-terminal kinase (JNK) inhibitors. Stimulation of OSCC cells with IL-6 promoted Syk and JNK phosphorylation. Furthermore, IL-6 enhanced AP-1 activity, and the IL-6R mAb, Syk inhibitor, or JNK inhibitor all reduced IL-6-mediated c-Jun phosphorylation, c-Jun binding to the ICAM-1 promoter, and c-Jun translocation into the nucleus. Our results indicate that IL-6 enhances the migration of OSCC cells by increasing ICAM-1 expression through the IL-6R receptor and the Syk, JNK, and AP-1 signal transduction pathways.
Highlights
Oral squamous cell carcinoma (OSCC), the most common head and neck cancer, represents 1%–2%of all human malignancies and is characterized by poor prognosis and a low survival rate
Our results indicate that IL-6 is a crucial factor during the metastasis of OSCC cells
IL-6-increased c-Jun accumulation in the nucleus (Figure 6G). These data suggest that activation of the IL-6R, Syk, and Jun N-terminal kinase (JNK) pathways are required for IL-6-induced activator protein (AP)-1 activation and tumor metastasis in human OSCC cells
Summary
Oral squamous cell carcinoma (OSCC), the most common head and neck cancer, represents 1%–2%. A recent study indicated that ICAM-1 plays an important role during lung cancer invasion [22]. ICAM-1 upregulation has been reported to play an important role during OSCC metastasis [24–26]. Previous studies confirmed that IL-6 is important in the metastasis of human cancer cells [14,27]. ICAM-1 is a potent metastatic factor that mediates cancer migration and metastasis. For IL-6 in metastasis has been implicated in some cancer cells, the signaling pathway for IL-6 in cell motility and ICAM-1 expression in human OSCC has not been extensively studied. We examined the intracellular signaling pathway involved in IL-6-induced ICAM-1 expression and tumor migration in human OSCC. We reported that the interaction between IL-6 and IL-6R activates the Syk, c-Jun N-terminal kinase (JNK), and activator protein (AP)-1 pathways, leading to upregulation of ICAM-1 expression and cell migration. Our results indicate that IL-6 is a crucial factor during the metastasis of OSCC cells
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