title: IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway.
abstract: Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. However, the precise molecular events that initiate this complex EMT process in head and neck cancers are poorly understood. Increasing evidence suggests that tumor microenvironment plays an important role in promoting EMT in tumor cells. We have previously shown that head and neck tumors exhibit significantly higher Bcl-2 expression in tumor-associated endothelial cells and overexpression of Bcl-2 alone in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a severe combined immunodeficient (SCID) mouse model. In this study, we show that endothelial cells expressing Bcl-2 (EC-Bcl-2), when cocultured with head and neck tumor cells (CAL27), significantly enhance EMT-related changes in tumor cells predominantly by the secretion of IL-6. Treatment with recombinant IL-6 or stable IL-6 overexpression in CAL27 cells or immortalized oral epithelial cells (IOE) significantly induced the expression of mesenchymal marker, vimentin, while repressing E-cadherin expression via the JAK/STAT3/Snail signaling pathway. These EMT-related changes were further associated with enhanced tumor and IOE cell scattering and motility. STAT3 knockdown significantly reversed IL-6-mediated tumor and IOE cell motility by inhibiting FAK activation. Furthermore, tumor cells overexpressing IL-6 showed marked increase in lymph node and lung metastasis in a SCID mouse xenograft model. Taken together, these results show a novel function for IL-6 in mediating EMT in head and neck tumor cells and increasing their metastatic potential.
authors: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors: Arti
authors: A
authors: Yadav
authors: Bhavna
authors: B
authors: Kumar
authors: Jharna
authors: J
authors: Datta
authors: Theodoros N
authors: TN
authors: Teknos
authors: Pawan
authors: P
authors: Kumar
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C508600:IL6 protein, human; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D051417:Focal Adhesion Kinase 1; D053612:Janus Kinases; C496050:PTK2 protein, human