title: Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma.
abstract: Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6 reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF expression and contributing the angiogenesis of human osteosarcoma cells.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Huey-En
authors.initials: HE
authors.lastname: Tzeng
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.forename: Zi-Ling
authors.initials: ZL
authors.lastname: Chang
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Su
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Hwang
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D001859:Bone Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009389:Neovascularization, Pathologic; D012516:Osteosarcoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D019947:Receptors, Interleukin-6 / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D048848:MAP Kinase Kinase Kinase 5