title: A galectin-3-dependent pathway upregulates interleukin-6 in the microenvironment of human neuroblastoma.
abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine with a broad range of physiologic and pathologic functions. Because in cancer, IL-6 contributes to a microenvironment that promotes tumor cell survival, angiogenesis, and inflammation, understanding the mechanism responsible for its production is important. In neuroblastoma, the second most common solid tumor in children, IL-6 is produced not by tumor cells but by stromal cells such as monocytes and bone marrow mesenchymal stem cells (BMMSC). Here we show that the production of IL-6 in BMMSCs is in part stimulated by galectin-3 binding protein (Gal-3BP) secreted by neuroblastoma cells. We identified a distal region of the IL-6 promoter that contains 3 CCATT/enhancer binding protein (C/EBP) binding domains involved in the transcriptional upregulation of IL-6 by Gal-3BP. Gal-3BP interacted with Galectin-3 (Gal-3) present in BMMSCs, and a Gal-3BP/Gal-3/Ras/MEK/ERK signaling pathway was responsible for the transcriptional upregulation of IL-6 in BMMSCs in which Gal-3 has a necessary function. In support of the role of this pathway in human neuroblastoma tumors, Gal-3BP was found to be present in tumor cells and in the adjacent extracellular matrix of 96% of 78 primary neuroblastoma tumor samples examined by immunohistochemistry. Considering the protumorigenic function of IL-6 in cancer, this tumor cell-stromal cell interactive pathway could be a target for anticancer therapy.
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Ayaka M
authors.initials: AM
authors.lastname: Silverman
authors.forename: Rie
authors.initials: R
authors.lastname: Nakata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D037502:Galectin 3 / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D059016:Tumor Microenvironment; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D037502:Galectin 3; D006023:Glycoproteins; D015850:Interleukin-6; D018631:ras Proteins; C508600:IL6 protein, human; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins