期刊
CANCER RESEARCH
卷 72, 期 9, 页码 2228-2238出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-2165
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资金
- NIH [P01 CA084103]
- Bogart Foundation Pediatric Cancer Research Program
- T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research
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. Cancer Res; 72(9); 2228-38. (C) 2012 AACR.
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