| Autor: |
Li Lu, Fen Zhu, Yangguang Li, Drennan, Amanda C., Shuichi Kimpara, Rumball, Ian, Selzer, Christopher, Cameron, Hunter, Kellicut, Ashley, Kelm, Amanda, Fangyu Wang, Lixin Rui, Waldmann, Thomas A., Meili Zhang |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 1/16/2018, Vol. 115 Issue 3, pE498-E505, 8p |
| Abstrakt: |
STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of IRF7, IRF9, STAT1, and STAT2. Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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