期刊
FEBS JOURNAL
卷 283, 期 5, 页码 834-849出版社
WILEY
DOI: 10.1111/febs.13633
关键词
heme oxygenase-1; interleukin-6; JAK2-STAT3; multiple myeloma; p38 mitogen-activated protein kinase
资金
- National Natural Science Foundation of China [81070444, 81270636, 81360501, 81470006]
- International Cooperation Project of Guizhou Province [2011-7010]
- Social Project of Guizhou Province [2011-3012]
- Provincial Governor Special Fund of Guizhou Province [2010-84]
- Science and Technology Bureau of Guiyang City [2012103-36]
- Science Project - Guiyang City Technology Bureau [2012103-36]
Interleukin (IL)-6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL-6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. HO-1 expression levels in bone marrow CD138(+) cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL-6 and intracellular IL-6 mRNA expression levels. Culture of U266, RPMI8226 and CD138(+) cells with exogenous IL-6 in vitro induced high HO-1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL-6-mediated activation of the Janus kinase 2-signal transducer and activator of transcription 3 pathway. In contrast, without IL-6 coculture, enhanced HO-1 expression in U266, RPMI8226 and bone marrow CD138(+) cells from MM patients significantly inreased IL-6 mRNA expression levels and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced p38 mitogen-activated protein kinase phosphorylation. Reduced HO-1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL-6 in the bone marrow microenvironment of MM patients stimulated high HO-1 expression in MM cells and their resistance to lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, and exacerbated drug resistance and disease. This study supports the use of HO-1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.
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