IL-6-induced activation of MYC is responsible for the down-regulation of CD33 expression in CD33(+) myeloma cells |
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Authors: | Karim Shamsasenjan Ken-ichiro Otsuyama Saeid Abroun Mohd S. Iqbal Maged S. Mahmoud Hideki Asaoku Michio M. Kawano |
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Affiliation: | (1) Laboratory of Cellular Signal Analysis, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube 755-8505, Japan;(2) Department of Clinical Pathology, Assiut University Hospital, Assiut, Egypt;(3) Hiroshima Red Cross Hospital, Hiroshima 730-0052, Japan |
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Abstract: | Human myeloma cells from about 10% of cases with multiple myeloma expressed CD33 and had monocytoid morphology with convoluted nuclei, and all these patients had no increase in serum CRP values. In CD33(+) myeloma cells as well as myeloma cell lines, CD33 expression levels were correlated with the increased expression levels of CEBPA (C/EBPα). This correlation was confirmed by the finding that transfection with the CEBPA gene induced CD33 expression in a CD33(−) myeloma cell line. As suggested by the lack of an increase in serum CRP values in CD33(+) myelomas, IL-6 down-regulated the expression of CD33 in CD33(+) myeloma cell lines along with the down-regulation of CEBPA gene expression. Cucurbitacin I (STAT3 inhibitor), but not U0126 (MAPK inhibitor), could abolish the effect of IL-6. Furthermore, IL-6 up-regulated the expression of MYC via STAT3 phosphorylation and MYC bound to the promoter region of the CEBPA gene followed by the down-regulation of CEBPA expression. It was confirmed that introduction of shRNA for MYC into a CD33(+) myeloma cell line blocked the IL-6-induced down-regulation of CD33 and CEBPA expression. Therefore, these results indicate that IL-6 can reverse the expression level of CD33 by up-regulating MYC followed by the down-regulation of CEBPA expression. |
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Keywords: | Multiple myeloma CD33 IL-6 C/EBPα c-MYC |
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