Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells
© Hao et al; licensee BioMed Central Ltd. 2011
Received: 24 August 2011
Accepted: 22 September 2011
Published: 22 September 2011
The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of myeloma (MM) cells. This study identified that microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC) with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells. Interleukin-6 (IL-6) produced by BMSCs suppressed the expression of miRNA-15a and 16 in a time- and dose- dependent pattern, with the suppression on miRNA-15a being more significant than on miRNA-16. miRNA-15a-transfected MM cells were found to be arrested in G1/S checkpoint, and the transfected MM cells had decreased growth and survival. In conclusion, our data suggest that via suppressing miRNA-15a and -16 expressions, IL-6 secreted by BMSCs promotes drug-resistance in myeloma cells.
To the Editor
microRNA -15a and -16 are located on chromosome 13, an area commonly deleted in MM. Deletion of chromosome 13 predicts a significantly reduced survival in patient with MM [9–11]. We thus focused on the functions of miRNA-15a and -16. We found that miRNA-15a/-16 expression in MM cells was significantly increased under melphalan and bortezomib treatment (Figure 1B). Moreover, dexamethasone sensitive MM cell line, MM1S, expressed higher level of miRNA-15a than the resistant MM1R. miRNA-15a expression in MMIS and MM1R was 909.73 ± 7.12 and 134.88 ± 19.85 (p < 0.01), respectively, and miRNA-16 expression in those cells was 9.83 ± 2.01 and 9.20 ± 3.81 (p > 0.05), respectively. Interestingly, the interaction of MM cells with MM-BMSCs inhibited miRNA-15a and -16 expressions in MM cells. (Figure 1B) IL-6 secreted by MM-BMSCs decreased expression of miRNA-15a and -16 in myeloma cells in a time- and dose- dependent pattern. (Figure 1C,D) The suppression on miRNA-15a was more significant than on miRNA-16 in myeloma cells. Previous study has identified cyclinD1, cyclinD2 and CDC25A as the targets of miRNA-15a . Our data further showed that miRNA-15a-transfected MM cells were arrested in G1/S checkpoint. The over-expression of miRNA-15a inhibited growth and survival of the transfected MM cells.
In conclusion, this study identified that microRNA-15a and -16 expressions correlated well with proliferation and drug sensitivity of MM cells. MM-BMSCs enhanced the survival of the MM cells and protected them from drug-induced apoptosis by suppressing miRNA-15a/-16 expression. IL-6 secreted by the MM-BMSCs plays a pivotal role in this process.
Conflicts of Interests
The authors declare that they have no competing interests.
List of Abbreviation
bone marrow stromal cells
Vascular-Endothelial Growth Factor
enzyme-linked immunosorbent assay
This work was supported in part by grants from the National Natural Science Foundation of China (30871095 & 81172255). Tianjin Science and Technology Supporting Programme (09ZCGYSF01000) and Foundation for Youth Researcher of CAMS & PUMC.
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