Reduction of Dicer1 By Multiple Myeloma Cells in Mesenchymal Stem Cells Promotes Cellular Senescence and Tumor-Supporting Effect and Decreases the Differentiation

Bone marrow mesenchymal stem cells (BM-MSCs) facilitate multiple myeloma (MM) cell growth, but the underlying mechanisms by which the MM-MSCs plays an oncogenic role in this disease remain ambiguous. In our investigation, it was demonstrated that the senescence of MM-MSCs significantly increased, as evinced by the decrease in proliferation, and the increase of SA-β-gal. Senescent MM-MSCs had decreased potential of differentiation and increased tumor-supporting capacity. Knockdown of Dicer1 expression in MSCs from healthy controls promoted cellular senescence and tumor-supporting capacity. Otherwise, the differentiation was significantly restrained by Dicer1 knockdown. Dicer1 overexpression in MM-MSCs reversed the differentiation properties and reduced cellular senescence. In addition, the decreased expression of the microRNA-17 family was identified as a potential factor responsible for increased senescence, with the expression of p21 increased in Dicer1 knockdown cells. Furthermore, we found decreased expression of miR-93 and miR-20a in MM-MSCs and overexpression of miR-93/miR-20a decreased cellular senescence with the increased p21 expression. Importantly, we found that myeloma cells could induce the senescence of HC-MSC, with the expression of Dicer1 and miR-93/miR-20a decreased and p21 increased. Taken together, our results demonstrate a positive feedback loop between MSCs and MM cells: MM cells promote the reduction of miR-93/miR-20a in MSCs which leads to senescence, and the senescent MSCs in turn favors MM cell growth, which most likely participates in disease progression.