Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in 
carcinogenesis and is significantly elevated in multiple myeloma (MM). In this 
study, we explored the role of miR-21 in human MM cells and searched for miR-21 
targets. By knocking down the expression of endogenous miR-21 in U266 myeloma 
cells, we observed reduced growth, an arrested cell cycle, and increased 
apoptosis. To further understand its molecular mechanism in the pathogenesis of 
MM, we employed a SILAC (stable isotope labeling by amino acids in cell 
culture)-based quantitative proteomic strategy to systematically identify 
potential targets of miR-21. In total, we found that the expression of 178 
proteins was up-regulated significantly by miR-21 inhibition, implying that they 
could be potential targets of miR-21. Among these, the protein inhibitor of 
activated STAT3 (PIAS3) was confirmed as a direct miR-21 target by Western 
blotting and reporter gene assays. We further demonstrated that miR-21 enhances 
the STAT3-dependent signal pathway by inhibiting the function of PIAS3 and that 
down-regulation of PIAS3 contributes to the oncogenic function of miR-21. This 
elucidation of the role of PIAS3 in the miR-21-STAT3 positive regulatory loop 
not only may shed light on the molecular basis of the biological effects of 
miR-21 observed in MM cells but also has direct implications for the development 
of novel anti-MM therapeutic strategies.