期刊
JOURNAL OF PROTEOME RESEARCH
卷 11, 期 4, 页码 2078-2090出版社
AMER CHEMICAL SOC
DOI: 10.1021/pr201079y
关键词
microRNA-21 (miR-21); multiple myeloma (MM); stable isotope labeling by amino acids in cell culture (SILAC); signal transducer and activator of transcription 3 (STAT3); protein inhibitor of activated STAT3 (PIAS3)
资金
- National Basic Research Program of China (973 Program) [2012CB518700]
- Chinese Academy of Sciences
- National Laboratory of Biomacromolecules
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.
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