miR-125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5.

miR-125a is a microRNA that is frequently diminished in various human malignancies. However, the mechanism by which impaired miR-125a promotes cancer growth remains undefined. In this study, we investigated the role of miR-125a in the proliferation and apoptosis of multiple myeloma (MM). To do this, we used MM tissue samples (from 40 anonymous patients), normal matched control samples, and five MM-derived cell lines. We also established a mouse model of MM xenograft to explore the effect of overexpression of miR-125a on the MM growth in vivo. Quantitative real-time polymerase chain reaction revealed that the miR-125a expression was broadly reduced in MM tissues and cell lines. The impairment of miR-125a in MM tissues was functionally relevant because the overexpression of miR-125a remarkably decreased the cell viability and colony-forming activity, at least in part, by promoting apoptosis in two miR-125a-deficient MM cell lines: NCI-H929 and U266. Interestingly, we also discovered that the human gene encoding the ubiquitin-specific peptidase 5 (USP5), which is known to promote cellular deubiquitination and ubiquitin/proteasome-dependent proteolysis, was a direct transcriptional target for miR-125a to repress. More importantly, the heterologous expression of USP5 significantly reversed the growth-inhibitory effects of miR-125a on MM cells in vitro. In the mouse xenograft model, overexpressed miR-125a prominently inhibited the growth of MM tumors and concomitantly reduced the expression of USP5 in tumor tissues. These results suggest that miR-125a inhibits the expression of USP5, thereby mitigating the proliferation and survival of malignant MM cells. We propose that USP5 acts as an oncoprotein in miR-125a-missing cancers.

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