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

Abstract

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.

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

“…miR-125a targets ubiquitin-specific peptidase 5 (USP5) mRNA, an oncoprotein that enhances cellular deubiquitination and proteolysis. Highly expressed miR-125a significantly repressed tumor growth of MM and lowered USP5 expression in vivo [ 154 ]. miR-101-3p was down-regulated and survivin (BIRC5) was up-regulated in MM cells.…”

Long non‐coding RNA NEAT1 serves as a novel biomarker for treatment response and survival profiles via microRNA‐125a in multiple myeloma

“…Another one indicates that lncRNA NEAT1 promotes M2 macrophage polarization, hence accelerating MM progression 13 . In addition, based on miRanda database analysis and previous studies, one of lncRNA NEAT1 target microRNAs is microRNA‐125a (miRNA‐125a), and miRNA‐125a is shown to suppress MM progression 14‐16 . According to these evidences and the result of our preliminary study with small sample size, which indicated that lncRNA NEAT1 was upregulated in MM patients compared with healthy controls, the hypothesis was raised that lncRNA NEAT1 was involved in MM development and prognosis via interaction with miR‐125a; however, the related research is limited.…”

Identification of MicroRNAs With In Vivo Efficacy in Multiple Myeloma-related Xenograft Models

“…miR-125a ( Figure 2) expression is low in MM cell lines and tissues in comparison to matching control cells and tissues (74). Overexpression of miR-125a in NCI-H929 and U266 MM cells decreases cell viability and colonyforming ability by promotion of apoptosis (74). Overexpression of miR-125a in a mouse xenograft model inhibits TG (74).…”

“…Overexpression of miR-125a in NCI-H929 and U266 MM cells decreases cell viability and colonyforming ability by promotion of apoptosis (74). Overexpression of miR-125a in a mouse xenograft model inhibits TG (74). Ubiquitin-specific peptidase 5 (USP5) was identified as a direct target of miR-125a (74).…”

“…Overexpression of miR-125a in a mouse xenograft model inhibits TG (74). Ubiquitin-specific peptidase 5 (USP5) was identified as a direct target of miR-125a (74). USP5 cleaves linear and branched ubiquitin polymers and therefore inhibits CANCER GENOMICS & PROTEOMICS 17: 321-334 (2020) the proteosomal pathway in MM cells (75,76).…”