Abstract
USP15 has been shown to stabilize transcription factors, to be amplified in many cancers and to mediate cancer cell survival. However, the underlying mechanism by which USP15 regulates multiple myeloma (MM) cell proliferation and apoptosis has not been established. Here, our results showed that USP15 mRNA expression was upregulated in MM patients. USP15 silencing induced MM cell proliferation inhibition, apoptosis, and the expression of nuclear and cytoplasmic NF-κBp65, while USP15 overexpression exhibited an inverse effect. Moreover, in vivo experiments indicated that USP15 silencing inhibited MM tumor growth and NF-κBp65 expression. PDTC treatment significantly inhibited USP15 overexpression-induced cell proliferation, apoptosis inhibition, and NF-κBp65 expression. USP15 overexpression promoted NF-κBp65 expression through inhibition of its ubiquitination, whereas NF-κBp65 promoted USP15 expression as a positive regulator. Taken together, the USP15-NF-κBp65 loop is involved in MM tumorigenesis and may be a potential therapeutic target for MM.
Highlights
Multiple myeloma (MM) is a malignant blood system disease derived from B cells
We found that USP15 expression was higher in MM cell lines compared with control cells, with the highest expression detected in RPMI 8226 and U266 cells compared with other MM cell lines (Fig. 1b, c)
These results suggest that USP15 may participant in the development and progression of MM
Summary
Multiple myeloma (MM) is a malignant blood system disease derived from B cells. It is characterized by clonal expansion of plasma cells in the bone marrow, which secretes a large number of monoclonal immunoglobulins, together with a series of dissolved bone lesions, clinical symptoms, and organ dysfunction, such as bone disease, pathological fractures, renal failure, and anemia[1,2]. Since the pathogenesis of MM is complex, the number and structural abnormalities of chromosomes, activation of oncogenes, inactivation of tumor suppressors, IL-6-dependent cytokine network disorders, and changes in bone marrow microenvironment are all related to the occurrence of myeloma[4,5]. With the application of proteasome inhibitors and immunomodulators, the therapeutic efforts in MM patients have improved[6].
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