Abstract
MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
Highlights
Since a single miRNA is able to bind to and regulate approximately up to 100 different transcripts,[3,4]
We evaluated by high-density microarrays miRNA profiling the expression of miR-29b in primary CD138 þ cells from intramedullary MM (n 1⁄4 38) or plasma cells (PCs) leukemia (PCL; n 1⁄4 2) patients
We investigated the role of miR-29b on Sp1 mRNA regulation by transfecting into MM cells a luciferase reporter vector that contains the 30UTR region of Sp1 predicted to interact with miR-29b
Summary
Since a single miRNA is able to bind to and regulate approximately up to 100 different transcripts,[3,4]. MiRNAs truly represent master regulators of gene expression and influence virtually all cell activities and events, including cell proliferation, cell death, differentiation, metabolism, infection and cancer.[5] Deregulation of miRNA expression commonly occurs in human cancer and is involved in cancer initiation and progression;[6,7] miRNA expression profiles have prognostic implications,[8] while targeting the miRNA network exerts anti-tumor effects in vivo,[9] indicating a great therapeutic potential of miRNAs for cancer treatment.[10] Noteworthy, miRNAs that are deleted or downregulated in malignancies generally play a tumor-suppressor function, whereas those that are upregulated act as transforming oncogenes.[11,12]. 3-kinase; PTEN, phosphatase and tensin homolog; REL, relative expression level; Rb, retinoblastoma protein; SC, subcutaneous; SD, standard deviation; Sp1, specificity protein 1; UTR, untranslated region
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