Abstract
Clinical outcomes of patients with multiple myeloma (MM) have almost doubled the overall survival over the last decade owing to the use of proteasome inhibitor such as bortezomib (BTZ). However, some patients with MM develop primary resistance to BTZ, whereas others develop resistance after treatment. In this study, we investigated relationships between BTZ resistance and dysfunction of long non-coding RNAs (lncRNAs) in patients with MM. Bone marrow samples were collected from patients with MM and healthy donors for lncRNA microarray and survival analyses. To investigate functions and underlying mechanisms of lncRNA-mediated BTZ resistance in MM, we performed CCK-8 assays, flow cytometry analyses, dual luciferase report gene assays, and RNA pulldown assays with samples from nude mice carrying tumor xenografts and in clinical samples. Differentially expressed lncRNA myocardial infarction associated transcripts (MIAT) were highly expressed in patients with MM compared with healthy controls, and were predictive of poor survival outcomes. Moreover, MIAT expression was significantly increased in BTZ-resistant patients with MM compared with newly diagnosed patients with MM, and was identified as a BTZ-inducible lncRNA. Specifically, BTZ upregulated MIAT expression through increased stat1 phosphorylation. Silencing of MIAT inhibited MM cell growth and sensitized MM cells to BTZ by negatively regulating miR-29b. Our data demonstrated the utility of MIAT as a tool for overcoming BTZ resistance in patients with MM.