LncRNA PRAL is closely related to clinical prognosis of multiple myeloma and the bortezomib sensitivity

Abstract

Chromosome 17p deletions (del(17p)) are present in about 11% of newly diagnosed multiple myeloma (MM) patients and related to inferior prognosis. Bortezomib (BTZ), the first proteasome inhibitor anticancer drug, has a good therapeutic effect for newly diagnosed, relapsed or refractory MM, but is unable to improve the outcome of MM patients with del(17p). Long noncoding RNA (lncRNA) PRAL is located on chromosome 17p, and is associated with the progression and prognosis of different types of cancers. However, little is known about its role in MM. Here, we found that PRAL was downregulated in primary MM cells and cell lines, especially in MM cells with del(17p), and was associated with ISS (international staging system) stage and Durie-Salmon stage in MM patients. Survival curves showed that MM patients with low PRAL expression had a significantly shorter disease-free survival (DFS) and overall survival (OS) than the patients with high PRAL expression. Multivariate Cox regression analysis showed that PRAL expression was an independent predictor for DFS and OS. Then cell proliferation, viability, Ki67 expression, and caspase-3 activity detection showed that PRAL promoted MM cell growth inhibition and apoptosis, and potentiated the anti-MM effect of BTZ in vitro. We further identified and confirmed that miR-210 was the target of PRAL, and miR-210 overexpression overturned the potentiation effect of PRAL on BTZ efficacy. Subsequently, bone morphogenetic protein 2 (BMP2) was confirmed to be the target of miR-210, and PRAL positively regulated the derepression of BMP2 by sponging miR-210. Overexpression of BMP2 potentiated the anti-MM effect of BTZ in vitro. In addition, animal experiments further confirmed that PRAL potentiated BTZ efficacy in vivo. Collectively, our study first revealed a critical role of PRAL-miR-210-BMP2 axis in MM progression, prognosis and treatment with BTZ, and PRAL could become a novel diagnostic, prognostic and therapeutic candidate for MM patients especially for the MM patients harboring del(17p) in the future.

Keywords: BMP2; Bortezomib; Chromosome 17p deletions; Long noncoding RNA PRAL; Multiple myeloma; miR-210.