Hematology of Shanghai Xuhui Centre Hospital, Shanghai Clinical Centre of Chinese Acadymy of Sciences, CAS, Shanghai 200031, PR China.
Hematology of Shanghai Xuhui Centre Hospital, Shanghai Clinical Centre of Chinese Acadymy of Sciences, CAS, Shanghai 200031, PR China.
Exp Cell Res. 2018 Sep 15;370(2):254-263. doi: 10.1016/j.yexcr.2018.06.026. Epub 2018 Jun 23.
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.
17 号染色体缺失（del(17p)）在约 11%的新诊断多发性骨髓瘤（MM）患者中存在，与预后不良有关。硼替佐米（BTZ），第一个蛋白酶体抑制剂抗癌药物，对新诊断、复发或难治性 MM 具有良好的治疗效果，但不能改善 del(17p)的 MM 患者的结局。长链非编码 RNA（lncRNA）PRAL 位于 17 号染色体上，与不同类型癌症的进展和预后有关。然而，其在 MM 中的作用知之甚少。在这里，我们发现 PRAL 在原发性 MM 细胞和细胞系中下调，特别是在具有 del(17p)的 MM 细胞中下调，与 MM 患者的国际分期系统（ISS）分期和 Durie-Salmon 分期相关。生存曲线表明，PRAL 低表达的 MM 患者无病生存（DFS）和总生存（OS）明显短于 PRAL 高表达的患者。多变量 Cox 回归分析表明，PRAL 表达是 DFS 和 OS 的独立预测因子。然后，通过细胞增殖、活力、Ki67 表达和 caspase-3 活性检测发现，PRAL 促进 MM 细胞生长抑制和凋亡，并增强 BTZ 的体外抗 MM 作用。我们进一步鉴定并证实 miR-210 是 PRAL 的靶标，而 miR-210 的过表达推翻了 PRAL 对 BTZ 疗效的增强作用。随后，骨形态发生蛋白 2（BMP2）被确认为 miR-210 的靶标，PRAL 通过海绵 miR-210 正向调节 BMP2 的去抑制。BMP2 的过表达增强了 BTZ 在体外的抗 MM 作用。此外，动物实验进一步证实 PRAL 在体内增强了 BTZ 的疗效。总之，我们的研究首次揭示了 PRAL-miR-210-BMP2 轴在 MM 进展、预后和 BTZ 治疗中的关键作用，PRAL 可能成为 MM 患者的一种新的诊断、预后和治疗候选物，特别是对于携带 del(17p)的 MM 患者。
