LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Blood. 2012 Nov 8;120(19):3958-67. doi: 10.1182/blood-2012-01-401794. Epub 2012 Sep 14.
miRs play a critical role in tumor pathogenesis as either oncogenes or tumor-suppressor genes. However, the role of miRs and their regulation in response to proteasome inhibitors in multiple myeloma (MM) is unclear. In the current study, miR profiling in proteasome inhibitor MLN2238-treated MM.1S MM cells shows up-regulation of miR33b. Mechanistic studies indicate that the induction of miR33b is predominantly via transcriptional regulation. Examination of miR33b in patient MM cells showed a constitutively low expression. Overexpression of miR33b decreased MM cell viability, migration, colony formation, and increased apoptosis and sensitivity of MM cells to MLN2238 treatment. In addition, overexpression of miR33b or MLN2238 exposure negatively regulated oncogene PIM-1 and blocked PIM-1 wild-type, but not PIM-1 mutant, luciferase activity. Moreover, PIM-1 overexpression led to significant abrogation of miR33b- or MLN2238-induced cell death. SGI-1776, a biochemical inhibitor of PIM-1, triggered apoptosis in MM. Finally, overexpression of miR33b inhibited tumor growth and prolonged survival in both subcutaneous and disseminated human MM xenograft models. Our results show that miR33b is a tumor suppressor that plays a role during MLN2238-induced apoptotic signaling in MM cells, and these data provide the basis for novel therapeutic strategies targeting miR33b in MM.
miRs 在肿瘤发病机制中发挥着关键作用，它们可以作为癌基因或肿瘤抑制基因。然而，miRs 的作用及其在多发性骨髓瘤 (MM) 中对蛋白酶体抑制剂的反应的调节尚不清楚。在本研究中，我们对蛋白酶体抑制剂 MLN2238 处理的 MM.1S MM 细胞中的 miR 谱进行了分析，结果显示 miR33b 上调。机制研究表明，miR33b 的诱导主要是通过转录调控。对患者 MM 细胞中 miR33b 的检测显示其表达持续下调。miR33b 的过表达降低了 MM 细胞的活力、迁移、集落形成，并增加了 MM 细胞的凋亡和对 MLN2238 治疗的敏感性。此外，miR33b 的过表达或 MLN2238 的暴露负调控癌基因 PIM-1，并阻断 PIM-1 野生型，但不阻断 PIM-1 突变型的荧光素酶活性。此外，PIM-1 的过表达导致 miR33b 或 MLN2238 诱导的细胞死亡明显被阻断。PIM-1 的生化抑制剂 SGI-1776 可引发 MM 细胞凋亡。最后，miR33b 的过表达抑制了皮下和播散性人 MM 异种移植模型中的肿瘤生长并延长了生存期。我们的结果表明，miR33b 是一种肿瘤抑制因子，在 MM 细胞中 MLN2238 诱导的凋亡信号中发挥作用，这些数据为针对 MM 中 miR33b 的新型治疗策略提供了依据。
