Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom’s macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3′UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.
失调的microRNA（miR）/转录因子（TF）调控网络是癌症的重要标志。本文报道了一个新型c-Myc/miR-23b/Sp1前馈环路，该环路在多发性骨髓瘤（MM）和华氏巨球蛋白血症（WM）细胞生长与存活中起关键作用。我们发现miR-23b在MM和WM细胞中表达下调，尤其在肿瘤骨髓微环境成分存在时更为明显。启动子甲基化是骨髓瘤中miR-23b受抑制的机制之一。通过功能获得性研究（使用miR-23b模拟物转染或稳定表达miR-23b的MM/WM细胞系），我们观察到细胞增殖和存活显著降低，同时随时间推移caspase-3/7活性被诱导，这支持了miR-23b的肿瘤抑制功能。在分子水平上，miR-23b靶向Sp1的3'UTR区域，并显著降低Sp1驱动的核因子κB活性。最后，已知能刺激MM细胞增殖的重要致癌转录因子c-Myc，在转录水平上抑制了miR-23b表达。因此，骨髓瘤细胞中MYC依赖的miR-23b抑制可能促进致癌性Sp1介导的信号通路激活，这代表了首个在骨髓瘤中具有关键生长和生存作用的前馈环路。
miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth
肿瘤(癌症)患者之家